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The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review

  • K. Sun
    Affiliations
    Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
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  • J. Luo
    Affiliations
    The Center for Biomedical Research, The Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China
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  • J. Guo
    Affiliations
    Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
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  • X. Yao
    Affiliations
    Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
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  • X. Jing
    Affiliations
    Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
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  • F. Guo
    Correspondence
    Address correspondence and reprint requests to: Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
    Affiliations
    Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
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Open ArchivePublished:February 18, 2020DOI:https://doi.org/10.1016/j.joca.2020.02.027

      Summary

      Osteoarthritis (OA) is a complicated degenerative disease that affects whole joint tissue. Currently, apart from surgical approaches to treat late stage OA, effective treatments to reverse OA are not available. Thus, the mechanisms leading to OA, and more effective approaches to treat OA should be investigated. According to available evidence, the PI3K/AKT/mTOR signaling pathway is essential for normal metabolism of joint tissues, but is also involved in development of OA. To provide a wide viewpoint to roles of PI3K/AKT/mTOR signaling pathway in osteoarthritis, a comprehensive literature search was performed using PubMed terms ‘PI3K OR AKT OR mTOR’ and ‘osteoarthritis’. This review highlights the role of PI3K/AKT/mTOR signaling in cartilage degradation, subchondral bone dysfunction, and synovial inflammation, and discusses how this signaling pathway affects development of the disease. We also summarize recent evidences of therapeutic approaches to treat OA by targeting the PI3K/AKT/mTOR pathway, and discuss potential challenges in developing these strategies for clinical treatment of OA.

      Keywords

      Abbreviations:

      OA (Osteoarthritis), NSAIDs (nonsteroidal anti-inflammatory drugs), ECM (extracellular matrix), RTK (receptor tyrosine kinases), GPCRs (G protein-coupled receptors), PIP2 (phosphatidylinositol-4,5-bisphosphate), PIP3 (phosphatidylinositol-3,4,5-trisphosphate), PTEN (phosphatase and tensin homologue), PDK1 (phosphoinositide-dependent kinase-1), mTORC2 (mammalian target of rapamycin complex 2), TSC2 (tuberous sclerosis complex 2), S6K-1 (S6 kinase-1), 4EBP-1 (eukaryotic translation initiation factor 4E binding protein-1), ULK1 (unc-51-like kinase 1), MMPs (matrix metalloproteinases), ADAMTSs (a disintegrin and metalloprotease with thrombospondin motifs), IL-1β (interleukin -1β), LPS (lipopolysaccharide), TNF-α (tumor necrosis factor α), tBHP (tert-butyl hydroperoxide), MRI (magnetic resonance imaging), RA (rheumatoid arthritis), iNOS (inducible nitric oxide synthase), COX-2 (cyclooxygenase-2), ERK (extracellular regulated kinase), FLS (fibroblast-like synoviocytes), PTGS2 (prostaglandin-endoperoxide synthase 2), BCP (basic calcium phosphate), PRDX4 (peroxiredoxin 4), AKT (protein kinase B), PH (pleckstrin homology), PKA (protein kinase A), PPARγ (peroxisome proliferator-activated receptor gamma), BAX (BCL-2-associated X apoptosis regulator)

      Introduction

      Osteoarthritis (OA), a common degenerative disease affecting more than 240 million people, is a primary cause of disability
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      Osteoarthritis year in review 2017: clinical.
      . It is characterized by destructive alteration of articular cartilage, synovial tissue, and subchondral bone which are responsible for pain, joint dysfunction, and loss of tissue integrity
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      . To date, non-surgical treatments for OA, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and physical therapy have not reversed the course of the disease
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      Osteoarthritis year in review 2017: clinical.
      . Therefore, more specific therapeutic approaches need to be researched and developed. Current evidence demonstrates that OA causes progressive degeneration and dysfunction of whole joints, accompanied by chondrocyte loss, inflammatory responses, and imbalance in extracellular matrix (ECM) homeostasis
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      . Complex signaling networks have been suggested to mediate these cell fate events. In particular, the PI3K/AKT/mTOR signaling pathway is essential for maintaining joint health, and is correlated with OA pathogenesis
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      Synergistic collagenase expression and cartilage collagenolysis are phosphatidylinositol 3-kinase/Akt signaling-dependent.
      . Based on these reports, we focused on the PI3K/AKT/mTOR signaling pathway and its multiple functions in cartilage, synovial tissue, and subchondral bone, and its interactions with other signaling pathways. We also present an overview of therapeutic approaches for targeting PI3K/AKT/mTOR to comprehensively understand the role of this signaling pathway in the pathological progression of OA.

      The PI3K/AKT/mTOR signaling pathway

      Various molecules, including insulin, glucose, and many growth factors and cytokines can initiate PI3K/AKT/mTOR signaling
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      . Activated PI3K converts phosphatidylinositol-4,5-bisphosphate (PIP2) into phosphatidylinositol-3,4,5-trisphosphate (PIP3), and further activates downstream effectors such as AKT
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      The PI3K/AKT pathway and renal cell carcinoma.
      . In the process, phosphatase and tensin homologue (PTEN), a negative regulator of PI3K, acts to limit signal strength by reversing PIP3 to PIP2
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      The functions and regulation of the PTEN tumour suppressor: new modes and prospects.
      .
      Protein kinase B (AKT) is a vital messenger in PI3K signaling. In the canonical PI3K/AKT pathway, phosphoinositide-dependent kinase-1 (PDK1) and AKT are recruited to the inner surface of the cell membrane via pleckstrin homology (PH) domains, where PDK1 initiates AKT1 phosphorylation at Thr308
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      Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha.
      . Another vital AKT activating pathway is mediated by the mTORC2, which interacts with the regulatory hydrophobic domain of AKT to phosphorylate it at Ser473
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      A complex interplay between Akt, TSC2 and the two mTOR complexes.
      . Activated AKT transfers into other cell compartments to activate various downstream substrates such as protein kinases, E3 ubiquitin ligases, regulators of small G proteins, metabolic enzymes, transcription factors, and cell cycle regulators
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      • Toker A.
      AKT/PKB signaling: navigating the network.
      . A critical downstream branch of AKT is mTORC1. Phosphorylated AKT can phosphorylate mTOR at Ser 2448 to directly activate mTORC1, and phosphorylate tuberous sclerosis complex 2 (TSC2) to indirectly activate mTORC1
      • Manning B.D.
      • Toker A.
      AKT/PKB signaling: navigating the network.
      . Specifically, tuberous sclerosis complex (TSC) contains two subunits: TSC1 and TSC2. TSC2 is a negative regulator of mTOR. inactivation of TSC2 by AKT can inhibit the function of the TSC1/TSC2 complex, resulting in mTORC1 activation When the complex is activated, the downstream Rheb-GTP is converted to Rheb-GDP, which stabilizes mTORC1
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      Regulation of mTORC1 by PI3K signaling.
      . Altered activity of mTORC1 subsequently affects its effectors including S6 kinase-1 (S6K-1), eukaryotic translation initiation factor 4E binding protein-1 (4EBP-1), and unc-51-like kinase 1 (ULK1)
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      The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14.
      ,
      • Laplante M.
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      mTOR signaling in growth control and disease.
      . S6K-1 and 4EBP-1 serve as regulators of cell cycle progression or angiogenesis by enhancing translation of mRNAs encoding HIF-1α, cyclin D1, and c-Myc
      • Laplante M.
      • Sabatini D.M.
      mTOR signaling in growth control and disease.
      . Moreover, mTORC1 is a master regulator of ULK1, which correlates with initiation of autophagy. Treatment with rapamycin, an inhibitor of mTORC1, improves ULK1 kinase activity
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      • et al.
      The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14.
      . On the other hand, Rheb-mediated active mTORC1 potently represses ULK1
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      • et al.
      TFEB-driven endocytosis coordinates MTORC1 signaling and autophagy.
      . ULK1 functions in a complex with ATG13 and FIP200, which serves as a node that translates autophagic signals into autophagosome biogenesis
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      ULK1·ATG13·FIP200 complex mediates mTOR signaling and is essential for autophagy.
      (Fig. 1).
      Fig. 1
      Fig. 1Simplified scheme of PI3K/AKT/mTOR signaling pathway in chondrocyte.
      PI3K/AKT/mTOR is an important and quite complex signaling pathway in which over 150 proteins have been identified to involve in this pathway
      • Jafari M.
      • Ghadami E.
      • Dadkhah T.
      • Akhavan-Niaki H.
      PI3k/AKT signaling pathway: erythropoiesis and beyond.
      . Through these effectors, PI3K/AKT/mTOR fulfills functions in many cellular processes essential for homeostasis, including the cell cycle, cell survival, inflammation, metabolism, and apoptosis
      • Tang F.
      • Wang Y.
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      • Rüegg C.
      • Xue G.
      PKB/Akt-dependent regulation of inflammation in cancer.
      ,
      • Cravero J.D.
      • Carlson C.S.
      • Im H.J.
      • Yammani R.R.
      • Long D.
      • Loeser R.F.
      Increased expression of the Akt/PKB inhibitor TRB3 in osteoarthritic chondrocytes inhibits insulin-like growth factor 1-mediated cell survival and proteoglycan synthesis.
      . Misregulation of these pathways is related to initiation and progression of diseases-such as cancer, diabetes, and cardiovascular diseases
      • Laplante M.
      • Sabatini D.M.
      mTOR signaling in growth control and disease.
      ,
      • Lin Z.
      • Zhou P.
      • von Gise A.
      • Gu F.
      • Ma Q.
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      • et al.
      Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival.
      ,
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      • Marette A.
      Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice.
      . Moreover, increased evidence supports the involvement of PI3K/AKT/mTOR in OA development
      • Fisch K.M.
      • Gamini R.
      • Alvarez-Garcia O.
      • Akagi R.
      • Saito M.
      • Muramatsu Y.
      • et al.
      Identification of transcription factors responsible for dysregulated networks in human osteoarthritis cartilage by global gene expression analysis.
      . We here review the literature describing the close relationship between the PI3K/AKT/mTOR axis and OA pathophysiology.

      The PI3K/AKT/mTOR pathway in the pathogenesis of OA

      OA is a complex disease with multiple underlying molecular mechanisms, that affects whole-joints with cartilage degeneration, synovial inflammation, and subchondral bone sclerosis (Fig. 2). We will focus on the role of the PI3K/AKT/mTOR pathway in these three aspects.
      Fig. 2
      Fig. 2Phenotypes of osteoarthritis. OA is a whole-joint disease, charactercised by cartilage degeneration, synovial inflammation, subchondral bone sclerosis and osteophyte formation. The PI3K/AKT/mTOR signaling pathway is responsible for the destructive alteration of these tissues. The depicts shows how PI3K/AKT/mTOR signaling pathway regulates synovial inflammation, subchondral bone sclerosis, ECM homeostasis, chondrocyte proliferation, apoptosis, autophagy and inflammation. An imbalance in these cell processes contributes to OA progression.

      Cartilage

      Cartilage homeostasis

      Cartilage homeostasis, defined as the state in which synthesis of ECM is balanced by its degradation, is vital to articular health. The destruction of cartilage homeostasis, marked by elevated production of matrix metalloproteinases (MMPs), and a disintegrin and metalloprotease with thrombospondin motifs (ADAMTSs) and reduced collagen II and aggrecan, is the initiator and booster of OA pathogenesis
      • Mobasheri A.
      • Rayman M.P.
      • Gualillo O.
      • Sellam J.
      • van der Kraan P.
      • Fearon U.
      The role of metabolism in the pathogenesis of osteoarthritis.
      . The PI3K/AKT/mTOR pathway are required for cartilage homeostasis
      • Rosa S.C.
      • Rufino A.T.
      • Judas F.
      • Tenreiro C.
      • Lopes M.C.
      • Mendes A.F.
      Expression and function of the insulin receptor in normal and osteoarthritic human chondrocytes: modulation of anabolic gene expression, glucose transport and GLUT-1 content by insulin.
      . Previous analysis has revealed that the PI3K-AKT pathway is downregulated in human cartilage tissues with OA, compared to normal cartilage
      • Rosa S.C.
      • Rufino A.T.
      • Judas F.
      • Tenreiro C.
      • Lopes M.C.
      • Mendes A.F.
      Expression and function of the insulin receptor in normal and osteoarthritic human chondrocytes: modulation of anabolic gene expression, glucose transport and GLUT-1 content by insulin.
      . Similar decreased PI3K-AKT pathway activity has been found in OA-like chondrocytes exposed to interleukin -1β (IL-1β), tumor necrosis factor α (TNF-α), and tert-butyl hydroperoxide (tBHP, an organic hydrogen peroxide far more stable than H2O2)
      • Stanic I.
      • Facchini A.
      • Borzi R.M.
      • Vitellozzi R.
      • Stefanelli C.
      • Goldring M.B.
      • et al.
      Polyamine depletion inhibits apoptosis following blocking of survival pathways in human chondrocytes stimulated by tumor necrosis factor-alpha.
      • Yao X.
      • Zhang J.
      • Jing X.
      • Ye Y.
      • Guo J.
      • Sun K.
      • et al.
      Fibroblast growth factor 18 exerts anti-osteoarthritic effects through PI3K-AKT signaling and mitochondrial fusion and fission.
      • Iwasa K.
      • Hayashi S.
      • Fujishiro T.
      • Kanzaki N.
      • Hashimoto S.
      • Sakata S.
      • et al.
      PTEN regulates matrix synthesis in adult human chondrocytes under oxidative stress.
      . IGF-1, a strong activator of AKT phosphorylation, can activate AKT to promote synthesis of collagen II
      • Greene M.A.
      • Loeser R.F.
      Function of the chondrocyte PI-3 kinase-Akt signaling pathway is stimulus dependent.
      . Additionally, IGF-1 has an inhibitory effect on IL-1β-induced NF-κB activation in human chondrocytes, which is closely involved in cartilage degradation. The inhibitory effect could be abolished by treatment with inhibitors of PI3K (wortmannin) or AKT (SH-5)
      • Greene M.A.
      • Loeser R.F.
      Function of the chondrocyte PI-3 kinase-Akt signaling pathway is stimulus dependent.
      . Oxidative stress is associated with osteoarthritic cartilage, causing reduced matrix synthesis, while overexpression of AKT dramatically enhanced proteoglycan synthesis in human chondrocytes under the stimulation of tBHP. Not only that, the knockdown of PTEN promoted the expression of Col2a1 and aggrecan by increasing AKT phosphorylation under oxidative stress
      • Iwasa K.
      • Hayashi S.
      • Fujishiro T.
      • Kanzaki N.
      • Hashimoto S.
      • Sakata S.
      • et al.
      PTEN regulates matrix synthesis in adult human chondrocytes under oxidative stress.
      . These findings indicate PI3K/AKT pathway involves in the ECM synthesis.
      This pathway also plays a role in ECM catabolism in addition to stimulating ECM anabolism. Venkatesan, J K et al. found recombinant adeno-associated virus (rAAV)- mediated production of TGF-β reduced expression of MMP13 in human OA chondrocytes and cartilage explants
      • Venkatesan J.K.
      • Rey-Rico A.
      • Schmitt G.
      • Wezel A.
      • Madry H.
      • Cucchiarini M.
      rAAV-mediated overexpression of TGF-β stably restructures human osteoarthritic articular cartilage in situ.
      . In agreement with this evidence, activation of PI3K/AKT by TGF-β can attenuate rat cartilage injury by decreasing expression of MMP13
      • Zhang Q.
      • Lai S.
      • Hou X.
      • Cao W.
      • Zhang Y.
      • Zhang Z.
      Protective effects of PI3K/Akt signal pathway induced cell autophagy in rat knee joint cartilage injury.
      , and chemical inhibitors of PI3K/AKT can repress expression of TIMP-3, a natural inhibitor of MMPs
      • Qureshi H.Y.
      • Ahmad R.
      • Sylvester J.
      • Zafarullah M.
      Requirement of phosphatidylinositol 3-kinase/Akt signaling pathway for regulation of tissue inhibitor of metalloproteinases-3 gene expression by TGF-beta in human chondrocytes.
      . Above data indicates PI3K/AKT mediates inhibitory effect of TGF-β on ECM catabolism. In addition, another study demonstrated IGF-1 can promote expression of Col2a1and inhibit expression of MMP13 with activation of PI3K and extracellular signal-regulated kinase (ERK). The PI3K inhibitor (Wortmannin) markedly reversed the IGF-1 effect on Col2a1 expression without affecting effect of IGF-1 on MMP-13 expression
      • Zhang M.
      • Zhou Q.
      • Liang Q.Q.
      • Li C.G.
      • Holz J.D.
      • Tang D.
      • et al.
      IGF-1 regulation of type II collagen and MMP-13 expression in rat endplate chondrocytes via distinct signaling pathways.
      . It suggests that PI3K may not be involved in IGF-1-induced changes in the expression of MMP13. By contrast, leptin can induce increased MMPs expression in chondrocytes, Selective inhibitors of PI3K and AKT significantly reduce MMPs expression
      • Hui W.
      • Litherland G.J.
      • Elias M.S.
      • Kitson G.I.
      • Cawston T.E.
      • Rowan A.D.
      • et al.
      Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases.
      . Collectively, although activation of PI3K/AKT promotes ECM anabolism, the precise effects of PI3K/AKT on ECM catabolism remain unclear. Thus, further studies are needed to determine the function of PI3K/AKT in cartilage homeostasis.

      Inflammatory response

      Previous studies have shown inflammatory response always occurs with OA pathogenesis and OA-related symptoms
      • Robinson W.H.
      • Lepus C.M.
      • Wang Q.
      • Raghu H.
      • Mao R.
      • Lindstrom T.M.
      • et al.
      Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis.
      . During OA progression, affected chondrocytes and synovial cells overproduce inflammatory mediators such as IL-1β and nitric oxide (NO) to accelerate cartilage degradation
      • Kapoor M.
      • Martel-Pelletier J.
      • Lajeunesse D.
      • Pelletier J.
      • Fahmi H.
      Role of proinflammatory cytokines in the pathophysiology of osteoarthritis.
      . In particular, IL-1β could trigger strong inflammatory responses by activating complex signaling pathway networks in which PI3K/AKT signaling is closely intertwined with IL-1β-induced inflammation
      • Park C.
      • Jeong J.W.
      • Lee D.S.
      • Yim M.J.
      • Lee J.M.
      • Han M.H.
      • et al.
      Extract attenuates interleukin-1β-induced oxidative stress and inflammatory response in chondrocytes by suppressing the activation of NF-κB, p38 MAPK, and PI3K/Akt.
      . Numerous studies suggest PI3K and AKT are rapidly phosphorylated under the stimulation of IL-1β
      • Hu Z.C.
      • Gong L.F.
      • Li X.B.
      • Fu X.
      • Xuan J.W.
      • Feng Z.H.
      • et al.
      Inhibition of PI3K/Akt/NF-κB signaling with leonurine for ameliorating the progression of osteoarthritis: in vitro and in vivo studies.
      ,
      • Xue J.F.
      • Shi Z.M.
      • Zou J.
      • Li X.L.
      Inhibition of PI3K/AKT/mTOR signaling pathway promotes autophagy of articular chondrocytes and attenuates inflammatory response in rats with osteoarthritis.
      . Moreover, some biological and chemical compounds exert both inhibitory effects on IL-1β-induced PI3K, AKT, and NF-κB phosphorylation, and inflammatory responses
      • Lu C.
      • Li Y.
      • Hu S.
      • Cai Y.
      • Yang Z.
      • Peng K.
      Scoparone prevents IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through the PI3K/Akt/NF-κB pathway.
      , indicating that PI3K/AKT/NF-κB pathway might mediate initiation of an inflammatory response. Mechanistically, NF-κB is a master regulator of OA-related inflammatory mediators
      • Choi M.C.
      • Jo J.
      • Park J.
      • Kang H.K.
      • Park Y.
      NF-κB signaling pathways in osteoarthritic cartilage destruction.
      and activated mainly by IκB kinases-mediated IκBα degradation and p65/RelA phosphorylation. Protein kinase A (PKA)/AKT could activate NF-κB by affecting its upstream IκB kinases
      • Balwani S.
      • Chaudhuri R.
      • Nandi D.
      • Jaisankar P.
      • Agrawal A.
      • Ghosh B.
      Regulation of NF-κB activation through a novel PI-3K-independent and PKA/Akt-dependent pathway in human umbilical vein endothelial cells.
      . Thus, active PI3K and AKT are involved in NF-κB p65 phosphorylation and nuclear translocation, promoting production of inflammatory mediators.

      Chondrocyte proliferation and apoptosis

      Chondrocytes (the only cell type in cartilage) are the dominant influence on the health and function of cartilage
      • Hunter D.J.
      • Bierma-Zeinstra S.
      Osteoarthritis.
      . Excessive chondrocyte apoptosis and reduced proliferation are frequent companions to cartilage degradation
      • Kühn K.
      • D'Lima D.D.
      • Hashimoto S.
      • Lotz M.
      Cell death in cartilage.
      ,
      • Varela-Eirin M.
      • Loureiro J.
      • Fonseca E.
      • Corrochano S.
      • Caeiro J.R.
      • Collado M.
      • et al.
      Cartilage regeneration and ageing: targeting cellular plasticity in osteoarthritis.
      . The PI3K/AKT signaling pathway is a vital regulator of chondrocyte survival and apoptosis
      • Cravero J.D.
      • Carlson C.S.
      • Im H.J.
      • Yammani R.R.
      • Long D.
      • Loeser R.F.
      Increased expression of the Akt/PKB inhibitor TRB3 in osteoarthritic chondrocytes inhibits insulin-like growth factor 1-mediated cell survival and proteoglycan synthesis.
      . 17β-estradiol (E2) loss may be accompanied by increased incidence of knee and hip OA
      • Sowers M.R.
      • McConnell D.
      • Jannausch M.
      • Buyuktur A.G.
      • Hochberg M.
      • Jamadar D.A.
      Estradiol and its metabolites and their association with knee osteoarthritis.
      . By contrast, E2 mediated PI3K/AKT activation significantly promotes cell proliferation in rat OA model chondrocytes
      • Huang J.G.
      • Xia C.
      • Zheng X.P.
      • Yi T.T.
      • Wang X.Y.
      • Song G.
      • et al.
      17β-Estradiol promotes cell proliferation in rat osteoarthritis model chondrocytes via PI3K/Akt pathway.
      . Administration of 17β-estradiol also elevates proliferation and viability of ATDC5 chondrocytes via this signaling
      • Fan D.X.
      • Yang X.H.
      • Li Y.N.
      • Guo L.
      17β-Estradiol on the expression of G-protein coupled estrogen receptor (GPER/GPR30) mitophagy, and the PI3K/Akt signaling pathway in ATDC5 chondrocytes in vitro.
      . In addition, a study by Huang et al. suggested that PTEN silencing increased AKT phosphorylation, and promoted proliferation of OA chondrocytes
      • Huang Z.
      • Zhang N.
      • Ma W.
      • Dai X.
      • Liu J.
      MiR-337-3p promotes chondrocytes proliferation and inhibits apoptosis by regulating PTEN/AKT axis in osteoarthritis.
      . Rapid cellular proliferation is also found during cartilage repair under exosomal CD73-mediated adenosine activation of AKT and extracellular regulated kinase (ERK) signaling while inhibitors of AKT or ERK phosphorylation repress exosome-mediated increases in cell proliferation
      • Zhang S.
      • Chuah S.J.
      • Lai R.C.
      • Hui J.
      • Lim S.K.
      • Toh W.S.
      MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity.
      . Apart from regulating cell proliferation, PI3K/AKT could minimize cartilage degeneration by preventing chondrocyte death. Overproduction of NO in articular chondrocytes induces apoptosis by modulating multiple intracellular signaling processes including PI3K/AKT signaling
      • Kim S.J.
      • Hwang S.G.
      • Kim I.C.
      • Chun J.S.
      Actin cytoskeletal architecture regulates nitric oxide-induced apoptosis, dedifferentiation, and cyclooxygenase-2 expression in articular chondrocytes via mitogen-activated protein kinase and protein kinase C pathways.
      . Chun-Do et al. reported that NO production in chondrocytes led to cell apoptosis, with downregulation of PI3K and AKT activities, while IGF-1 treatment blocked the process through PI3K and AKT activation
      • Oh C.D.
      • Chun J.S.
      Signaling mechanisms leading to the regulation of differentiation and apoptosis of articular chondrocytes by insulin-like growth factor-1.
      . Notably, IL-1β is also a crucial inducer of cell apoptosis, which simultaneously suppresses PI3K and AKT activity
      • Qu R.
      • Chen X.
      • Wang W.
      • Qiu C.
      • Ban M.
      • Guo L.
      • et al.
      Ghrelin protects against osteoarthritis through interplay with Akt and NF-κB signaling pathways.
      . Growing evidence indicates multiple growth factors, such as FGF18
      • Yao X.
      • Zhang J.
      • Jing X.
      • Ye Y.
      • Guo J.
      • Sun K.
      • et al.
      Fibroblast growth factor 18 exerts anti-osteoarthritic effects through PI3K-AKT signaling and mitochondrial fusion and fission.
      , IGF-1, and platelet-derived growth factor
      • Montaseri A.
      • Busch F.
      • Mobasheri A.
      • Buhrmann C.
      • Aldinger C.
      • Rad J.S.
      • et al.
      IGF-1 and PDGF-bb suppress IL-1β-induced cartilage degradation through down-regulation of NF-κB signaling: involvement of Src/PI-3K/AKT pathway.
      , could rescue IL-1β-induced increase in mitochondrial-related apoptosis by the activation of PI3K/AKT. Not only that, many bioactive compounds including berberine
      • Zhao H.
      • Zhang T.
      • Xia C.
      • Shi L.
      • Wang S.
      • Zheng X.
      • et al.
      Berberine ameliorates cartilage degeneration in interleukin-1β-stimulated rat chondrocytes and in a rat model of osteoarthritis via Akt signalling.
      and tormentic acid
      • Yang Y.
      • Wang Y.
      • Zhao M.
      • Jia H.
      • Li B.
      • Xing D.
      Tormentic acid inhibits IL-1β-induced chondrocyte apoptosis by activating the PI3K/Akt signaling pathway.
      , exert similar anti-apoptotic effects via PI3K/AKT activation. Consistent with these results, other evidence reveals that activated PI3K/AKT can block OA chondrocyte apoptosis induced by TNF-α and LPS
      • Stanic I.
      • Facchini A.
      • Borzi R.M.
      • Vitellozzi R.
      • Stefanelli C.
      • Goldring M.B.
      • et al.
      Polyamine depletion inhibits apoptosis following blocking of survival pathways in human chondrocytes stimulated by tumor necrosis factor-alpha.
      ,
      • Vasheghani F.
      • Zhang Y.
      • Li Y.H.
      • Blati M.
      • Fahmi H.
      • Lussier B.
      • et al.
      PPARgamma deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage.
      . Taken together, the PI3K/AKT signaling negatively modulates chondrocyte apoptosis under multiple pathological conditions and the activated signaling can protect against OA by reducing chondrocyte apoptosis.

      Autophagy

      Autophagy, an essential regulator of energy utilization and nutrient metabolism, is a cellular homeostasis mechanism that removes dysfunctional and damaged macromolecules and organelles
      • Levine B.
      • Kroemer G.
      Autophagy in the pathogenesis of disease.
      . Failure to perform autophagy leads to elevated production of reactive oxygen species and mitochondrial dysfunction, and can result in death at the cellular level
      • Mathew R.
      • Karp C.M.
      • Beaudoin B.
      • Vuong N.
      • Chen G.
      • Chen H.Y.
      • et al.
      Autophagy suppresses tumorigenesis through elimination of p62.
      . A switch from autophagy to apoptosis is implicated in progression of chondrocytes to OA
      • Duarte J.H.
      Osteoarthritis: autophagy prevents age-related OA.
      . The mTOR pathway is a key suppressor of autophagy, and is centrally regulated by upstream signaling pathways involving PI3K/AKT, and AMPK
      • Dalle P.P.
      • Ruf S.
      • Sonntag A.G.
      • Langelaar-Makkinje M.
      • Hall P.
      • Heberle A.M.
      • et al.
      A systems study reveals concurrent activation of AMPK and mTOR by amino acids.
      . Upregulated mTOR in OA cartilage is linked to increased chondrocyte apoptosis and decreased expression of autophagy-related genes. Cartilage-knockdown of mTOR upregulates autophagy, and reduces apoptosis, altering cartilage homeostasis in mice
      • Zhang Y.
      • Vasheghani F.
      • Li Y.H.
      • Blati M.
      • Simeone K.
      • Fahmi H.
      • et al.
      Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis.
      . Rapamycin, an mTOR inhibitor, also attenuates the severity of experimental osteoarthritis by activating autophagy
      • Caramés B.
      • Hasegawa A.
      • Taniguchi N.
      • Miyaki S.
      • Blanco F.J.
      • Lotz M.
      Autophagy activation by rapamycin reduces severity of experimental osteoarthritis.
      . By contrast, mTORC1 activation by genetic deletion of TSC1 or by addition of the activator MHY1485 could result in opposite effects
      • Yang H.
      • Wen Y.
      • Zhang M.
      • Liu Q.
      • Zhang H.
      • Zhang J.
      • et al.
      MTORC1 coordinates the autophagy and apoptosis signaling in articular chondrocytes in osteoarthritic temporomandibular joint.
      .
      In addition to its involvement in apoptosis, mTOR-regulated autophagy is correlated with the inflammatory response. OA activity associated with synovitis is accompanied by increased expression of mTOR in peripheral blood mononuclear cells in OA patients
      • Tchetina E.V.
      • Poole A.R.
      • Zaitseva E.M.
      • Sharapova E.P.
      • Kashevarova N.G.
      • Taskina E.A.
      • et al.
      Differences in Mammalian target of rapamycin gene expression in the peripheral blood and articular cartilages of osteoarthritic patients and disease activity.
      . Pro-inflammatory cytokine IL-1β exposure also results in an obvious increase in mTOR expression in human OA chondrocytes
      • Tchetina E.V.
      • Poole A.R.
      • Zaitseva E.M.
      • Sharapova E.P.
      • Kashevarova N.G.
      • Taskina E.A.
      • et al.
      Differences in Mammalian target of rapamycin gene expression in the peripheral blood and articular cartilages of osteoarthritic patients and disease activity.
      . Inhibiting autophagy has been shown to enhance inflammasome activity, whereas promoting autophagy limits production of IL-1β
      • Shi C.S.
      • Shenderov K.
      • Huang N.N.
      • Kabat J.
      • Abu-Asab M.
      • Fitzgerald K.A.
      • et al.
      Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction.
      . In mouse chondrocytes, peroxisome proliferator-activated receptor gamma (PPARγ) deficiency-induced dysregulated expression of mTOR is associated with suppression of critical autophagy markers and consequently induces abnormal expression of inflammatory markers inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), ultimately exacerbating inflammatory activity in cartilage
      • Vasheghani F.
      • Zhang Y.
      • Li Y.H.
      • Blati M.
      • Fahmi H.
      • Lussier B.
      • et al.
      PPARgamma deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage.
      . In addition, Ansari MY et al. found hydromethanolic extract of Butea monosperma (BME) repressed IL-1β-induced overexpression of IL-6, MMP3, 9, and 13. The effects were autophagy dependent with upregulated protein expression of LC3-II and increased number of autophagosomes, and could be abolished by inhibition of autophagy
      • Ansari M.Y.
      • Khan N.M.
      • Haqqi T.M.
      A standardized extract of Butea monosperma (Lam.) flowers suppresses the IL-1β-induced expression of IL-6 and matrix-metalloproteases by activating autophagy in human osteoarthritis chondrocytes.
      . In vivo, rapamycin treatment of OA mice decreases IL-1β expression and maintains cartilage cellularity
      • Caramés B.
      • Hasegawa A.
      • Taniguchi N.
      • Miyaki S.
      • Blanco F.J.
      • Lotz M.
      Autophagy activation by rapamycin reduces severity of experimental osteoarthritis.
      . Thus, mTOR is an essential link between inflammation and autophagy in OA pathogenesis.

      Subchondral bone

      Recently, a growing number of studies have indicated that subchondral bone-cartilage crosstalk exerts a regulatory effect on OA development
      • Goldring S.R.
      • Goldring M.B.
      Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk.
      . Subchondral bone, best known as the bony component lying under articular cartilage, supports articular cartilage, and spreads mechanical loads across joint surfaces
      • Goldring S.R.
      • Goldring M.B.
      Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk.
      . Thus, micro-architecture changes in subchondral bone might lead to cartilage destabilization, and further contribute to cartilage degeneration. In turn, abnormal mechanical stresses from cartilage may cause microfractures in the subchondral bone, or osteochondral junction, which promotes subchondral bone remodeling and further accelerates development of subchondral sclerosis as well as osteophyte formation
      • Funck-Brentano T.
      • Cohen-Solal M.
      Subchondral bone and osteoarthritis.
      . PI3K/AKT/mTOR is a key metabolic pathway in subchondral bone in osteoarthritis
      • Guo S.M.
      • Wang J.X.
      • Li J.
      • Xu F.Y.
      • Wei Q.
      • Wang H.M.
      • et al.
      Identification of gene expression profiles and key genes in subchondral bone of osteoarthritis using weighted gene coexpression network analysis.
      . Increased phosphorylation of AKT is seen in subchondral bone in a mouse model of post-traumatic OA, promoting osteogenic differentiation and osteoblastic proliferation, and resulting in aberrant bone formation. By contrast, PI3K/AKT inhibitor (LY294002) treatment reduces subchondral bone sclerosis by decreasing osteogenesis in OA mice, and simultaneously attenuates cartilage degeneration
      • Lin C.
      • Shao Y.
      • Zeng C.
      • Zhao C.
      • Fang H.
      • Wang L.
      • et al.
      Blocking PI3K/AKT signaling inhibits bone sclerosis in subchondral bone and attenuates post-traumatic osteoarthritis.
      . A report by Lin et.al. found that mTORC1 was activated in subchondral bone preosteoblasts in OA patients and mice. Activated mTORC1 in preosteoblasts stimulated bone sclerosis and secretion of CXCL12 which aggravate OA. Nevertheless, inhibiting mTORC1 by disrupting Raptor (an mTORC1-specific component) delayed subchondral bone formation and cartilage degeneration in OA mice
      • Lin C.
      • Liu L.
      • Zeng C.
      • Cui Z.K.
      • Chen Y.
      • Lai P.
      • et al.
      Activation of mTORC1 in subchondral bone preosteoblasts promotes osteoarthritis by stimulating bone sclerosis and secretion of CXCL12.
      . Consistent with these results, activation of PI3K/AKT/mTOR also promoted osteoblastic differentiation in pre-osteoblasts and bone mesenchymal stem cells, and targeted inhibition of PI3K/AKT signaling reduced bone formation in vivo and in vitro
      • Baker N.
      • Sohn J.
      • Tuan R.S.
      Promotion of human mesenchymal stem cell osteogenesis by PI3-kinase/Akt signaling, and the influence of caveolin-1/cholesterol homeostasis.
      ,
      • Lauzon M.A.
      • Drevelle O.
      • Daviau A.
      • Faucheux N.
      Effects of BMP-9 and BMP-2 on the PI3K/Akt pathway in MC3T3-E1 preosteoblasts.
      . However, there are two side to bone formation as reduced bone formation is also substantially responsible for osteoporosis
      • Compston J.E.
      • McClung M.R.
      • Leslie W.D.
      Osteoporosis.
      . To avoid the potential side effects induced by pharmacological inhibition of PI3K/AKT, inhibitors that can specifically target subchondral bone should be further researched.

      Synovium

      Synovial inflammation is a critical component of the pathophysiology of OA and it has shown to predict the progression of structural damage. A clinical study has found that synovitis occurred in ∼50% of OA patients (n = 422)
      • Ayral X.
      • Pickering E.H.
      • Woodworth T.G.
      • Mackillop N.
      • Dougados M.
      Synovitis: a potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis -- results of a 1 year longitudinal arthroscopic study in 422 patients.
      . Likewise, magnetic resonance imaging (MRI)-estimated synovitis predicts the risk of incident knee OA
      • Felson D.T.
      • Niu J.
      • Neogi T.
      • Goggins J.
      • Nevitt M.C.
      • Roemer F.
      • et al.
      Synovitis and the risk of knee osteoarthritis: the MOST Study.
      . Synovitis is mainly triggered by release of cytokines and catabolic products by synovial cells including synoviocytes, fibroblasts, and macrophages
      • Marchev A.S.
      • Dimitrova P.A.
      • Burns A.J.
      • Kostov R.V.
      • Dinkova-Kostova A.T.
      • Georgiev M.I.
      Oxidative stress and chronic inflammation in osteoarthritis: can NRF2 counteract these partners in crime?.
      . These cytokines, such as IL-1β, IL-6, and TNF-α, diffuse into the cartilage, further stimulating secretion of damage mediators in chondrocytes to amplify synovial inflammation and cartilage destruction
      • Bhattaram P.
      • Chandrasekharan U.
      The joint synovium: a critical determinant of articular cartilage fate in inflammatory joint diseases.
      . PI3Kδ and PI3Kγ are highly expressed in rheumatoid arthritis (RA) synovium and cultured synoviocytes, and closely related to modulation of synovial inflammation
      • Bartok B.
      • Boyle D.L.
      • Liu Y.
      • Ren P.
      • Ball S.T.
      • Bugbee W.D.
      • et al.
      PI3 kinase δ is a key regulator of synoviocyte function in rheumatoid arthritis.
      ,
      • Hayer S.
      • Pundt N.
      • Peters M.A.
      • Wunrau C.
      • Kühnel I.
      • Neugebauer K.
      • et al.
      PI3Kgamma regulates cartilage damage in chronic inflammatory arthritis.
      . PI3Kδ is known to control the proliferation and migration of fibroblast-like synoviocytes (FLS), which may contribute to cartilage damage. Also, PI3Kδ expression is stimulated by inflammatory cytokines IL-1β and TNF-α. Targeting PI3Kδ could decrease inflammatory levels in synoviocytes
      • Bartok B.
      • Boyle D.L.
      • Liu Y.
      • Ren P.
      • Ball S.T.
      • Bugbee W.D.
      • et al.
      PI3 kinase δ is a key regulator of synoviocyte function in rheumatoid arthritis.
      . In addition, PI3Kγ deficiency reduces TNF-α-induced MMP expression, and activation of AKT and ERK in synovial fibroblasts
      • Hayer S.
      • Pundt N.
      • Peters M.A.
      • Wunrau C.
      • Kühnel I.
      • Neugebauer K.
      • et al.
      PI3Kgamma regulates cartilage damage in chronic inflammatory arthritis.
      . IPI-145, a novel inhibitor of PI3Kδ, and γ, represses inflammatory arthritis and cartilage damage
      • Boyle D.L.
      • Kim H.R.
      • Topolewski K.
      • Bartok B.
      • Firestein G.S.
      Novel phosphoinositide 3-kinase δ,γ inhibitor: potent anti-inflammatory effects and joint protection in models of rheumatoid arthritis.
      . The PI3K downstream effector mTOR also serves as a pro-inflammatory response regulator in synovium. TNF-α stimulates mTOR activation in cultured FLSs, while mTOR negatively modulates TNF-upregulated expression of multiple pro-inflammatory cytokines or chemokines such as IL-6, IL-8, CCL20, CXCL11, MMP1, MMP3, and prostaglandin-endoperoxide synthase 2 (PTGS2) by limiting activation of NF-κB signaling to shift synovial FLS inflammation
      • Karonitsch T.
      • Kandasamy R.K.
      • Kartnig F.
      • Herdy B.
      • Dalwigk K.
      • Niederreiter B.
      • et al.
      mTOR senses environmental cues to shape the fibroblast-like synoviocyte response to inflammation.
      . In OA, the mTOR inhibitor rapamycin alleviates synovitis and IL-1β levels in synovial tissue in OA mouse knees
      • Caramés B.
      • Hasegawa A.
      • Taniguchi N.
      • Miyaki S.
      • Blanco F.J.
      • Lotz M.
      Autophagy activation by rapamycin reduces severity of experimental osteoarthritis.
      . This finding suggests mTOR might positively modulates OA-related inflammation response. The different roles of mTOR on synovial inflammation between RA and OA may attribute to different pathogenesis of the deceases and should be further clarified. In addition, accumulating evidence indicates basic calcium phosphate (BCP) crystals are present in the majority of OA joints, and are potent drivers of inflammation correlated with OA progression
      • Pazár B.
      • Ea H.K.
      • Narayan S.
      • Kolly L.
      • Bagnoud N.
      • Chobaz V.
      • et al.
      Basic calcium phosphate crystals induce monocyte/macrophage IL-1β secretion through the NLRP3 inflammasome in vitro.
      . Synovial macrophages are reportedly involved in initiating and enhancing BCP-induced damage
      • Pazár B.
      • Ea H.K.
      • Narayan S.
      • Kolly L.
      • Bagnoud N.
      • Chobaz V.
      • et al.
      Basic calcium phosphate crystals induce monocyte/macrophage IL-1β secretion through the NLRP3 inflammasome in vitro.
      . Activation of Syk and PI3 kinase, induced by BCP crystals in macrophages might mediate production of damage-associated molecules. Administration of Syk and PI3 kinase inhibitors reverses excess production of these molecule, identifying Syk and PI3 kinase as regulators for treatment of BCP-related OA
      • Corr E.M.
      • Cunningham C.C.
      • Helbert L.
      • McCarthy G.M.
      • Dunne A.
      Osteoarthritis-associated basic calcium phosphate crystals activate membrane proximal kinases in human innate immune cells.
      . Taken together, these results suggest inhibition of PI3K/AKT/mTOR could alleviate synovial inflammation in OA. Nevertheless, synovial microenvironment is complex and synovium contains many kinds of cells. The precise mechanism of the regulatory role of PI3K/AKT/mTOR signaling in these cells still not clear and needs more investigations.

      Therapeutic prospects

      To date, the key management strategies for osteoarthritis have included non-pharmacological (e.g., education and self-management, exercises, weight loss if overweight), pharmacological (e.g., NSAIDs and intra-articular injection of corticosteroids), and surgical approaches
      • Nelson A.E.
      • Allen K.D.
      • Golightly Y.M.
      • Goode A.P.
      • Jordan J.M.
      A systematic review of recommendations and guidelines for the management of osteoarthritis: the chronic osteoarthritis management initiative of the U.S. bone and joint initiative.
      . Traditional therapies are effective for alleviating related clinical symptoms and improving quality of life to some extent. Nevertheless, they fail to reverse cartilage degradation, and may cause adverse events
      • Ghouri A.
      • Conaghan P.G.
      Update on novel pharmacological therapies for osteoarthritis.
      . The targeting of key molecules and signaling pathways involved in the pathogenesis of OA has been extensively investigated. Considering the important role of PI3K/AKT/mTOR signaling in OA, it might offer promising targets for treatment of OA (Table I). Currently, PI3K/AKT/mTOR signaling-based intervention strategies for OA can be divided into two main categories: (1) inhibition of PI3K/AKT/mTOR signaling attenuates joint damage due to OA by restoring cartilage homeostasis, enhancing autophagy, and suppressing inflammatory responses. (2) Activation of PI3K/AKT/mTOR signaling may play an anti-arthritic role by promoting chondrocyte proliferation, and reducing apoptosis.
      Table IPotential PI3K/AKT/mTOR signaling-related inhibitors and regulators in OA treatment
      Inhibitor/regulatorTarget cell/tissueTargetMain findingsReference
      IGF-1Rat endplate chondrocytesPI3KInduces increased expression of col2a1 and reduced expression of MMP13
      • Venkatesan J.K.
      • Rey-Rico A.
      • Schmitt G.
      • Wezel A.
      • Madry H.
      • Cucchiarini M.
      rAAV-mediated overexpression of TGF-β stably restructures human osteoarthritic articular cartilage in situ.
      TGF-βRat cartilagePI3K/AKTInduces decreased expression of MMP13
      • Venkatesan J.K.
      • Rey-Rico A.
      • Schmitt G.
      • Wezel A.
      • Madry H.
      • Cucchiarini M.
      rAAV-mediated overexpression of TGF-β stably restructures human osteoarthritic articular cartilage in situ.
      LeonurineMousePI3K/AKT/NF-κBReduces IL-1β-induced inflammatory response
      • Xue J.F.
      • Shi Z.M.
      • Zou J.
      • Li X.L.
      Inhibition of PI3K/AKT/mTOR signaling pathway promotes autophagy of articular chondrocytes and attenuates inflammatory response in rats with osteoarthritis.
      ScoparoneHuman chondrocytesPI3K/AKT/NF-κBReduces IL-1β-induced inflammatory response
      • Choi M.C.
      • Jo J.
      • Park J.
      • Kang H.K.
      • Park Y.
      NF-κB signaling pathways in osteoarthritic cartilage destruction.
      LY294002

      Casodex

      Rapamycin
      Rat chondrocytesPI3K

      AKT

      mTOR
      Promotes autophagy of articular chondrocytes and attenuates inflammatory response
      • Xue J.F.
      • Shi Z.M.
      • Zou J.
      • Li X.L.
      Inhibition of PI3K/AKT/mTOR signaling pathway promotes autophagy of articular chondrocytes and attenuates inflammatory response in rats with osteoarthritis.
      Vanillic acidRat chondrocytesMAPK and PI3K/AKT/NF-κBAttenuates inflammatory response and cartilage degeneration
      • Huang X.
      • Xi Y.
      • Mao Z.
      • Chu X.
      • Zhang R.
      • Ma X.
      • et al.
      Vanillic acid attenuates cartilage degeneration by regulating the MAPK and PI3K/AKT/NF-κB pathways.
      17beta-EstradiolRat OA chondrocytesPI3K/AKTPromotes cell proliferation
      • Huang J.G.
      • Xia C.
      • Zheng X.P.
      • Yi T.T.
      • Wang X.Y.
      • Song G.
      • et al.
      17beta-Estradiol promotes cell proliferation in rat osteoarthritis model chondrocytes via PI3K/Akt pathway.
      FGF18Rat chondrocytesPI3K/AKTPromotes chondrocyte proliferation and migration and attenuates IL-1β-induced apoptosis in vitro. attenuates cartilage degradation in vivo
      • Iwasa K.
      • Hayashi S.
      • Fujishiro T.
      • Kanzaki N.
      • Hashimoto S.
      • Sakata S.
      • et al.
      PTEN regulates matrix synthesis in adult human chondrocytes under oxidative stress.
      GhrelinHuman chondrocyte and cartilageAKTDown-regulates the production of various inflammatory cytokines, inhibits apoptosis of chondrocytes, attenuate ECM degradation
      • Montaseri A.
      • Busch F.
      • Mobasheri A.
      • Buhrmann C.
      • Aldinger C.
      • Rad J.S.
      • et al.
      IGF-1 and PDGF-bb suppress IL-1β-induced cartilage degradation through down-regulation of NF-κB signaling: involvement of Src/PI-3K/AKT pathway.
      miR-218-5pSW1353 and C28/I2 cellsPI3K/AKT/mTORmiR-218-5p inhibitor alleviates mice cartilage degradation with reduced proteoglycan loss and reduced loss of articular chondrocyte cellularity
      • Lu J.
      • Ji M.L.
      • Zhang X.J.
      • Shi P.L.
      • Wu H.
      • Wang C.
      • et al.
      MicroRNA-218-5p as a potential target for the treatment of human osteoarthritis.
      miR-27aHumanPI3K/AKT/mTORPromotes the autophagy and apoptosis of IL-1β treated-articular chondrocytes
      • Cai C.
      • Min S.
      • Yan B.
      • Liu W.
      • Yang X.
      • Li L.
      • et al.
      MiR-27a promotes the autophagy and apoptosis of IL-1β treated-articular chondrocytes in osteoarthritis through PI3K/AKT/mTOR signaling.
      Peroxiredoxin 4 (PRDX4)Rat chondrocytesAKTPRDX4 overexpression reverses IL-1β-stimulated apoptosis
      • Rao Z.
      • Wang S.
      • Wang J.
      Peroxiredoxin 4 inhibits IL-1β-induced chondrocyte apoptosis via PI3K/AKT signaling.
      LiraglutideRat chondrocytesGLP-1R/PI3K/AKTProtects chondrocytes against endoplasmic reticulum stress and apoptosis induced by interleukin (IL)-1β or triglycerides and attenuates rat cartilage degeneration in an OA model of knee joints in vivo
      • Chen J.
      • Xie J.J.
      • Shi K.S.
      • Gu Y.T.
      • Wu C.C.
      • Xuan J.
      • et al.
      Glucagon-like peptide-1 receptor regulates endoplasmic reticulum stress-induced apoptosis and the associated inflammatory response in chondrocytes and the progression of osteoarthritis in rat.
      Platelet-derived growth factorHumanSrc/PI-3K/AKTRescues IL-1β-induced increases in mitochondrial-related apoptosis
      • Zhao H.
      • Zhang T.
      • Xia C.
      • Shi L.
      • Wang S.
      • Zheng X.
      • et al.
      Berberine ameliorates cartilage degeneration in interleukin-1β-stimulated rat chondrocytes and in a rat model of osteoarthritis via Akt signalling.
      BerberineRat chondrocytesAKTAmeliorates cartilage degeneration from OA by promoting cell survival and matrix production of chondrocytes
      • Yang Y.
      • Wang Y.
      • Zhao M.
      • Jia H.
      • Li B.
      • Xing D.
      Tormentic acid inhibits IL-1β-induced chondrocyte apoptosis by activating the PI3K/Akt signaling pathway.
      Tormentic acidHumanPI3K/AKTInhibits IL-1β-induced cytotoxicity and apoptosis in chondrocytes
      • Vasheghani F.
      • Zhang Y.
      • Li Y.H.
      • Blati M.
      • Fahmi H.
      • Lussier B.
      • et al.
      PPARgamma deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage.
      PPARgammaMurine cartilagemTORPPARgamma maintains articular cartilage homeostasis, in part, by regulating mTOR pathway
      • Stanic I.
      • Facchini A.
      • Borzi R.M.
      • Vitellozzi R.
      • Stefanelli C.
      • Goldring M.B.
      • et al.
      Polyamine depletion inhibits apoptosis following blocking of survival pathways in human chondrocytes stimulated by tumor necrosis factor-alpha.
      The hydromethanolic extract of Butea monosperma (BME)HumanmTORBME has strong potential to activate autophagy and suppress IL-1β induced expression of IL-6 and MMP-3, -9 and - via inhibition of mTOR
      • Caramés B.
      • Hasegawa A.
      • Taniguchi N.
      • Miyaki S.
      • Blanco F.J.
      • Lotz M.
      Autophagy activation by rapamycin reduces severity of experimental osteoarthritis.
      RapamycinMouse articular cartilage and synoviummTORInduces autophagy activation and alleviates synovitis and IL-1β levels in synovial tissue in OA mouse knees.
      • Caramés B.
      • Hasegawa A.
      • Taniguchi N.
      • Miyaki S.
      • Blanco F.J.
      • Lotz M.
      Autophagy activation by rapamycin reduces severity of experimental osteoarthritis.
      RaptorPreosteoblastsmTORC1Disruption of Raptor reduces subchondral bone formation and cartilage degeneration, and attenuated post-traumatic OA in mice
      • Baker N.
      • Sohn J.
      • Tuan R.S.
      Promotion of human mesenchymal stem cell osteogenesis by PI3-kinase/Akt signaling, and the influence of caveolin-1/cholesterol homeostasis.
      LY294002Primary human macrophagesPI3KReduces BCP-induced production of the pro-inflammatory cytokines
      • Corr E.M.
      • Cunningham C.C.
      • Helbert L.
      • McCarthy G.M.
      • Dunne A.
      Osteoarthritis-associated basic calcium phosphate crystals activate membrane proximal kinases in human innate immune cells.
      LY294002Mouse osteoblastic cellsPI3KReduces bone sclerosis in subchondral bone and delays post-traumatic osteoarthritis.
      • Lin C.
      • Liu L.
      • Zeng C.
      • Cui Z.K.
      • Chen Y.
      • Lai P.
      • et al.
      Activation of mTORC1 in subchondral bone preosteoblasts promotes osteoarthritis by stimulating bone sclerosis and secretion of CXCL12.
      LY294002Human bone marrow MSCsPI3K/AKTReduces bone formation in vivo and in vitro
      • Lauzon M.A.
      • Drevelle O.
      • Daviau A.
      • Faucheux N.
      Effects of BMP-9 and BMP-2 on the PI3K/Akt pathway in MC3T3-E1 preosteoblasts.
      Some approaches and agents that could block transduction of PI3K/AKT/mTOR signaling might be beneficial to patients with the disease. For example, small-molecule inhibitors of PI3K, AKT, and mTOR (LY294002, Casodex, and rapamycin) are shown to promote autophagy of articular chondrocytes, and attenuate the inflammation response in rats with OA
      • Xue J.F.
      • Shi Z.M.
      • Zou J.
      • Li X.L.
      Inhibition of PI3K/AKT/mTOR signaling pathway promotes autophagy of articular chondrocytes and attenuates inflammatory response in rats with osteoarthritis.
      . Additionally, blocking PI3K/AKT signaling with LY294002 reduces bone sclerosis in subchondral bone, and delays post-traumatic osteoarthritis
      • Lin C.
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      • et al.
      Blocking PI3K/AKT signaling inhibits bone sclerosis in subchondral bone and attenuates post-traumatic osteoarthritis.
      . Apart from well characterized inhibitors, some bioactive compounds isolated from herbs could protect joints from OA via inhibition of this pathway. Leonurine, vanillic acid, and scoparone have been demonstrated to ameliorate both chondrocyte and cartilage injury in mice by promoting autophagy and/or repressing inflammatory responses
      • Hu Z.C.
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      • et al.
      Inhibition of PI3K/Akt/NF-κB signaling with leonurine for ameliorating the progression of osteoarthritis: in vitro and in vivo studies.
      ,
      • Lu C.
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      Scoparone prevents IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through the PI3K/Akt/NF-κB pathway.
      ,
      • Huang X.
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      • Mao Z.
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      • Ma X.
      • et al.
      Vanillic acid attenuates cartilage degeneration by regulating the MAPK and PI3K/AKT/NF-κB pathways.
      . The key downstream effectors, mTOR and NF-κB serve as master modulators responsible for initiation of autophagy and inflammation.
      In another way, activation of PI3K/AKT/mTOR signaling may be beneficial for patients with the disease. Activated PI3K/AKT/mTOR signaling has been found to promote chondrocyte proliferation and reduce apoptosis. Thus, development of some therapeutic approach to activate signaling for its protective aspect is a worthy pursuit. As expected, some agents, such as 17β-estradiol (E2), FGF18, and ghrelin, which have been correlated with PI3K/AKT activation have a potential protective effect against OA by increasing chondrocyte proliferation or reducing apoptosis
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      Fibroblast growth factor 18 exerts anti-osteoarthritic effects through PI3K-AKT signaling and mitochondrial fusion and fission.
      ,
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      • Ban M.
      • Guo L.
      • et al.
      Ghrelin protects against osteoarthritis through interplay with Akt and NF-κB signaling pathways.
      ,
      • Huang J.G.
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      • Yi T.T.
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      • Song G.
      • et al.
      17beta-Estradiol promotes cell proliferation in rat osteoarthritis model chondrocytes via PI3K/Akt pathway.
      . Furthermore, microRNAs play an essential role in modulating PI3K/AKT/mTOR signaling and its effects on OA development. Cai et.al. found miR-27a is a regulator of the PI3K-AKT-mTOR axis in human chondrocytes and participates in OA pathogenesis. Chondrocytes transfected with miR-27a inhibitor reduced IL-1β-induced apoptosis via upregulation of PI3K activity
      • Cai C.
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      MiR-27a promotes the autophagy and apoptosis of IL-1β treated-articular chondrocytes in osteoarthritis through PI3K/AKT/mTOR signaling.
      . Similarly, miR-218-5p, shown to target PIK3C2A mRNA, is a novel inducer of cartilage destruction. Its expression substantially affected expression of matrix synthesis genes, chondrocyte proliferation, and apoptosis. OA mice exposed to a miR-218-5p inhibitor were protected from cartilage degradation
      • Lu J.
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      • Zhang X.J.
      • Shi P.L.
      • Wu H.
      • Wang C.
      • et al.
      MicroRNA-218-5p as a potential target for the treatment of human osteoarthritis.
      . These evidences suggest microRNAs have potential as therapeutic targets in osteoarthritis. In addition, some molecules that affect PI3K/AKT/mTOR activity might also be considered as potential therapeutic targets. For example, peroxiredoxin 4 (PRDX4) overexpression could activate AKT, to reverse IL-1β-stimulated apoptosis mediated by increased BCL-2-associated X apoptosis regulator (BAX) levels and Caspase-3/9 activation
      • Rao Z.
      • Wang S.
      • Wang J.
      Peroxiredoxin 4 inhibits IL-1β-induced chondrocyte apoptosis via PI3K/AKT signaling.
      . Consistent with the effects of PRDX4, activated glucagon-like peptide-1 receptor exerts a similar influence on the PI3K/AKT axis and downstream cell apoptosis
      • Chen J.
      • Xie J.J.
      • Shi K.S.
      • Gu Y.T.
      • Wu C.C.
      • Xuan J.
      • et al.
      Glucagon-like peptide-1 receptor regulates endoplasmic reticulum stress-induced apoptosis and the associated inflammatory response in chondrocytes and the progression of osteoarthritis in rat.
      . Targeting these genes provide new insights and approaches to regulating the functions of PI3K/AKT/mTOR in OA development.
      As PI3K/AKT/mTOR signaling undertakes multiple functions in normal and abnormal cells, its effects are complex, making it difficult to verify the effects of this axis in OA in general, and there remain many prominent issues to be addressed. First, does activation or inhibition contribute most to OA pathogenesis, and which best protects against OA progression. In other words, the PI3K/AKT/mTOR axis, at least in part, mediates inflammation, autophagy, proliferation, apoptosis, ECM homeostasis, and other cell processes in chondrocytes. Which are the dominant ones? What are the cross talks among them? Cross talks between prominent cellular processes related to the PI3K/AKT/mTOR pathway can occur also in joint cells in a timely manner during the OA process. Thus, more detailed research into these cellular processes is needed to clarify their connection to PI3K/AKT/mTOR signaling. Moreover, its role in mammals varies from tissue to tissue, particularly for whole joints, which include cartilage, subchondral bone, and synovium. Hence, it is also important to target tissues precisely and correctly to achieve axis-mediated protective effects during OA treatment. As a consequence, it is not appropriate to simplistically link PI3K/AKT/mTOR to the disease, and develop modifying agents. The challenges we discussed above need to be solved (Fig. 3).
      Fig. 3
      Fig. 3Challenges of the PI3K/AKT/mTOR-based treatment for OA. The PI3K/AKT/mTOR signaling mediated synovial inflammation, subchondral bone sclerosis, ECM homeostasis, chondrocyte proliferation, apoptosis, autophagy, and inflammation greatly affect cell fate and OA pathophysiology. There will be an imbalance among these cell processes if simply activating or inhibiting PI3K/AKT/mTOR signaling. Thus, how this axis interacts with other signaling pathways, and how to target its function in OA without disrupting important physiological axis-regulated processes need to be clarfied.

      Conclusion

      As described in this review, PI3K/AKT/mTOR is a complex signaling pathway with multiple regulators and effectors. Most importantly, this signaling is essential for development of OA. Current research also provides evidence that targeting this axis may be a viable therapeutic approach. However, simply activating or inhibiting PI3K/AKT/mTOR signaling to protect against OA may be a double-edged sword, since side effects seem to be unavoidable with this approach. Therefore, in the near future, it is imperative to clarify the roles of PI3K/AKT/mTOR in OA during different pathophysiological stages, and elucidate more specific molecular mechanisms, such as how this axis interacts with other signaling pathways, and how to target its function in OA without disrupting important physiological axis-regulated processes. If these intractable points are addressed, PI3K/AKT/mTOR-based treatments for OA may become safe and effective.

      Authors' contributions

      Fengjing Guo worked on design and conception of this review. Kai Sun drafted the paper. Jiahui Luo, Jiachao Guo, Xudong Yao and Xingzhi Jing contributed to revise the paper. Fengjing Guo gave final approval of the version to be submitted.

      Conflict of interest

      The authors confirm that there are no conflicts of interest.

      Funding sources

      National Natural Science Foundation of China [no. 81874020].

      Acknowledgments

      This study was supported by the National Natural Science Foundation of China [no. 81874020].

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