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Address correspondence and reprint requests to: Y. Jiang, Institute for Tissue Engineering and Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. Tel.: 852-39435153; fax: 852-26035123.
Institute for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, ChinaSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, ChinaDepartment of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
This year in review on osteoarthritis biology summarizes a series of research articles published between the 2020 and 2021 Osteoarthritis Research Society International (OARSI) World Congress. Research hightlights were selected and discussed based on the new discoveries of OA's cellular molecular mechanism, anatomical signatures, potential therapeutic targets, and regenerative therapy. The recently developed potential therapeutic targets are summarized, and the research focuses on TGFβ and WNT signaling in joint tissue homeostasis, joint aging and the dynamic of synolytics in OA joint, and the roles of TRP2, LDHA, OSCAR in cartilage homeostasis and OA joints are highlighted. Subsquencially, new anatomical structures and OA features are introduced, such as synovitis-induced venous portal circulation, horiozontal fissures between cartilage and subchondral bone, the cellular derivation of osteophytes formation, OA subtypes, and subchondral remodeling and pain biology. Then, research on the possibility of tissue regeneration in OA joints are discussed; skeletal stem cells in OA cartilage regeneration, and preclinical results of regenerative therapy for meniscus tear and osteochondral tissue morphoghesis are included. At last, the clinical evidence of the importance of delivery site of bone marrow stem cells for OA treatment is discussed. These findings represent advances in our understanding of OA pathophysiology.
The articles included in this year in review of OA biology were published between 2020 and 2021 Osteoarthritis Research Society International (OARSI) World Congress within the field of OA biology (April 2020–April 2021). Twenty two representative articles from PubMed search results were selected by personal opinion, covering the topics of (1) OA biology and pathology, (2) cellular and molecular signatures, (3) newly developed potential therapeutic targets, and (4) clinical research on regenerative therapy, and excluded publications on OA epidemiology and therapy, imaging, rehabilitation and outcomes, biomechanics, biomarkers, genetics, genomics, and epigenetics, which are covered by other sessions in the year in review series.
The updates during the year included new understanding of transforming growth factor β (TGFβ) and wingless-related integration site (WNT) signaling in OA; recent developed strategies and targets, such as senolytics; bone changes; and regenerative therapies. To assist readers in locating these new insights, recently identified OA biology research targets and examples of OA targeting strategies are listed in Table I.
Table IRecent OA biology research targets and OA targeting strategies
Mechanosensitive control of articular cartilage and subchondral bone homeostasis in mice requires osteocytic transforming growth factor beta signaling.
Effects of a single intra-articular injection of a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: a double-blinded, randomized, placebo-controlled, multinational study.
J Bone Joint Surg Am.2018; 100 (Epub 2018/04/18. PubMed PMID: 29664853; PubMed Central PMCID: PMCPMC5916484): 666-677https://doi.org/10.2106/JBJS.17.00154
Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial. Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip.
Effect of intra-articular sprifermin vs placebo on femorotibial joint cartilage thickness in patients with osteoarthritis: the FORWARD randomized clinical trial.
Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint.
Bisphosphonate use is protective of radiographic knee osteoarthritis progression among those with low disease severity and being non-overweight: data from the osteoarthritis initiative.
Key molecules and signaling in joint and cartilage homeostasis
TGFβ signaling
TGFβ signaling is essential for joint tissue development and maintaining cartilage homeostasis. Detailed knowledge regarding the key molecules of this pathway and their roles in OA has been obtained with the help of transgenic mice models to achieve tissue-specific, cell-specific, and time-specific regulation.
CC Wang et al. found that forkhead box class O1 (FOXO1) is a crucial mediator of the TGFβ/TGFβ-activated kinase 1 (TAK1) pathway in articular cartilage homeostasis
. The tissue-specific gain-of-function of FoxO1 in articular cartilage (with Agc1CreERT2; Rosa-FoxO1f/f mice) protects against OA development, as shown in both a meniscal ligament injury (MLI) model and a loss-of-TGFβ-induced OA model generated in TGFβR2 loss-of-function mice (Col2CreERT2; Tgfbr2f/f; Rosa-FoxO1f/f). Autophagy was found to be modulated by the TGFβ-FOXO1 axis via TAK1 signaling
(Fig. 1(A), panel a). Similarly, GL Wang et al. established a role for F-box protein 6 (FBXO6), a component of the ubiquitin E3 ligases, in cartilage homeostasis as a downstream component of the TGFβ-SMAD2/3 pathway, and reported that FBXO6 mediates MMP14 ubiquitination and promotes MMP14 proteasomal degradation
. In this study, the authors observed a decrease in FBXO6 expression in human OA samples, ACLT-surgically-induced OA mouse models, spontaneous OA STR/ort mice, and in aged mouse samples; either global knockout via FBXO6−/− transgenic, or conditional tissue-specific knockout of FBXO6 via a Col2a1-CreERT2;FBXO6f/f approach both demonstrated increased OA pathology in ACLT surgically induced OA mice at 8 weeks post-surgery. The FBXO6-MMP14 ubiquitination regulation axis was identified from profiling of FBXO6 docking proteins by immunoprecipitation from HEK293T cell, and compared with the significantly affected proteins in mouse FBXO6 knockout chondrocytes, then confirmed in ATDC5 cells and SW1353 cell line. The low level of pSMAD2/3-FBXO6 in OA chondrocytes was found in OA mice, STR/ort mice and SMAD2−/− mice, meanwhile TGFβ could enhance FBXO6 expression via pSMAD2/3 in ATDC5 cells, indicated a TGFβ-pSMAD2/3-FBXO6 axis in cartilage homeostasis. Then the authors asked if overexpression of FBXO6 could rescue OA phenotype in vivo. Intra-articular injection (I.A.) of lentiviral particles of FBXO6 after ACLT surgery lead to overexpression of FBXO6 in joint chondrocytes, and effectively alleviated the cartilage destruction and reducing the severity of synovial inflammation, and no significantly differenced was observed in the subchondral bone
Mechanosensitive control of articular cartilage and subchondral bone homeostasis in mice requires osteocytic transforming growth factor beta signaling.
TGFβ also plays an important role in how joints sense and react to mechanical loadings. There are updates in the field of mechanobiology concerning the regulation of TGFβ signaling (Fig. 1(A), panels c and d). Regionally high concentrations of TGFβ are usually found in the extracellular matrix (ECM) and tissues surrounding OA cartilage, such as in subchondral bone, and this can lead to OA progression. GH Zhen et al. reported that articular chondrocytes sense mechanical stress and TGFβ via αV integrin- and talin-centered cytoskeletal reorganization
. Moreover, knockout of αV integrin in chondrocytes with Col2a-CreERT;αVfl/fl (αV−/−) mice at 1 month after ACLT surgery results in insensitivity to TGFβ-mediated regulation, which reduces cartilage degeneration and prevents OA development
(Fig. 1(A), panel c). The importance of TGFβ signaling to mechanical sensitivity in subchondral bone is further supported by a study by KN Bailey et al., who depleted TGFβRII in osteocytes (Dmp1Cre-TgfbrIIfl/fl), which led to abnormality in subchondral bone and an OA phenotype in male TgfbrIIocy−/− mice but not in female TgfbrIIocy−/− mice
Mechanosensitive control of articular cartilage and subchondral bone homeostasis in mice requires osteocytic transforming growth factor beta signaling.
Mechanosensitive control of articular cartilage and subchondral bone homeostasis in mice requires osteocytic transforming growth factor beta signaling.
. Calcification of cartilage with basic calcium phosphate (BCP) crystals is commonly found in OA, and it links to chondrocyte hypertrophy and severity of OA. Wnt3a is one of the morphogens regulating hypertrophic cartilage formation, but how the signal is amplified and transduced in OA cartilage was unclear. In this study, the authors analyzed calcification and sulfation of extracellular matrix of the articular cartilage over a time course from 6 to 22 weeks in mice and different OA grades of human cartilage. They found that OA cartilage exhibited enhanced pericellular matrix sulfation (e.g., 6-O-sulfation), with Wnt3A co-localization with heparan sulfate proteoglycans. BCP crystals physically bind to Wnt3A; these Wnt3A molecules cluster and concentrate in pericellular areas, which enhances WNT signaling pathway activation and chondrocyte hypertrophy in OA cartilage
Another new WNT-signaling related therapeutic target for OA is receptor tyrosine kinase-like orphan receptor 2 (ROR2), a co-receptor of Wnt5A. ROR2 is essential for skeletal development, and mutations in the encoding gene cause severe skeletal dysplasia with short stature
. AS Thorup et al. found higher expression of ROR2 in OA cartilage; I.A. ROR2 blockade with 7 μl of 20μM ROR2-siRNA conjugated to 0.5% atelocollagen (ROR2i) could maintain cartilage integrity, and attenuate OA phenotype and pain in destabilization of the medial meniscus (DMM) and meniscal-ligament injury (MLI) mice models. Furthermore, the increase in chondrogenic differentiation induced by ROR2 blockade is likely mediated through yes-associated protein (YAP) (Fig. 1(B), panel b)
The transient receptor potential (TRP) channels are a group of ion channels involved in sensory reception. A clinical trial of TRP vanilloid 1 (TRPV1) inhibitor as a treatment option for chronic OA pain is currently in phase III (CNTX-4975-05, NCT03429049 at ClinicalTrials.gov). The role of another member in TRPV subfamily, TRPV2, in cartilage homeostasis and OA development, was newly investigated and reported by H Nakamoto et al.
. TRPV2 is a Ca2+ permeable channel for intracellular Ca2+ current in responsive to mechanical stimuli, and this TRPV2 channel is distributed in the middle to deep layers of human adult articular cartilage and osteophytic lesions in OA joints
. The role of TRPV2 in OA development was investigated by creating OA in mice by resection of the medial meniscus, and resection of the medial collateral ligament (MCL), and DMM models in Trpv2 cartilage specific knockout mice (Col2Cre-Trpv2fl/fl) and Trpv2fl/fl mice strain, and OA related phenotypes were evaluated at 8 weeks, 16 weeks, and 18 months after surgery. Trvp2 KO mice were found with advanced OA, enhanced articular cartilage degradation and periarticular ectopic ossification, and a lower expression of lubricin/Prg4. Mechanical stress–induced Ca2+ influx was abolished in chondrocytes isolated from Trvp2 KO mice, and the Ca2+ influx-TRPV2-Prg4 axis in chondrocytes were thus found in vitro. Meanwhile, from analysis the early development stage of the animals, enhanced chondrocyte hypertrophic differentiation was found in Trpv2 KO mice derived chondrocytes. Therefore, the protective role of TRPV2 in joint tissue may depend on its induction role of proteoglycan 4 (PRG4; Fig. 1(D))
Chondrocytes in OA joints are under inflammation stress, and their behavior is different from that of normal joints. M Arra et al. reported a metabolic shift that the metabolic profile of OA chondrocytes is more dependent on glycolysis and have higher lactate dehydrogenase A (LDHA). Tissue-specific knockout of LDHA in cartilage (MLI model; AggrecancreERT2, Ldhafl/fl) inhibits reactive oxygen species (ROS) generation via stabilization of IκB-ζ and attenuates OA development
, thus targeting LDHA-medicated ROS generation in OA chondrocytes may help to develop new therapies.
Another study aimed at regulating OA chondrocytes under inflammation was inspired by a known modulator of osteoclast differentiation, the osteoclast-associated receptor (OSCAR). Park DR et al., reported the role of OSCAR, a collagen-recognition and immunoglobulin-like activating receptor, in OA cartilage. Increased Oscar/OSCAR was found in mice and human OA articular chondrocytes, and Oscar−/- mice exhibit reduced OA pathogenesis. OSCAR blockade prevents OA chondrocyte apoptosis via the TNFα-related apoptosis-inducing ligand (TRAIL) pathway; moreover, the genetic depletion of OSCAR or using a fusion protein-mediated blockade of OSCAR (hOSCAR-FC, 2 mg/kg, I.A.), attenuates OA development in mice models
Senolytics are drugs that selectively clear senescent cells and were shown to have the capability of maintaining cartilage homeostasis in OA animals. HJ Faust et al. reported the systematic effects of senolytics in aged OA mice
[Fig. 1(C)]. A Th17-mediated immune response was observed in aged OA mice following local administration of senolytics in the joint and systematic administration of the senolytics UBX0101 (an inhibitor of the MDM2-p53 protein interaction) and Navitoclax, and the IL-17 immune signature was reduced in young and aged mice with post traumatic OA
. The senescent fibroblasts and chondrocytes in OA joints regulated the Th17 and Th1 T cells via TGFβ. Furthermore, in aged, damaged joints, an IL-17low and IL-4high environment was required for senolysis, indicating a special state of immune-mediated environment in joint, i.e., a joint immunosenescence state, or perhaps, a joint-aging clock
, and this state may be related to, or could predict the therapeutic efficacy of senolytics.
OA bone changes
Anatomy/pathology
New pathological findings in subchondral bone and crosstalk between OA subchondral bone and adjacent tissues have been reported. HJ Seeherman et al. reported synovitis-induced venous portal circulation connecting the synovium and subchondral bone in 21 arthritic joints of monkeys
[Fig. 2(A)]. Bone remodeling and synovitis occurred in response to the I.A. injection of bone morphogenetic protein 2 (BMP2)/calcium phosphate matrix (CPM). The diffusion of 125I-labeled BMP2 was blocked by the tidemark between cartilage and bone, however BMP2 and CPM crystals were observed in the subchondral bone area via the newly developed venous portal circulation
. Pdgfrα platelet-derived growth factor receptor A; Gdf5 growth differentiation factor 5; Prg4 proteoglycan 4, i.e., lubricin. This figure is created with BioRender with license to publish.
Another anatomic feature observed in obese OA patients is horizontal fissuring between the cartilage and subchondral bone [Fig. 2(B)], which is observed in a study aimed to investigate the correlation between obesity and early total knee arthroplasty (TKA)
. LZ Chen et al. reported this new histological property for obese OA patients based on the body mass index (BMI) and age information of 41,023 patients who underwent total knee joint replacement
. They found that in Australia, 57% of patients who underwent total knee replacement were obese. The correlation between BMI and age at which patients undergo TKA suggested that the overweight OA patients receive TKA at a younger age, which is 1.89, 4.48 and 8.08 years earlier in overweight groups than the normal weight group in the obese class I&II and class III categories (BMI for underweight and normal weight: <24.9 kg/m2; overweight: 25–29.9 kg/m2; obese class I&II: 30–39.9 kg/m2; obese class III: ≥40 kg/m2), respectively
. The increased BMI is associated with less articular cartilage degradation and increased osteoid formation and structure model index in subchondral bone, but total bone volume and bone mineralized density were decreased. Horizontal fissures with cartilage erosion at the osteochondral interface were found in 75% of patients in the obese class III category (n = 9 in 12), compared with 7.7% of patients in the normal weight group (n = 2 in 26). This pathological feature is likely unique in obese OA patients, and the author estimated that a unit of BMI (1 kg/m2) weight increase will increase the odds of horizontal fissures by 14.7%
The mechanism of osteophyte formation has been a scientific question in OA pathology. AJ Roelofs et al. reported interesting results regarding cell lineage tracing in osteophyte formation
[Fig. 2(C)]. It was revealed that osteophytes are derived not from articular chondrocytes nor skeletal stem cells (SSCs), but from Pdgfα+ stem/progenitor cells in the periosteum and synovium, and these cells are the descendants of Gdf5+ stem cells in the embryonic joint interzone during development. Osteophytes also express a group of Sox9-expression progenitors in the periosteum during early osteophyte formation. In addition, the osteophyte cartilage cap is generated from Prg4+ progenitor cells in the synovial lining, but not from the bone
[Fig. 2(C)]. These results offer significant insight into OA pathology.
OA subtypes
The identification of OA subtypes has long been a topic of discussion with respect to the selection of corresponding interventions for treatment responders. Researchers have grouped OA subtypes according to biomechanical, osteoporotic, metabolic, inflammatory, and genetic characteristics
. The gene expression signatures of cartilage, subchondral bone, and synovium were likely correlated to certain clinical phenotypes: (1) the glycosaminoglycan metabolic disorder group with high ACAN and low VCAN; (2) the collagen metabolic disorder group with higher expression of COL5A1, COL6A1, and TGFBI, which were associated with osteophyte formation; (3) the activated sensory neuron group comprised younger patients with a higher pain sensitivity and may have risk of earlier TKA; and (4) the high inflammation group was associated with narrow joint space, and anti-inflammatory agents were recommended as the primary treatment
. The mechanically supportive role played by subchondral bone, the metabolic regulation of joint homeostasis, nerve innervation and pain, are all important events related to subchondral bone during the middle and late stages of OA, and occur immediately after irreversible cartilage degeneration.
Updates regarding subchondral bone in OA include studies on the nerves and vascularization of subchondral bone, which provided some clues for the link between pain and subchondral bone in OA. Aso et al. reported the contributions of nerves within osteochondral channels in humans and rats and how treatment with a TrkA inhibitor could reduce OA pain
. Zhu et al. reported a potential subchondral bone-induced OA pain pathway that may be caused by osteoblast-derived prostaglandin E2 via EP4 in peripheral nerves and the Nav1.8 channel in dorsal root ganglia neurons
. Regulating subchondral bone remodeling in joints during the early stages of OA could delay disease development, and some bone-acting agents, such as estrogen, bisphosphonates
Bisphosphonate use is protective of radiographic knee osteoarthritis progression among those with low disease severity and being non-overweight: data from the osteoarthritis initiative.
, and strontium ranelate, have been reported to be beneficial for certain OA patients. Sun et al. reported that intermittent parathyroid hormone, an osteoporotic drug, reduced OA pain in mice by inhibiting subchondral sensory innervation, subchondral bone deterioration, and articular cartilage degeneration
Bisphosphonate use is protective of radiographic knee osteoarthritis progression among those with low disease severity and being non-overweight: data from the osteoarthritis initiative.
Regulation of tissue-resident stem cells and enhancement of tissue repair
In addition to anti-inflammatory drugs and pain control, researchers have explored the possibility of enhancing tissue repair and regeneration in osteoarthritic joints during the early stage of OA
. Studies on regenerative therapy have provided several clues. It is now gradually well accepted that adult articular cartilage has tissue-resident stem/progenitor cells which can be used in clinical applications
. The derivation of tissue resident stem cells in joints, and how to regulate their cell fate are important scientific questions that remain to be answered. Murphy MP et al. reported the articular cartilage regeneration ability of SSCs at different aged mice, and possible cellular contribution of SSCs for in situ cartilage formation
. To investigate the remained cell population of SSCs in aged joints, the authors created random colorimetric labeling of cells systemically in β actin-CreERT/Rainbow mice at different age of postnatal day 3 (newborn), 2 week (juvenile), 6 week (adult), and 1 year (old), and have found a dramatic reduced SSC number in chondral regions in adult mice (95.9% vs 57.6%, between newborn and adult mice). The authors then used a microfracture (MF) model to investigate the endogenous reparative ability of tissue resident SSCs at cartilage surface in the β actin-CreERT/Rainbow mice. EdU-labeled proliferating cells were found in the defected area, and the increase of SSCs in MF defect is likely due to local expansion, rather than recruitment, demonstrated by a GFP/non-GFP parabiont mice model. To observe the reparative capacity of SSCs in OA joints, MF were created in the DMM induced OA joints, and the tissue resident SSCs with higher clonality within the defect were observed after 1, 2, and 4 weeks of MF, but it resulted in fibrocartilage formation. The chondrogenesis differentiation ability and regenerative capacity of SSCs for articular cartilage can be enhanced by modifying the tissue-forming microenvironment, optimized and purified cellular donors, and adding corresponding combination of growth factors. Specifically, the differentiation of SSCs requires BMP2 and soluble vascular endothelial growth factor receptor 1 (sVEGFR1), and OA/MF mice treated with 20,000 mSSCs and BMP2 + sVEGFR1 achieved increased cartilage repair both in size and quality
. In general, this study revealed that aging mice retain reservoirs of SSCs, which could partially contribute to joint cartilage and bone regeneration in OA joints
. Again, the role of tissue resident stem cells in OA is still clear, and more research is needed to study how to regenerate damaged tissues in OA joints.
Beside the damage of articular cartilage, meniscal tears are also the main starting point of knee OA. Lee et al. analyzed RNA sequencing data from 37 human tissues and found that Mohawk (MKX), a transcription factor that regulates tendon differentiation during embryological development, is enriched in meniscus too. Enhancing MKX expression by adenoviral MKX (Ad-MKX) in together with TGFβ3 in mesenchymal stem cells (MSCs) could induce the phenotype of meniscus cells, and facilitate the formation of engineered meniscus tissue with decellularized bioactive scaffolds. Ad-MKX injection into mouse knee joints after DMM surgery suppressed meniscus and cartilage damage; Ad-MKX treatment promoted the healing of human OA meniscus explants and corrected pathogenic gene expression ex vivo, suggested MKX in meniscus may be a therapeutic target for OA prevention
Furthermore, SE Eldridge et al. reported that Argin, a signaling proteoglycan that can suppress WNT/β-catenin signaling, was found a role in inducing chondrogenesis and osteochondral tissue regeneration. The small molecule ARGIN attracts resident Gdf5+ progenitor cells in the joints to sites of injury, which was observed in Gdf5-Cre;Tom transgenic mice 8 weeks after osteochondral defects. More importantly, directly application of ARGIN in type I collagen gel in critical-size osteochondral defect (8-mm diameter and 5-mm deep) at joint weight-bearing region of sheep induces long-term osteochondral regeneration after 6 months
. These studies demonstrate the key factors and principles underlying the enhancement of tissue repair in OA joints.
Mesenchymal stem cells for OA treatment and the importance of the delivery site
MSCs are being actively investigated as a potential therapy for OA. Clinical trials are currently in phase I/II, and results indicate certain pain relief and functional improvement
Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint.
. However, the low survival rate of stem cells in inflammatory OA joints and the duration of the therapeutic effect are concerns. The application of stem cells as intervention for OA has been highlighted in two clinical studies conducted by P Hernigou et al.
Subchondral bone or intra-articular injection of bone marrow concentrate mesenchymal stem cells in bilateral knee osteoarthritis: what better postpone knee arthroplasty at fifteen years? A randomized study.
Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: a prospective randomized study versus contralateral arthroplasty at a mean fifteen year follow-up.
(Fig. 3). The first study compared the delivery sites of bone marrow-derived stem cells (BMSCs) in patients with OA. Patients with bilateral knee OA received a similar dose of BMSCs (approximately 1.1 × 105 cells/joint) either by I.A. injection or cell delivery directly to subchondral bone marrow lesions (BML) (n = 60 knees per group). Fifteen years later, 70% of knees in the I.A. injection group required TKA and whereas only 20% in the subchondral injection group required TKA
Subchondral bone or intra-articular injection of bone marrow concentrate mesenchymal stem cells in bilateral knee osteoarthritis: what better postpone knee arthroplasty at fifteen years? A randomized study.
. These results indicate the significance of the stem cell delivery site in treating OA - BMSCs delivered to the BML aid in the repair of injured subchondral bone, likely prevented further OA progression in these patients. The same research group reported another long-term follow-up clinical study of using BMSCs to treat 140 patients with late-stage OA
Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: a prospective randomized study versus contralateral arthroplasty at a mean fifteen year follow-up.
. All patients were eligible for TKA in both knees; one knee was injected with BMSCs (approximately 1.56 × 106 cells/joint) to the subchondral BML, and the other knee underwent regular TKA. Fifteen years later, the knee scores were similar across both groups (approximately 80), and the incidence of TKA was also similar (approximately 1%/person/year)
Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: a prospective randomized study versus contralateral arthroplasty at a mean fifteen year follow-up.
. These results suggest that following the delivery of cell therapy to the BML, only a few knees with OA required the first TKA after 15 years, viz. BML regeneration can possibly delay primary knee joint replacement in some patients with OA by more than 10 years. These two clinical studies not only provide new insights into stem cell-based therapies for OA but also address the significant role of subchondral bone in OA joints.
Fig. 3Stem cell-based therapy for OA subchondral bone
Subchondral bone or intra-articular injection of bone marrow concentrate mesenchymal stem cells in bilateral knee osteoarthritis: what better postpone knee arthroplasty at fifteen years? A randomized study.
Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: a prospective randomized study versus contralateral arthroplasty at a mean fifteen year follow-up.
. IA intra-articular injection; BML bone marrow lesion; BMSCs bone marrow-derived stem cells; TKA total knee arthroplasty. This figure is created with BioRender with license to publish.
The selected studies reviewed above, although limited to publication during 2020–2021, illustrate the landscape of emerging pathological mechanisms and therapeutic targets in OA and the diverse potential therapies for OA. Aging, body weight, and systemic and joint-localized states of immunosenescence represent new perspectives on OA, and the identification of OA subtypes and drug responders may help in determining the most effective treatments. Novel insights into senolytics and stem cell-based therapies have shed light on both drug development and clinical applications.
Author contributions
Yangzi Jiang drafted, edited, and approved the final version of the article to be published.
Conflict of interest
There are no direct or indirect financial or other conflicts of interest related to this work.
Role of the funding source
The funding bodies had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript.
Acknowledgments
I apologize to all colleagues whose work could not be included due to space limitations. I am grateful to be able to study and enjoy the nice work and articles during the challenging times of the COVID-19 pandemic and thank my PhD student Mr. Zhu Xiaobo for sharing articles.
This work is supported by (i) the National Key R&D Program of China (project number 2019YFA0111900), which is financed by the Ministry of Science and Technology of the People's Republic of China (MOST, China), and (ii) The Chinese University of Hong Kong.
Figs. 2 and 3 were created with BioRender with license to publish.
Mechanosensitive control of articular cartilage and subchondral bone homeostasis in mice requires osteocytic transforming growth factor beta signaling.
Effects of a single intra-articular injection of a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: a double-blinded, randomized, placebo-controlled, multinational study.
J Bone Joint Surg Am.2018; 100 (Epub 2018/04/18. PubMed PMID: 29664853; PubMed Central PMCID: PMCPMC5916484): 666-677https://doi.org/10.2106/JBJS.17.00154
Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial. Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip.
Effect of intra-articular sprifermin vs placebo on femorotibial joint cartilage thickness in patients with osteoarthritis: the FORWARD randomized clinical trial.
Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint.
Bisphosphonate use is protective of radiographic knee osteoarthritis progression among those with low disease severity and being non-overweight: data from the osteoarthritis initiative.
Subchondral bone or intra-articular injection of bone marrow concentrate mesenchymal stem cells in bilateral knee osteoarthritis: what better postpone knee arthroplasty at fifteen years? A randomized study.
Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: a prospective randomized study versus contralateral arthroplasty at a mean fifteen year follow-up.
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