Summary
Objective
Osteoarthritis (OA) is a serious consequence of focal osteochondral defects. Gene
transfer of human transforming growth factor beta (hTGF-β) with recombinant adeno-associated
virus (rAAV) vectors offers a strategy to improve osteochondral repair. However, the
long-term in vivo effects of such rAAV-mediated TGF-β overexpression including its potential benefits
on OA development remain unknown.
Method
Focal osteochondral defects in minipig knees received rAAV-lacZ (control) or rAAV-hTGF-β in vivo. After one year, osteochondral repair and perifocal OA were visualized using validated
macroscopic scoring, ultra-high-field MRI at 9.4 T, and micro-CT. A quantitative estimation
of the cellular densities and a validated semi-quantitative scoring of histological
and immunohistological parameters completed the analysis of microarchitectural parameters.
Results
Direct rAAV-hTGF-β application induced and maintained significantly improved defect
filling and safranin O staining intensity and overall cartilage repair at one year
in vivo. In addition, rAAV-hTGF-β led to significantly higher chondrocyte densities within
the cartilaginous repair tissue without affecting chondrocyte hypertrophy and minimized
subarticular trabecular separation. Of note, rAAV-hTGF-β significantly improved the
adjacent cartilage structure and chondrocyte density and reduced overall perifocal
OA development after one year in vivo.
Conclusions
rAAV-hTGF-β treatment improves long-term osteochondral repair and delays the progression
of perifocal OA in a translational model. These findings have considerable potential
for targeted molecular approaches to treat focal osteochondral defects.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Osteoarthritis and CartilageAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- High rate of osteoarthritis after osteochondritis dissecans fragment excision compared with surgical restoration at a mean 16-year follow-up.Am J Sports Med. 2017; 45: 1799-1805
- Chondral lesions of the knee: an evidence-based approach.J Bone Jt Surg Am. 2021; 103: 629-645
- Surgical therapy in osteoarthritis.Osteoarthr Cartil. 2022; 30: 1019-1034
- TGF-Β family signaling in mesenchymal differentiation.Cold Spring Harb Perspect Biol. 2018; 10: a022202
- Transforming growth factor-β induces type II collagen and aggrecan expression via activation of extracellular signal-regulated kinase 1/2 and Smad2/3 signaling pathways.Mol Med Rep. 2015; 12: 5573-5579
- Articular cartilage repair: are the intrinsic biological constraints undermining this process insuperable?.Osteoarthr Cartil. 1999; 7: 15-28
- Cell origin and differentiation in the repair of full-thickness defects of articular cartilage.J Bone Jt Surg Am. 1993; 75: 532-553
- Definition of a critical size osteochondral knee defect and its negative effect on the surrounding articular cartilage in the rat.Osteoarthr Cartil. 2017; 25: 1531-1540
- Brief report: partial- and full-thickness focal cartilage defects contribute equally to development of new cartilage damage in knee osteoarthritis: the multicenter osteoarthritis study.Arthritis Rheumatol. 2017; 69: 560-564
- Biomaterial-guided delivery of gene vectors for targeted articular cartilage repair.Nat Rev Rheumatol. 2019; 15: 18-29
- Gene therapy returns to centre stage.Nature. 2015; 526: 351-360
- Effects of TGF-β overexpression via rAAV gene transfer on the early repair processes in an osteochondral defect model in minipigs.Am J Sports Med. 2018; 46: 1987-1996
- Effect of transforming growth factor β1 on chondrogenic differentiation of cultured equine mesenchymal stem cells.Am J Vet Res. 2000; 61: 1003-1010
- Differential role of transforming growth factor-β in an osteoarthritic or a healthy joint.J Bone Metab. 2018; 25: 65-72
- Sustained spatiotemporal release of TGF-β1 confers enhanced very early chondrogenic differentiation during osteochondral repair in specific topographic patterns.FASEB J. 2018; : 5298-5311
- Influence of insulin-like growth factor I overexpression via recombinant adeno-associated vector gene transfer upon the biological activities and differentiation potential of human bone marrow-derived mesenchymal stem cells.Stem Cell Res Ther. 2014; 5: 1-12
- Overexpression of human IGF-I via direct rAAV-mediated gene transfer improves the early repair of articular cartilage defects in vivo.Gene Ther. 2014; 21: 811-819
- Determination of the chondrogenic differentiation processes in human bone marrow-derived mesenchymal stem cells genetically modified to overexpress transforming growth factor-β via recombinant adeno-associated viral vectors.Hum Gene Ther. 2014; 25: 1050-1060
- rAAV-mediated overexpression of TGF-beta stably restructures human osteoarthritic articular cartilage in situ.J Transl Med. 2013; 11: 211
- Transforming growth factor-beta 1 stimulates articular chondrocyte proteoglycan synthesis and induces osteophyte formation in the murine knee joint.Lab Investig. 1994; 71: 279-290
- Differential effects of local application of BMP-2 or TGF-beta 1 on both articular cartilage composition and osteophyte formation.Osteoarthr Cartil. 1998; 6: 306-317
- Crucial role of synovial lining macrophages in the promotion of transforming growth factor beta-mediated osteophyte formation.Arthritis Rheumatol. 2004; 50: 103-111
- Overexpression of active TGF-β1 in the murine knee joint: evidence for synovial-layer-dependent chondro-osteophyte formation.Osteoarthr Cartil. 2001; 9: 128-136
- Adverse effects of adenovirus-mediated gene transfer of human transforming growth factor beta 1 into rabbit knees.Arthritis Res Ther. 2003; 5: R132-R139
- Reduction of sample size requirements by bilateral versus unilateral research designs in animal models for cartilage tissue engineering.Tissue Eng Part C Methods. 2013; 19: 885-891
- Direct rAAV SOX9 administration for durable articular cartilage repair with delayed terminal differentiation and hypertrophy in vivo.J Mol Med. 2013; 91: 625-636
- Experimental scoring systems for macroscopic articular cartilage repair correlate with the MOCART score assessed by a high-field MRI at 9.4 T – comparative evaluation of five macroscopic scoring systems in a large animal cartilage defect model.Osteoarthr Cartil. 2012; 20: 1046-1055
- Topographic modeling of early human osteoarthritis in sheep.Sci Transl Med. 2019; 11eaax6775
- 2D and 3D MOCART scoring systems assessed by 9.4 T high-field MRI correlate with elementary and complex histological scoring systems in a translational model of osteochondral repair.Osteoarthr Cartil. 2014; 22: 1386-1395
- Magnetic resonance observation of cartilage repair tissue (MOCART) for the evaluation of autologous chondrocyte transplantation: determination of interobserver variability and correlation to clinical outcome after 2 years.Eur J Radiol. 2006; 57: 16-23
- The effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) on the healing of full-thickness defects of articular cartilage.J Bone Jt Surg Am. 1997; 79: 1452-1463
- Parathyroid hormone [1-34] improves articular cartilage surface architecture and integration and subchondral bone reconstitution in osteochondral defects in vivo.Osteoarthr Cartil. 2013; 21: 614-624
- The OARSI histopathology initiative – recommendations for histological assessments of osteoarthritis in sheep and goats.Osteoarthr Cartil. 2010; 18: 80-92
- The role of growth factors in cartilage repair.Clin Orthop Relat Res. 2011; 469: 2706-2715
- Recent advances in TGF-β effects on chondrocyte metabolism. Potential therapeutic roles of TGF-β in cartilage disorders.Cytokine Growth Factor Rev. 2002; 13: 241-257
- Overexpression of TGF-beta1 enhances chondrogenic differentiation and proliferation of human synovium-derived stem cells.Biochem Biophys Res Commun. 2014; 450: 1593-1599
- Transforming growth factor-beta in stem cells and tissue homeostasis.Bone Res. 2018; 6: 2
- TGF-β1 promoted chondrocyte proliferation by regulating Sp1 through MSC-exosomes derived miR-135b.Cell Cycle. 2018; 17: 2756-2765
- TGF-beta1 does not induce senescence of multipotent mesenchymal stromal cells and has similar effects in early and late passages.PLoS One. 2013; 8e77656
- TGF-Β family signaling in the control of cell proliferation and survival.Cold Spring Harb Perspect Biol. 2017; 9: a022145
- Histological analysis of cartilage defects repaired with an autologous human stem cell construct 48 Weeks postimplantation reveals structural details not detected by T2-mapping MRI.Cartilage. 2021; 13: 694S-706S
- A polarized light microscopy method for accurate and reliable grading of collagen organization in cartilage repair.Osteoarthr Cartil. 2011; 19: 126-135
- Long-term stable expression of human growth hormone by rAAV promotes myocardial protection post-myocardial infarction.J Mol Cell Cardiol. 2007; 42: 390-399
- Improved tissue repair in articular cartilage defects in vivo by rAAV-mediated overexpression of human fibroblast growth factor 2.Mol Ther. 2005; 12: 229-238
- Articular cartilage degradation in osteoarthritis.HSS J. 2012; 8: 7-9
- Differential temporal expression of members of the transforming growth factor β superfamily during murine fracture healing.J Bone Miner Res. 2002; 17: 513-520
- TGF-β1-induced migration of bone mesenchymal stem cells couples bone resorption with formation.Nat Med. 2009; 15: 757-765
- Targeting TGF-β signaling in subchondral bone and articular cartilage homeostasis.Trends Pharmacol Sci. 2014; 35: 227-236
- Osteoarthritis.Lancet. 2019; 393: 1745-1759
- Inhibition of transforming growth factor-β in osteoarthritis. Discrepancy with reduced TGFβ signaling in normal joints.Osteoarthr Cartil Open. 2022; 4100238https://doi.org/10.1016/j.ocarto.2022.100238
- TGF-beta and osteoarthritis.Osteoarthr Cartil. 2007; 15: 597-604
- Protection from interleukin 1 induced destruction of articular cartilage by transforming growth factor β: studies in anatomically intact cartilage in vitro and in vivo.Ann Rheum Dis. 1993; 52: 185-191
Kolon TissueGene I. A randomized, double-blind, placebo-controlled, multi-center, phase 3 study to determine the efficacy of TG-C in subjects with Kellgren and Lawrence Grade (KLG) 2 or 3 osteoarthritis of the knee; 2022. NCT number: NCT03291470. Date accessed: 04.03.22.
- Imaging in osteoarthritis.Osteoarthr Cartil. 2022 Jul; 30 (Epub 2021 Sep 22): 913-934https://doi.org/10.1016/j.joca.2021.04.018
- Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis.Osteoarthr Cartil. 2015; 23: 1639-1653
- Potential predictive value of axial T2 mapping at 3 Tesla MRI in patients with untreated patellar cartilage defects over a mean follow-up of four years.Osteoarthr Cartil. 2020; 28: 215-222
- Mechanical stress determines the configuration of TGFbeta activation in articular cartilage.Nat Commun. 2021; 12: 1706
- Transforming growth factor-beta in calcium alginate beads for the treatment of articular cartilage defects in the rabbit.Arthroscopy. 2002; 18: 892-900
- Gene therapy for human osteoarthritis: principles and clinical translation.Expert Opin Biol Ther. 2016; 16: 331-346
- Gene therapy approaches to regenerating the musculoskeletal system.Nat Rev Rheumatol. 2015; 11: 234-242
- Anatomically shaped tissue-engineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing.Proc Natl Acad Sci U S A. 2016; 113: E4513-E4522
Article info
Publication history
Published online: December 05, 2022
Accepted:
November 3,
2022
Received:
May 8,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.
