Mesenchymal Stem Cells Based Therapy for Osteoarthritis: Modulating Osteoinduction via Wnt Signaling Pathway
Introduction: Osteoarthritis (OA) is a whole joint disease, involving structural alterations in the hyaline articular cartilage, subchondral bone, ligaments, capsule, synovium, and periarticular muscles. It is the leading cause of pain and disability in adults. The hallmarks of OA include joint space narrowing, osteophyte formation, subchondral sclerosis, and cysts. Currently, 32.5 million American adults are diagnosed with OA. There is no cure for OA and treatment is mainly supportive. At the cellular level, joint health is maintained by mesenchymal stem cells (MSCs) which reside in the synovial space and subchondral bone. MSCs are capable of differentiation into cartilage-forming chondrocytes, bone-forming osteoblasts, or adipocytes. Methods: Subchondral bone tissue from knee OA patients were collected and divided based on severity. Changes in the number of osteocytes were detected via hematoxylin and eosin (H&E). Immunohistochemical staining, and reverse‐transcription quantitative PCR (RT‐qPCR) were used for the measurement of Dkk3 and β‐catenin transcription and protein levels. Tibial plateaus were obtained from OA patients and RT‐qPCR was used for the detection of Dkk2 transcription. Human chondrocytes (HAC) were treated with TGFβ and Dkk3. Male Sprague-Dawley rats underwent surgery to induce an OA-like condition; one week post-surgery the rats were given intra articular SM04690 or XAV-939 injection.[2,5] Results: H&E staining revealed osteoblast and osteoclast number increased with the progression of OA. Immunohistochemistry assay demonstrated increased β‐catenin levels in osteocytes when comparing mild to moderate OA severity, whereas Dkk3 expression decreased. Interestingly, Dkk2 expression was markedly increased in osteoblasts. Expression of the tissue inhibitor of metalloproteinase-3, was dose-dependently enhanced in HAC when treated with TGFβ and Dkk3. Wnt inhibitor SM04690 promoted aggregation of hMSCs and inhibited the expression of catabolic enzymes and genes associated with osteoblast differentiation. Inhibition of Wnt with XAV-939 probably caused a reduction in levels of synovial fibroblasts in OA joints, but results were not statistically significant. Conclusion: It is proposed that OA is governed by an important paradox: high β-catenin levels (from excessive Wnt signaling) trigger osteogenesis and osteophyte formation (in the place of chondrocytes) but over-compensating inhibition (by Dkk2) causes inflammation. Inhibiting inflammatory cytokine and enhancing TGFβ signaling through Dkk3 has shown to counteract disease-associated progression of OA. Furthermore, both SM04690 and XAV-939 relieved OA through controlling cartilage degeneration and MMP production. Future work should aim to define the mechanisms and consequences of Wnt inhibition in OA with a view to developing therapeutics that maintain appropriate levels of chondrogenic signaling in the joint.
- Abramoff B, Caldera FE. Osteoarthritis: Pathology, Diagnosis, and Treatment Options. Med Clin North Am. 2020;104(2):293-311. doi:10.1016/j.mcna.2019.10.007
- Lietman C, Wu B, Lechner S, et al. Inhibition of Wnt/β-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis. JCI Insight. 2018;3(3):e96308. Published 2018 Feb 8. doi:10.1172/jci.insight.96308
- Liang X, Jin Q, Yang X, Jiang W. Dickkopf‑3 and β‑catenin play opposite roles in the Wnt/β‑catenin pathway during the abnormal subchondral bone formation of human knee osteoarthritis. Int J Mol Med. 2022;49(4):48. doi:10.3892/ijmm.2022.5103
- Snelling SJ, Davidson RK, Swingler TE, et al. Dickkopf-3 is upregulated in osteoarthritis and has a chondroprotective role. Osteoarthritis Cartilage. 2016;24(5):883-891. doi:10.1016/j.joca.2015.11.021
- Deshmukh V, Hu H, Barroga C, et al. A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee. Osteoarthritis Cartilage. 2018;26(1):18-27. doi:10.1016/j.joca.2017.08.015
- Chan TF, Couchourel D, Abed E, Delalandre A, Duval N, Lajeunesse D. Elevated Dickkopf-2 levels contribute to the abnormal phenotype of human osteoarthritic osteoblasts. J Bone Miner Res. 2011;26(7):1399-1410. doi:10.1002/jbmr.358