Jerry Liu

Background: Osteoarthritis is the most prevalent chronic joint disease³, and is a leading cause of disability in older adults.¹ OA involves the entire joint and works by causing articular cartilage loss.³ Pain, along with loss of range of motion, are both major symptoms of osteoarthritis.^1,2 First-line treatment involves non-pharmacological methods, followed by NSAIDs and intra-articular corticosteroids, and finally joint replacement surgery.¹ Although there is currently no cure², research is being done on mesenchymal stem cells (MSCs) as they can help repair cartilage loss in OA.⁴ The chondrogenic capability of these MSCs can be altered by the wingless/integrated (WNT) and bone morphogenic protein (BMP) pathways.⁵ Careful modulation of these pathways on MSCs have the potential to help create a cure for OA.

Objective: In this review, we explored how modulation of both the WNT and BMP pathways effect chondrogenesis in MSCs, and how these cells can be used for treatment in osteoarthritis.

Search Method: An online search was conducted on PubMed ranging from 2019-2023 using the following search terms: “Osteoarthritis”, “mesenchymal stem cells”, “WNT signaling pathway”, “BMP signaling pathway”, “Chondrogenesis”.

Results: The WNT pathway can be modified in a few different ways. First, bromoindirubin-3-oxin (BIO) activates canonical WNT pathway by blocking GSK-3β.⁶ In addition, it downregulates typical cartilage markers such as SOX9, COL2A1, and ACAN.⁶ In comparison PKF118-310 (PKF) has the opposite effect, inhibiting the WNT pathway and upregulating cartilage markers.⁶ In addition, WNT5A is a noncanonical protein in the WNT pathway, and inhibits chondrocyte differentiation and increases proliferation.⁷ miR-92a-3p targets WNT5A, decreasing its production.⁷ OA mice treated with miR-92a-3p have been found to have decreased WNT5A levels, inhibiting OA cartilage loss.⁷ The BMP pathway can also be modified in a few different ways. BMP-3 is an unusual BMP as it is antagonistic towards osteogenic BMPs while increasing cartilage formation.⁸ It was found that MSVs treated with recombinant adeno-associated virus (rAAV) vectors containing rAAV-hBMP-3 increased expression of BMP-3 and typical cartilage markers such as SOX9 and COL2A1.⁸ BMP-2 can be used to stimulate chondrogenic differentiation of MSCs.⁹ Fluvastatin, an HMG-CoA reductase inhibitor, increased BMP-2 levels in human adipose-derived MSCs.⁹ Clinical studies have been done on MSC injections in OA mice models.¹⁰ It was found that a single injection would help reduce cartilage loss, and that weekly injections could essentially preserve it.¹⁰ Additionally, injected MSCs showed increased levels of PRG-4, BMP-2, and BMP-6, all of which play roles in chondrogenic differentiation and cartilage maintenance.¹⁰ Preliminary results in human patients with OA knees have shown increased cartilage thickness after injection.¹⁰

Conclusion: Literature has shown that MSC injection can improve pain and increase cartilage volume. Additionally, high levels of expression of the WNT and BMP pathways increase osteogenesis in MSCs, however no WNT signaling and low levels of BMP signaling can push MSCs towards chondrogenesis. Modulation of these pathways in regards to injected MSCs have strong potential to create a cure for OA.

Works Cited:

1. Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019;393(10182):1745-1759. doi:10.1016/S0140-6736(19)30417-9
2. 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
3. O’Neill TW, Felson DT. Mechanisms of Osteoarthritis (OA) Pain. Curr Osteoporos Rep. 2018;16(5):611-616. doi:10.1007/s11914-018-0477-1
4. van den Bosch MHJ. Osteoarthritis year in review 2020: biology. Osteoarthritis Cartilage. 2021;29(2):143-150. doi:10.1016/j.joca.2020.10.006
5. Majidinia M, Sadeghpour A, Yousefi B. The roles of signaling pathways in bone repair and regeneration. J Cell Physiol. 2018;233(4):2937-2948. doi:10.1002/jcp.26042
6. Huang X, Zhong L, Hendriks J, Post JN, Karperien M. The Effects of the WNT-Signaling Modulators BIO and PKF118-310 on the Chondrogenic Differentiation of Human Mesenchymal Stem Cells. Int J Mol Sci. 2018;19(2):561. Published 2018 Feb 13. doi:10.3390/ijms19020561
7. Mao G, Zhang Z, Hu S, et al. Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A. Stem Cell Res Ther. 2018;9(1):247. Published 2018 Sep 26. doi:10.1186/s13287-018-1004-0
8. Venkatesan JK, Schmitt G, Speicher-Mentges S, Orth P, Madry H, Cucchiarini M. Effects of Recombinant Adeno-Associated Virus-Mediated Overexpression of Bone Morphogenetic Protein 3 on the Chondrogenic Fate of Human Bone Marrow-Derived Mesenchymal Stromal Cells. Hum Gene Ther. 2022;33(17-18):950-958. doi:10.1089/hum.2022.004
9. Kuwahara M, Akasaki Y, Goto N, et al. Fluvastatin promotes chondrogenic differentiation of adipose-derived mesenchymal stem cells by inducing bone morphogenetic protein 2. BMC Pharmacol Toxicol. 2022;23(1):61. Published 2022 Aug 9. doi:10.1186/s40360-022-00600-7
10. Sekiya I, Katano H, Ozeki N. Characteristics of MSCs in Synovial Fluid and Mode of Action of Intra-Articular Injections of Synovial MSCs in Knee Osteoarthritis. Int J Mol Sci. 2021;22(6):2838. Published 2021 Mar 11. doi:10.3390/ijms22062838