John Schmidt

Introduction. Osteoarthritis (OA) is a chronic degenerative joint disease that causes pain, decreased range of motion, osteophyte formation, and aberrant bone remodeling in over 27 million adults in the United States alone^1,2. Numerous interacting growth factors and inflammatory cytokines modulate the various pathways that lead to chondrocyte hypertrophy or dysregulation and eventual chondrocyte loss with subsequent cartilage degeneration². Moderate limitations, such as limited availability, donor site morbidity, and increased risk of disease transmission, accompany the currently available treatments, so an alternative treatment capable of regeneration would be impactful clinically³. Studies have shown mesenchymal stem cells (MSCs) to possess chondrogenic and inflammatory modulation capacity^3-6. These characteristics make MSCs a viable subject for use in new regenerative treatments targeting OA. Methods. Adipose-derived mesenchymal stem cells (AD-MSCs) from infrapatellar Hoffa fat, subcutaneous (SC) hip fat, and SC abdominal fat were cocultured in Transwells with chondrocytes or synoviocytes. Inflammatory factor levels were evaluated by quantitative reverse transcription–polymerase chain reaction or multiplex bead–based immunoassay⁴. Attachment of dual-labelled SF-MSCs was assessed in the synovial fluid (SF) of OA patients. SF was digested with hyaluronidase (hyase) and its effect on adhesion was observed using confocal microscopy⁵. MSCs collected from used bone marrow collection sets were seeded into hyaluronic acid-substituted-by-tyramine (HA-TA) scaffolds and introduced into a standard chondrogenic medium (SCM) culture, a BMP6-enhanced SCM medium culture, in vivo rat models, and in vitro cultures⁶. Results. AD-MSCs were found to down-regulate key pro-inflammatory factors that contribute to OA pathology, the most notable being IL‐1β, IL‐6, and CXCL8/IL‐8⁴. Hyaluronic acid is directly involved in MSC adhesion inhibition⁵. The HA-TA scaffold serves as a sufficient environment for MSC chondrogenesis⁶. BMP6-enhanced SCM is a more potent chondrogenic inducer than the SCM medium⁶. Conclusions. Studies have found that the HA present in the synovial fluid of joints inhibits the adhesion of MSCs and thus warrants the creation of delivery scaffolds that facilitate MSC binding and chondrogenesis. The HA-TA scaffold may be a successful example of one such scaffold. MSCs have also been shown to treat OA by reducing inflammation that contributes to OA’s pathogenesis.

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3. Chang YH, Liu HW, Wu KC, et al. Mesenchymal stem cells and their clinical applications in osteoarthritis. Cell Transplantation. 2016;25(5):937–950.
4. Manferdini C, Maumus M, Gabusi E, et al. Adipose-derived mesenchymal stem cells exert antiinflammatory effects on chondrocytes and synoviocytes from osteoarthritis patients through prostaglandin E2. Arthritis Rheumatol. 2013;65(5):1271–1281.
5. Baboolal TG, Mastbergen SC, Jones E, et al. Synovial fluid hyaluronan mediates MSC attachment to cartilage, a potential novel mechanism contributing to cartilage repair in osteoarthritis using knee joint distraction. Ann Rheum Dis. 2016;75(5): 908– 915.
6. Dvořáková J, Kučera L, Kučera J, et al. Chondrogenic differentiation of mesenchymal stem cells in a hydrogel system based on an enzymatically crosslinked tyramine derivative of hyaluronan. J Biomed Mater Res A. 2014;102(10): 3523–3530.