Qian Chen
Scientific Tracks Abstracts: Rheumatology & Orthopedics
M utations in cartilage extracellular matrix (ECM) protein matrilin-3 (MATN3) cause several forms of chondrodysplasia and osteoarthritis (OA). Although the mice deficient in the functional MATN3 gene undergo relatively normal skeletal development, they exhibit higher incidences of OA1. Therefore, normal MATN3 prevents OA pathogenesis in vivo. However, it is not known how MATN3 confers its chondroprotective properties. We discovered recently that treatment of chondrocytes with recombinant human matrilin-3 (rhMATN3) protein stimulates gene expression of major cartilage ECM components including COL2A1 and ACAN and inhibits gene expression of major matrix proteases such as MMP-13 and ADAMTS-5. Since these critical molecules in cartilage homeostasis are also regulated by IL-1 beta, we are testing whether regulation of these target molecules by MATN3 is dependent on its ability to stimulate interleukin-1 receptor antagonist (IL-1Ra), a potent inhibitor of IL-1 beta. We show that MATN3 stimulates the expression and release of a potent inhibitor of the IL-1 pathway, IL-1Ra. Furthermore MATN3 regulation of ADAMTS-5, COL2A1, and ACAN is IL-1Ra dependent whereas its regulation of MMP-13 is not. This reveals that there are at least two pathways that confer chondroprotective properties of MATN3. The first is mediated by IL-1Ra, which accounts for MATN3 regulation of ADAMTS-5, COL2A1, and ACAN. The second pathway is responsible for MATN3 regulation of MMP-13 gene expression, which is IL-1Ra independent. Elucidation and understanding these pathways may help in developing chondroprotective therapy to counter cartilage degeneration in OA
Dr. Qian Chen received PhD degree in cell, molecular, and developmental biology from Tufts University School of Medicine in Boston, and performed post-doctoral fellowship at Harvard Medical School and Massachusetts General Hospital. He is the Michael G. Ehrlich, MD Endowed Chair in Orthopaedic Research, Professor of Medical Science, and Vice Chair for Research in the Department of Orthopaedics at the Warren Alpert Medical School of Brown University. He is the director of the NIH Center of Biomedical Research Excellence in Skeletal Health and Repair in Rhode Island Hospital. Dr. Chen?s research interest includes cartilage molecular biology, mechanotransduction, and osteoarthritis
