The Roles of Androgen Receptor in Cartilage Damage and Repair

Osteoarthritis (OA) is the most common joint disorder and a leading cause of disability. While surgery provides some alternative treatments, there is yet no cure to delay and/or limit OA development and progression, and this is an urgent medical need. Progressive degeneration of articular cartilage is a major characteristic of the disease. Age, gender and joint injury are among the primary risk factors for OA development. Chondrocyte, the only cell type residing in the cartilage matrix, regulates the homeostatic balance between matrix synthesis and degradation, which fails in OA. Thus, one approach to rationally designed new OA therapies is to improve chondrocyte function by targeting pathogenesis of the disease. We recently discovered that androgen receptor (AR) activity is constitutively present in normal articular chondrocytes, but is gradually decreased with aging process. Global androgen receptor knockout (ARKO) mice in which AR gene has been inactivated in all tissues, has developed accelerated aging process, and among all phenotypes, an early stage of OA-like phenotypes was observed. At 6 month old, global ARKO mice displayed the cartilage superficial erosion, intermediate nucleus duplication, and a sign of infiltration in the meniscus from knee joints. At 11 months, increased severity of OA changes were seen in global ARKO mice radiographs in which the knee-joint space is barely seen, being filled with bony outgrowth (osteophytes). Mechanistically, we found that AR epigenetically activates IGF-1, Twist1 and HDAC4 gene expression via specifically suppressing the Histone 3 Lysine 27 (H3K27) tri-methylation and promotes chondrocyte cell growth. Building on these findings, we propose to test our central hypotheses that androgen/AR activity in chondrocytes is critical to articular cartilage homeostasis and that AR is a potential interventional target to delay and/or limit the onset and progression of OA. We specifically aim to: (1) Test the hypothesis that selective loss of AR activity in chondrocytes promotes OA development and progression in mice in vivo. (2) Define how AR-mediated gene activation is chondroprotective in vitro at the molecular and epigenetic level. (3) Test the translational hypothesis that therapeutic implantation of AR-activated chondroprogenitor cells delays and/or limits the development and progression of OA in mice. Completion of these studies will provide new insights into how androgen/AR-mediated epigenetic changes in chondrocyte affects cartilage homeostasis, and aid to develop a new therapeutic approach by targeting at AR to suppress the development and progression of OA.

Project ID:PC10601-0032
External Project ID:MOST104-2320-B182-013-MY3