EXPRESSION OF A TRUNCATED, KINASE-DEFECTIVE TGF-BETA TYPE-II RECEPTORIN MOUSE SKELETAL TISSUE PROMOTES TERMINAL CHONDROCYTE DIFFERENTIATION AND OSTEOARTHRITIS

Members of the TGF-beta superfamily are important regulators of skelet al development. TGF-beta s signal through heteromeric type I and type II receptor serine/threonine kinases. When over-expressed, a cytoplasm ically truncated type II receptor can compete with the endogenous rece ptors for complex formation, thereby acting as a dominant-negative mut ant (DNIIR). To determine the role of TGF-beta s in the development an d maintenance of the skeleton, we have generated transgenic mice (MT-D NIIR-4 and -27) that express the DNIIR in skeletal tissue. DNIIR mRNA expression was localized to the periosteum/perichondrium, synovium, an d articular cartilage. Lower levels of DNIIR mRNA were detected in gro wth plate cartilage. Transgenic mice frequently showed bifurcation of the xiphoid process and sternum. They also developed progressive skele tal degeneration, resulting by 4 to 8 mo of age in kyphoscoliosis and stiff and torqued joints. The histology of affected joints strongly re sembled human osteoarthritis. The articular surface was replaced by bo ne or hypertrophic cartilage as judged by the expression of type X col lagen, a marker of hypertrophic cartilage normally absent from articul ar cartilage. The synovium was hyperplastic, and cartilaginous metapla sia was observed in the joint space. We then tested the hypothesis tha t TGF-beta is required for normal differentiation of cartilage in vivo . By 4 and 8 wk of age, the level of type X collagen was increased in growth plate cartilage of transgenic mice relative to wild-type contro ls. Less proteoglycan staining was detected in the growth plate and ar ticular cartilage matrix of transgenic mice. Mice that express DNIIR i n skeletal tissue also demonstrated increased Indian hedgehog (IHH) ex pression. IHH is a secreted protein that is expressed in chondrocytes that are committed to becoming hypertrophic. It is thought to be invol ved in a feedback loop that signals through the periosteum/perichondri um to inhibit cartilage differentiation. The data suggest that TGF-bet a may be critical for multifaceted maintenance of synovial joints. Los s of responsiveness io TGF-beta promotes chondrocyte terminal differen tiation and results in development of degenerative joint disease resem bling osteoarthritis in humans.