Osteoarthritis (OA) affects over 200 million people worldwide including 27 million Americans, and it is estimated that the US spends $128 billion dollars each year on OA related health care (1, 2). Current therapies for OA focus on decreasing pain while improving joint movement (3). As none of these treatments can restore joint structures damaged by the progression of OA, joint replacement is often required, with more than 600,000 joint replacement surgeries performed yearly in the US (4). As such, strategies aimed at ameliorating OA represent a highly significant opportunity to contain health care costs while enhancing the quality of life for many Americans. The role of bone morphogenetic proteins (BMPs), in the pathogenesis of OA remains controversial despite many years of study. BMP activity is necessary for initiating chondrogenesis during skeletal development and is required for formation of synovial joints (5-11). BMP signaling is also involved in the maintenance of functional synovial joints after birth (12). Paradoxically, too much BMP activity is also associated with OA (18-20). In this proposal, we focus on BMP2 and examine its role in maintaining postnatal synovial joint function. Our decision to target BMP2 is based on the phenotype of mice lacking BMP2 expression in mesenchymal cells of the early limb (Prx1cre;21, 22). These mice lose normal skeletal function as they age, as evidenced by spontaneous fractures throughout the limb skeleton and an ability to initiate fracture repair (22-24) and the progressive development of OA of the knee, elbow, wrist and ankle by 28 weeks of age (Fig 1). The development of OA in BMP2Prx1Cre mice is analogous to disease progression in human OA where there is a long delay between the event that initiates the disease and the development of an arthritic joint. If loss of BMP2 does indeed precede the pathological joint changes seen in OA, maintaining BMP2 at normal physiological levels may be a means to slow or halt joint changes that characterize OA. However, Bmp2Prx1cre mice have a variety of developmental limb defects that may predispose synovial joints to develop OA (25, 26) and these confounding factors must be sorted out in order to determine the importance of changing levels of BMP2 signaling in articular cartilage in the pathogenesis of OA. We propose to directly assess the role of BMP2 in OA by tracking BMP2 expression and BMP signaling in adult synovial joints (Aim 1) and determining if loss of BMP2 specifically from articular cartilage leads to a progressive OA phenotype (Aim 2). To perform these experiments we combine the use of BMP2 reporter mice with BMP signaling reporter mice and mice that drive deletion of BMP2 in articular cartilage. We also employ two state-of-the-art technologies to assess OA progression: ultra high resolution micro CT that allows for submicron 3-dimensional examination of both mineralized and soft tissues (27, 28) and atomic force microscopy -based nanoindentation (AFM-N), a method that allows for the quantification of the local mechanical properties of irregularly shaped, small volume musculoskeletal tissues (29). These technologies allow us to obtain precise images and corresponding functional assessments of joint tissues in the transgenic mice we plan to study.
Diseases associated with aging have a tremendous impact on the health and well being of all US citizens. This is particularly true for osteoarthritis (OA), a disorder that affects 27 million Americans;and it is estimated that the US spends $128 billion dollars each year on OA related health care. Strategies aimed at ameliorating OA represent a highly significant opportunity to contain health care costs while enhancing the quality of life for many Americans;in this proposal, we focus on BMP2 and examine its role in maintaining joint function and postponing OA.
