BMP Receptor Signaling Is Required for Postnatal Maintenance of Articular Cartilage

Abstract

Articular cartilage plays an essential role in health and mobility, but is frequently damaged or lost in millions of people that develop arthritis. The molecular mechanisms that create and maintain this thin layer of cartilage that covers the surface of bones in joint regions are poorly understood, in part because tools to manipulate gene expression specifically in this tissue have not been available. Here we use regulatory information from the mouse Gdf5 gene (a bone morphogenetic protein [BMP] family member) to develop new mouse lines that can be used to either activate or inactivate genes specifically in developing joints. Expression of Cre recombinase from Gdf5 bacterial artificial chromosome clones leads to specific activation or inactivation of floxed target genes in developing joints, including early joint interzones, adult articular cartilage, and the joint capsule. We have used this system to test the role of BMP receptor signaling in joint development. Mice with null mutations in Bmpr1a are known to die early in embryogenesis with multiple defects. However, combining a floxed Bmpr1a allele with the Gdf5-Cre driver bypasses this embryonic lethality, and leads to birth and postnatal development of mice missing the Bmpr1a gene in articular regions. Most joints in the body form normally in the absence of Bmpr1a receptor function. However, articular cartilage within the joints gradually wears away in receptor-deficient mice after birth in a process resembling human osteoarthritis. Gdf5-Cre mice provide a general system that can be used to test the role of genes in articular regions. BMP receptor signaling is required not only for early development and creation of multiple tissues, but also for ongoing maintenance of articular cartilage after birth. Genetic variation in the strength of BMP receptor signaling may be an important risk factor in human osteoarthritis, and treatments that mimic or augment BMP receptor signaling should be investigated as a possible therapeutic strategy for maintaining the health of joint linings.

Mechanisms of digit formation: Human malformation syndromes tell the story

“…Inactivation of BmpR1a function in the joints by means of a GDF5 driven Cre recombinase resulted in a gradual erosion of joint cartilage, similar to human osteoarthritis. Thus, BMP receptor signaling is required not only for the formation of cartilage condensations and joints, but also for ongoing maintenance of articular cartilage after birth (Rountree et al, 2004).…”

Inverse relationship between matrix remodeling and lipid metabolism during osteoarthritis progression in the STR/ORT mouse

“…However, the molecular changes associated with OA in these tissues have only recently begun to be elucidated (for review, see refs. [3][4][5][6][7][8].…”

Lessons from musculoskeletal stem cell research: The key to successful regenerative medicine development

“…For example, synovial membrane MSCs show preferential cartilage formation in vitro when compared with bone marrow and periosteal-derived MSCs (78). Conversely, adult bone marrow MSCs appear to have osteogenesis as a default differentiation pathway (79)(80)(81)(82). Therefore, MSCs demonstrate variability in their chondrogenic and osteogenic potentials that could possibly be related to their original environments.…”

“…Interestingly, the synovial membrane and joint cartilage share a common embryonic derivation (82), which may, at least in part, explain the reported superior chondrogenesis of adult synovial MSCs. Therefore, establishing stem cell populations with consistent and reproducible biologic behaviors, quality-controlled for specific therapeutic applications, will likely require knowledge of this functional heterogeneity in their native environments in vivo (83,84).…”