BMPs, TGFβ, and border security at the interzone

Synovial joints enable movement and protect the integrity of the articular cartilage. Joints form within skeletal condensations destined to undergo chondrogenesis. The suppression of this chondrogenic program in the interzone is the first morphological sign of joint formation. While we have a fairly good understanding of the essential roles of BMP and TGFβ family members in promoting chondrogenic differentiation in developing skeletal elements, we know very little about how BMP activity is suppressed specifically within the interzone, a crucial step in joint development. The function of the BMP ligand Gdf5 has been especially difficult to decipher. On the one hand, Gdf5 is required to promote chondrogenesis of articular elements. On the other hand, Gdf5 is highly expressed in the joint interzone where chondrogenesis must be suppressed for the formation of many joints. Here we review the evidence that BMP signaling must be suppressed within the joint interzone for joint morphogenesis to progress, and consider how Gdf5 exerts its divergent effects on chondrogenesis and joint formation. We also consider how TGFβ signaling impacts formation of the interzone. Finally, we propose a model whereby Gdf5 exerts distinct effects in the interzone vs. surrounding cartilage based on the repertoire of BMP receptors available in these tissues. Understanding how BMP antagonists and counteracting TGFβ signals intersect with Gdf5 to sculpt the joint interzone is essential for understanding the origin of osteoarthritis and other diseases of joint tissues.