TGF-β Type II Receptor/MCP-5 Axis: At the Crossroad between Joint and Growth Plate Development

Abstract

Despite its clinical significance, the mechanisms of joint morphogenesis are still elusive. Here, we show by combining laser-capture microdissection for RNA sampling with microarray analysis, that the setting in which joint-forming interzone cells develop is distinct from adjacent growth plate chondrocytes and is characterized by down-regulation of chemokines, such as monocyte-chemoattractant protein-5 (MCP-5). Using in-vivo, ex-vivo and in-vitro approaches, we showed that low levels of interzone-MCP-5 are essential for joint formation and contribute to proper growth plate organization. Mice lacking the TGF-β-type-II-receptor (TβRII) in their limbs (Tgfbr2Prx1KO), which lack joint development and fail chondrocyte hypertrophy, showed up-regulation of interzone-MCP-5. In-vivo and ex-vivo blockade of the sole MCP-5 receptor, CCR2, in Tgfbr2Prx1KO led to rescue of joint formation and growth plate maturation; while in control mice determined an acceleration of endochondral growth plate mineralization. Taken together, we characterized the TβRII/MCP-5 axis as an essential crossroad for joint development and endochondral growth