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

SummaryDespite its clinical significance, the mechanisms of joint morphogenesis are elusive. By combining laser-capture microdissection for RNA sampling with microarrays, we show that the setting in which joint-forming interzone cells develop is distinct from adjacent growth plate chondrocytes and is characterized by downregulation of chemokines, such as monocyte-chemoattractant protein-5 (MCP-5). Using in vivo, ex vivo, and in vitro approaches, we show 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, show upregulation of interzone-MCP-5. In vivo and ex vivo blockade of the sole MCP-5 receptor, CCR2, led to the rescue of joint formation and growth plate maturation in Tgfbr2Prx1KO but an acceleration of growth plate mineralization in control mice. Our study characterized the TβRII/MCP-5 axis as an essential crossroad for joint development and endochondral growth.Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon belowHelp with MP4 filesOptionsDownload video (69989 K)

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (381 K)Download as PowerPoint slideHighlights► MCP-5 is downregulated in joint interzone cells compared to adjacent chondrocytes ► MCP-5 low expression in interzone is needed for joint and growth plate development ► TGF-β signaling in limbs is needed to establish a low MCP-5 interzone expression ► MCP-5 expression in chondrocytes contributes to growth plate development