LAUSR

The ion channel TRPM7 mediates Ca2+ fluctuations in growth plate chondrocytes that are needed for proper bone growth. Ca2+ fluctuations promote growth plate chondrogenesis In the growth plates of long bones, ordered arrays of chondrocytes proliferate, mature, secrete cartilage matrix, and then undergo apoptosis. The cartilage matrix is subsequently replaced with trabecular bone. Because Ca2+ signaling is implicated in chondrogenesis in vitro, Qian et al. performed Ca2+ imaging of live chondrocytes in slices of embryonic mouse femurs. Growth plate chondrocytes generated spontaneous Ca2+ fluctuations that depended on the cation channel TRPM7. Experiments in bone slices and in cultured metatarsal bones in which Trpm7 was conditionally knocked out indicated that Trpm7-mediated Ca2+ fluctuations were required for the proper development of chondrocytes and bone outgrowth. Furthermore, chondrocyte-specific knockout of Trpm7 in mice caused defects in chondrocyte Ca2+ fluctuations, growth plate morphology, and bone outgrowth. During endochondral ossification of long bones, the proliferation and differentiation of chondrocytes cause them to be arranged into layered structures constituting the epiphyseal growth plate, where they secrete the cartilage matrix that is subsequently converted into trabecular bone. Ca2+ signaling has been implicated in chondrogenesis in vitro. Through fluorometric imaging of bone slices from embryonic mice, we demonstrated that live growth plate chondrocytes generated small, cell-autonomous Ca2+ fluctuations that were associated with weak and intermittent Ca2+ influx. Several genes encoding Ca2+-permeable channels were expressed in growth plate chondrocytes, but only pharmacological inhibitors of transient receptor potential cation channel subfamily M member 7 (TRPM7) reduced the spontaneous Ca2+ fluctuations. The TRPM7-mediated Ca2+ influx was likely activated downstream of basal phospholipase C activity and was potentiated upon cell hyperpolarization induced by big-conductance Ca2+-dependent K+ channels. Bones from embryos in which Trpm7 was conditionally knocked out during ex vivo culture exhibited reduced outgrowth and displayed histological abnormalities accompanied by insufficient autophosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the growth plate. The link between TRPM7-mediated Ca2+ fluctuations and CaMKII-dependent chondrogenesis was further supported by experiments with chondrocyte-specific Trpm7 knockout mice. Thus, growth plate chondrocytes generate spontaneous, TRPM7-mediated Ca2+ fluctuations that promote self-maturation and bone development.