Abstract
Transmembrane and coiled-coil domains 1 (TMCO1) is a recently identified Ca2+ leak channel in the endoplasmic reticulum. TMCO1 dysfunction in humans is associated with dysmorphism, mental retardation, glaucoma and the occurrence of cancer. Here we show an essential role of TMCO1 in osteogenesis mediated by local Ca2+/CaMKII signaling in osteoblasts. TMCO1 levels were significantly decreased in bone from both osteoporosis patients and bone-loss mouse models. Tmco1−/− mice exhibited loss of bone mass and altered microarchitecture characteristic of osteoporosis. In the absence of TMCO1, decreased HDAC4 phosphorylation resulted in nuclear enrichment of HADC4, which leads to deacetylation and degradation of RUNX2, the master regulator of osteogenesis. We further demonstrate that TMCO1-mediated Ca2+ leak provides local Ca2+ signals to activate the CaMKII-HDAC4-RUNX2 signaling axis. The establishment of TMCO1 as a pivotal player in osteogenesis uncovers a novel potential therapeutic target for ameliorating osteoporosis.
Highlights
Transmembrane and coiled-coil domains 1 (TMCO1) is a recently identified Ca2+ leak channel in the endoplasmic reticulum
The results showed that decreased TMCO1 protein levels were accompanied by reduced osteoblast function in these model mice (Fig. 1c, d; Supplementary Fig. 1a, b)
The results showed that TMCO1 expression in Col1a-positive osteoblasts after unloading and OVX was much lower than that of control, while there was no difference in OSCAR-positive osteoclasts (Supplementary Fig. 1c–f)
Summary
Transmembrane and coiled-coil domains 1 (TMCO1) is a recently identified Ca2+ leak channel in the endoplasmic reticulum. We show an essential role of TMCO1 in osteogenesis mediated by local Ca2+/CaMKII signaling in osteoblasts. Ca2+ homeostasis in the ER is important for the intracellular Ca2+ signaling and is involved in the regulation of a variety of cellular processes, such as proliferation, differentiation, and programmed cell death, in bone cells[14,15]. We further demonstrated that loss of TMCO1 in osteoblasts disrupted ER Ca2+ homeostasis and promoted CaMKII-HDAC4 axis-mediated RUNX2 degradation in a local Ca2+ signaling-dependent manner. These results define the critical functions of TMCO1 in osteoblasts and highlight the importance of Ca2+ signaling in RUNX2 protein stability regulation, which suggests a key role for TMCO1 in the pathophysiological process that leads to reduced bone formation in osteoporosis
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