Abstract
Intermittent injections of parathyroid hormone (iPTH) are applied clinically to stimulate bone formation by osteoblasts, although continuous elevation of parathyroid hormone (PTH) primarily results in increased bone resorption. Here, we identified Calca, encoding the sepsis biomarker procalcitonin (ProCT), as a novel target gene of PTH in murine osteoblasts that inhibits osteoclast formation. During iPTH treatment, mice lacking ProCT develop increased bone resorption with excessive osteoclast formation in both the long bones and axial skeleton. Mechanistically, ProCT inhibits the expression of key mediators involved in the recruitment of macrophages, representing osteoclast precursors. Accordingly, ProCT arrests macrophage migration and causes inhibition of early but not late osteoclastogenesis. In conclusion, our results reveal a potential role of osteoblast-derived ProCT in the bone microenvironment that is required to limit bone resorption during iPTH.
Highlights
Bone is a highly dynamic tissue that is remodeled throughout the lifespan
ProCT does not affect osteoblast differentiation or function Collectively, these data showed that calcitonin receptor (CTR) limits the anabolic response to injections of parathyroid hormone (iPTH), whereas αCGRP is irrelevant for its therapeutic effect. This observation is in line with our previous findings, where we demonstrated that CTR exhibits an S1P-dependent, inhibitory effect on the bone formation rate through its expression in osteoclasts.[25]
While no alterations in circulating 1,25-dihydroxyvitamin D levels were detected, mice lacking Calca and Calcr displayed elevated serum concentrations of fibroblast growth factor 23 (FGF23) under baseline conditions, which normalized 2 h after teriparatide injection. As these observations did not explain the bone resorption phenotype in iPTH-treated mice lacking Calca, we investigated whether ProCT exerts a direct effect on osteoblast differentiation and function in vitro
Summary
Bone is a highly dynamic tissue that is remodeled throughout the lifespan. Bone turnover includes the degradation of old or damaged bone and the formation of new bone, which is carried out by two highly specialized cell types — osteoclasts and osteoblasts, respectively.[1,2] Osteoblasts differentiate from mesenchymal stem cells, whereas osteoclasts form through the recruitment and fusion of macrophages.[2]. The BV/TV in spine and tibia sections was significantly been treated with iPTH (daily injection of teriparatide) for 4 weeks, increased by iPTH treatment in mice of all genotypes, as indicated no effects were observed in the thyroid gland, lung, liver, spleen or separately (Fig. 2b, d; blue P values) To understand these observations at the cellular level, we expression in skeletal tissues, including the calvaria, femur, and analyzed osteoblast parameters and bone formation in lumbar spine (Fig. 1d). While no alterations in circulating 1,25-dihydroxyvitamin D levels were detected, mice lacking Calca and Calcr displayed elevated serum concentrations of fibroblast growth factor 23 (FGF23) under baseline conditions, which normalized 2 h after teriparatide injection As these observations did not explain the bone resorption phenotype in iPTH-treated mice lacking Calca, we investigated whether ProCT exerts a direct effect on osteoblast differentiation and function in vitro. A comparable lack of impact on osteoblast differentiation was observed in Calca-deficient osteoblasts, which did not exhibit a cell-autonomous defect and showed unchanged (Oc.S/BS)/%
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