gms | German Medical Science

Objectives: Despite extensive research effort, osteoporosis still represents the most common bone disease worldwide with limited treatment options. In this regard, daily injections of teriparatide (iPTH), an active fragment of parathyroid hormone, represent one of the few pharmaceutical options to stimulate bone formation by osteoblasts. Interestingly, iPTH injections are not accompanied by increased bone resorption, contrary to patients with hyperparathyroidism, who display excessive osteoclast activation. Recently, we reported that iPTH induces the expression of procalcitonin (ProCT) in osteoblasts. Likewise, we observed that mice lacking ProCT develop increased bone resorption during iPTH treatment. Therefore, the aim of the study was to unravel the molecular mechanism, through which osteoblast-derived ProCT affects bone resorption during iPTH injections.

Methods: WT and ProCT-deficient mice (Calca^-/-) received daily teriparatide injections (iPTH). After four weeks, the cell composition of bone and bone marrow was analyzed histologically and through flow cytometry. In vitro, primary murine osteoblasts, osteoclasts and macrophages were stimulated with recombinant ProCT. The effect of ProCT on macrophage migration and osteoclastogenesis were evaluated by scratch- and transwell assays, genome wide expression arrays and qRT-PCR. All experiments were approved by the animal protection authorities.

Results and Conclusion: The increased cortical and calvarial porosity induced by iPTH in ProCT-deficient mice was caused by increased osteoclast numbers and osteoclast activity, indicating that ProCT inhibits osteoclastogenesis. This observation was confirmed in bone marrow cells in vitro, where conditioned medium of PTH-stimulated osteoblasts inhibited early osteoclast differentiation. Using genome-wide expression analysis, we identified ProCT to regulate the expression of specific target genes in macrophages, which function as osteoclast precursors. Among others, the respective genes included biglycan, fibronectin and lysyl oxidase, all of which were previously shown to regulate macrophage migration. Accordingly, ProCT arrested macrophage migration in scratch- and transwell assays, and inhibited Rankl-induced transformation of macrophages into osteoclasts. As assessed by flow cytometry and immunohistochemistry in vivo, iPTH resulted in increased macrophage numbers in the bone marrow of ProCT-deficient mice, which was blunted by concomitant ProCT-treatment. In summary, our results demonstrate an essential role of osteoblast-derived ProCT in regulating macrophage migration, which limits bone resorption during iPTH.