Article
Calca signaling controls the osteoanabolic effect of intermittent PTH
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Published: | October 23, 2017 |
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Fragestellung: Osteoporosis represents a major public health problem as affected patients are at high risk for experiencing fractures. Although several pharmaceutical agents are clinically available to prevent further bone resorption, only intermittent injections of teriparatide, a recombinant fragment of parathyroid hormone (PTH), have proven efficient in stimulating bone formation and reversing bone loss. In the search for molecules modulating the anabolic response of teriparatide, calcitonin (CT) is of specific scientific and clinical interest, as it is regarded the natural counterpart of PTH. CT and its precursor procalcitonin (PCT) are encoded by the common gene Calca, whose deletion in mice results in a high turnover skeletal phenotype. Moreover, we recently demonstrated that calcitonin (CT) inhibits bone formation through the calcitonin receptor (CTR) expressed in osteoclasts, whereas PCT inhibits osteoclast differentiation and function independent of CTR.
Methodik: To study a potential role of PCT and CT signaling in the osteoanabolic action of intermittent PTH, we treated 12 week old female Calca- and CTR-deficient mice with daily injections of teriparatide intraperitoneally for 4 weeks. Littermate offspring receiving vehicle were used as controls. Using undecalcified spine sections, a full static, cellular and dynamic histomorphometric analysis was performed at the end of the study, in addition to serum analyses for the assessment of bone resorption markers. Biomechanical stability of the femora was determined by three point-bending assays. For in vitro experiments, primary osteoblasts were obtained from the calvariae of 5 days old wildtype mice and stimulated at day 10 of osteogenic differentiation with teriparatide for 6 hours, followed by expression analyses using qRT-PCR.
Ergebnisse und Schlussfolgerung: Our study shows that Calca signaling exerts a major impact on the skeletal effects of teriparatide. In vitro, teriparatide induced Calca expression in murine primary osteoblasts, suggesting local synthesis of PCT. In vivo, CTR-deficient mice lacking CT signaling displayed an augmentation of the PTH-induced increase in bone mass due to a striking increase in the bone formation rate whereas the number of osteoblasts was not affected. In contrast, Calca-deficient mice lacking CT and PCT signaling were characterized by a dramatic increase in osteoclast activity upon teriparatide administration which occurred despite a reduction in osteoclast numbers. Biomechanically, this translated into a maximum force until failure and stiffness in femora derived from treated CTR-deficient mice compared to all other groups studied. These results indicate that CT signaling limits the osteoanabolic potential of teriparatide, whereas PCT expression is required to inhibit its pro-resorptive effects. Taken together, our results demonstrate pivotal modulatory effects of Calca signaling on intermittent PTH which may be used pharmacologically to optimize the osteoanabolic action of teriparatide.