gms | German Medical Science

Objectives: Osteoporosis is a common disease in elderly people causing fractures and significantly increases overall mortality in affected patients. Through the past demographic development, a high clinical demand arises for improved treatment strategies. Although several pharmaceutical agents are clinically available to prevent bone resorption, intermittent injections of parathyroid hormone (iPTH) represent the only approved treatment regimen to stimulate bone formation and revers bone loss. As continuous elevation of parathyroid hormone stimulates both bone formation and bone resorption, it remained unclear why iPTH predominantly results in an increased bone formation rate with only minor elevations in bone degradation. Here we show that excessive bone resorption during iPTH is retained through osteoblast-specific induction of Calca, the gene encoding calcitonin (CT), its precursor procalcitonin (PCT), as well as calcitonin gene-related peptide alpha (αCGRP).

Methods: PCT-deficient (Calca^-/-), Calcitonin receptor-deficient (Calcr^-/-) and αCGRP-deficient (Cgrp^-/-) mice received daily iPTH (PTH1-34, Teriparatide) injections. After four weeks, bone parameters of the lumbar vertebrae and femur were investigated by micro-CT and histological analyses. The expression of Calca derived peptides was evaluated in 12 different organs of iPTH-treated mice. To test the effect of PCT in vitro, osteoblasts and osteoclasts were cultured and treated with recombinant PCT or osteoblast-derived conditioned medium.

Results and conclusion: While the expected rise in bone formation is not affected during iPTH, PCT-deficient mice develop a striking phenotype of high bone-turnover with increased cortical porosity. In contrast, mice with inactivated CT or αCGRP signaling do not display elevated bone resorption following iPTH. In vitro, iPTH results in a temporary increase in PCT, but not CT or αCGRP expression in osteoblasts. In vivo, multi-tissue screening following iPTH reveals induction of PCT expression in bone, but not in other tissues studied. Mechanistically, PCT exerts an inhibitory effect on early osteoclast differentiation while not affecting osteoblast differentiation or function. In line with this, osteoblasts activated with iPTH inhibit osteoclast differentiation in a PCT-dependent manner. Taken together, our results suggest a pivotal role of osteoblast-derived PCT in controlling the therapeutic effect of iPTH.