gms | German Medical Science

Objectives: Despite significant advances in surgical techniques, treatment options for impaired bone healing are still limited. Specifically, up to 15% of patients with fractures suffer from impaired healing, including delayed- and non-unions. This is not only associated with pain, prolonged immobilization and often multiple revision surgeries, but also with high socioeconomic costs. Hence, there is an urgent demand for novel therapeutic options, whose development requires a deep understanding of the bone healing process. In this regard, we previously showed that mice lacking the calcitonin receptor (CTR), a G-protein coupled surface receptor specifically expressed in osteoclasts, display increased bone formation by osteoblasts. This is explained by an inhibitory effect of CTR on osteoclastic secretion of sphingosine-1-phosphate (S1P), a bone-anabolic substance promoting osteoblast function. Although strong evidence is now available for the crucial role of osteoclast-to-osteoblast coupling in normal bone hemostasis, the relevance of this paracrine crosstalk during bone regeneration is unknown to date. Therefore, our study was designed to test whether increased osteoclast-to-osteoblast coupling, as observed in CTR-deficient mice, may positively affect fracture repair.

Methods: Female 12-14 weeks old wild-type (WT) and CTR-deficient mice were used according to the German Animal Welfare Act. All experiments were approved by the animal protection authorities. A standardized femoral osteotomy with external fixation was induced. Fracture healing was analyzed radiologically (μCT) and histomorphometrically 7, 14, 21 days post-surgery, representing the inflammation, the soft callus and the remodeling phase of bone regeneration.

Results and Conclusion: Compared to WT controls, CTR-deficient mice displayed no alteration in radiologic callus parameters including total bone volume and tissue volume at any time point, as assessed by µCT. Likewise, static histomorphometry of cyro-embedded femur sections demonstrated normal callus microstructure in CTR-deficient mice. Furthermore, no differences in the osseous bridging of fracture ends were noted between WT and CTR-deficient mice. In conclusion, bone regeneration is not accelerated in CTR-deficient mice, despite their increased bone mass and enhanced osteoblast function in intact bone. Contrary its osteoanabolic action in normal bone turnover, our data thus suggests that osteoclast-to-osteoblast coupling, specifically involving the CTR-S1P axis, maybe a different relevance during bone regeneration.