gms | German Medical Science

Objectives: Calcitonin (CT) regulates bone remodeling by binding to the Calcitonin receptor (CTR), which is highly expressed in osteoclasts and functions as an essential regulator of bone formation. However, the role of CT-CTR cascades in osteoarthritis (OA) remains controversial. A number of studies suggested a beneficial effect of exogenous CT on OA progression, including the inhibition of abnormal subchondral bone turnover and reduction of cartilage degeneration. However, two phase 3 trails reported that oral salmon CT did not provide reproducible clinical benefits in patients with symptomatic knee OA. Furthermore, none of the experimental studies reported to date used genetic modified mouse model to demonstrate a direct effect of CT-CTR signaling on OA development. Therefore, in this study we subjected mice lacking CTR globally to experimental, post-traumatic OA (ptOA) to test a potential role of the CTR in OA progression.

Methods: Female WT and CTR-deficient mice were subjected to anterior cruciate ligament transection (ACLT) of the right knee at the age of 12 weeks to induce ptOA. Radiological and histological analyses of the bilateral knees were carried out at 4 weeks (early stage) and 8 weeks (late stage) post-operatively. Gene expression of CTR was measured in ACLT- and sham-operated knees of 12-week-old female WT mice 2, 4, and 8 weeks after ACLT using qRT-PCR.

Results and conclusion: Compared to sham-operated knees, the expression of CTR was significantly induced throughout ptOA progression in ACLT-operated knees. Immunofluorescence of knees of WT mice confirmed a pronounced expression of CTR in the articular cartilage and subchondral bone. Histological analyses revealed no significant changes in the OARSI score between CTR-deficient and WT mice 4 and 8 weeks after surgery. Likewise, the ratio of hyaline and calcified cartilage (HC/CC) was decreased to the same extent in WT and CTR-deficient mice. µCT scanning demonstrated that CTR-deficient mice displayed the same degree of subchondral trabecular bone loss as WT controls. Interestingly however, osteoclast parameters were significantly increased in the subchondral bone of WT ptOA knees, while it remained unchanged in mice lacking CTR. Finally, in CTR-deficient mice significantly less pronounced formation of tibial osteophytes was observed at both post-operative time points analysed. Taken together, our data suggest that CTR moderately affects ptOA progression of the murine knee. While CTR-deficiency does not impact cartilage degeneration and subchondral bone loss following ACLT, osteophyte formation is significantly reduced. Further studies are warranted to delineate the mechanistic function of CTR signalling in the formation of these exostoses, which represent a hallmark pathologic feature of OA.