Introduction:​ Diverging bone phenotypes have been described in spondylarthritis. Both pathogenic new bone formation and bone loss are observed which may be explained by pleiotropic effects of IL-17A. Studies in mice have yielded contradictory results regarding the effect of IL-17A signaling in osteoclasts and osteoblasts. As IL-17A signals through a receptor composed of IL-17RA and IL-17RC chains, we sought to elucidate the bone phenotypes caused by IL-17A-mediated inflammation in mice with cell-type specific conditional deletion of the Il17rc gene.

Methods:​ Il17rcf/f mice were crossed with Cathepsin K-cre (Ctsk-cre) and Prx1-cre driver mice to abrogate IL-17A signaling in osteoclasts and mesenchymal cells, respectively. Baseline studies were conducted in 12-week-old male and female Il17rcf/f, Il17rcf/f.Ctsk-cre and Il17rcf/f.Prx1-cre mice. A second cohort of female mice underwent ovariectomy (OVX) or sham surgery at 12 weeks of age with analysis 8 weeks post OVX. A third cohort of male mice was hydrodynamically injected with IL-23 minicircles at 8 weeks of age. Animals were weighed weekly and analyzed after 4 weeks. For each cohort, cortical and trabecular bone parameters were measured by micro-CT. Serum was harvested for analysis of CTX-1, P1NP and IL-17A by ELISA. In a separate experiment, osteoclast precursors in the bone marrow were quantified by flow cytometry 2 weeks after OVX.

Results:​ There were no baseline differences in trabecular or cortical bone parameters, CTX-1, P1NP, or IL-17A serum concentrations between Il17rcf/f, Il17rcf/f.Ctsk-cre and Il17rcf/f.Prx1-cre mice. In contrast, OVX-induced bone loss was partially abrogated in Ctsk-cre mice (Figure 1), without significant differences in IL-17A, CTX-1 or P1NP serum concentrations between genotypes. The frequency of osteoclast precursors decreased after OVX compared with sham, without significant differences between Il17rcf/f and Il17rcf/f.Ctk-cre mice. Significant trabecular bone loss was observed in response to IL-23 minicircle injection. However, there were no significant differences in bone parameters between Il17rcf/f, Il17rcf/f.Ctsk-cre and Il17rcf/f.Prx1-cre mice overexpressing IL-23.

Conclusions:​ Mice with conditional deletion of Il17rc in osteoclasts or mesenchymal cells, respectively, had phenotypically normal bones at baseline. Il17rc deletion in osteoclasts (Ctsk-cre mice) partially abrogated the bone loss induced by OVX. In contrast, bone loss due to IL-23 overexpression appeared to be independent of IL-17A signaling in osteoclasts or osteoblasts.