Cortical bone adaptation to a moderate level of mechanical loading in male Sost deficient mice

Abstract

Loss-of-function mutations in the Sost gene lead to high bone mass phenotypes. Pharmacological inhibition of Sost/sclerostin provides a new drug strategy for treating osteoporosis. Questions remain as to how physical activity may affect bone mass under sclerostin inhibition and if that effect differs between males and females. We previously observed in female Sost knockout (KO) mice an enhanced cortical bone formation response to a moderate level of applied loading (900 με at the tibial midshaft). The purpose of the present study was to examine cortical bone adaptation to the same strain level applied to male Sost KO mice. Strain-matched in vivo compressive loading was applied to the tibiae of 10-, 26- and 52-week-old male Sost KO and littermate control (LC) mice. The effect of tibial loading on bone (re)modeling was measured by microCT, 3D time-lapse in vivo morphometry, 2D histomorphometry and gene expression analyses. As expected, Sost deficiency led to high cortical bone mass in 10- and 26-week-old male mice as a result of increased bone formation. However, the enhanced bone formation associated with Sost deficiency did not appear to diminish with skeletal maturation. An increase in bone resorption was observed with skeletal maturation in male LC and Sost KO mice. Two weeks of in vivo loading (900 με at the tibial midshaft) induced only a mild anabolic response in 10- and 26-week-old male mice, independent of Sost deficiency. A decrease in the Wnt inhibitor Dkk1 expression was observed 3 h after loading in 52-week-old Sost KO and LC mice, and an increase in Lef1 expression was observed 8 h after loading in 10-week-old Sost KO mice. The current results suggest that long-term inhibition of sclerostin in male mice does not influence the adaptive response of cortical bone to moderate levels of loading. In contrast with our previous strain-matched study in females showing enhanced bone responses with Sost ablation, these results in males indicate that the influence of Sost deficiency on the cortical bone formation response to a moderate level of loading differs between males and females. Clinical studies examining antibodies to inhibit sclerostin may need to consider that the efficacy of additional physical activity regimens may be sex dependent.

Differential Expression of Dickkopf 1 and Periostin in Mouse Strains with High and Low Bone Mass

“…This experimental study evaluating mice during bone growth showed that the expression of SOST evaluated in the cortical compartment was significantly lower in the high bone mass strain at eight weeks of age. These results concur with the physiological function of SOST and the increased bone formation of 10-week-old SOST-deficient mice [24].…”

Spatial variations in the osteocyte lacuno-canalicular network density and analysis of the connectomic parameters

“…In our study, we chose to examine skeletally mature, 26-week-old female C57BL/6J mice, since previous research has shown a more pronounced mechanoresponse in female C57BL/6 mice compared to males [ 39 , 40 ]. In addition, the reduced aggressive behaviour of female mice results in a lower background of physical activity, which makes detection of the bone’s mechanoresponse to in vivo loading much easier [ 41 ].…”

Testicular Immunity and Its Connection with the Microbiota. Physiological and Clinical Implications in the Light of Personalized Medicine

“…Despite the detection of the testicular microbiota, its role in the testis is still debated. According to a recent report, testicular microbiota seems to expand IL-17, producing gamma-delta T cells during puberty, promoting gonadal immune surveillance [ 80 ]. It is noteworthy that current research in this specific field has been focused on the link between gut microbiota and testicular microbiota.…”