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

Haisheng Yang,Catherine Julien,Tobias Thiele,Michaela Kneissel,Georg N Duda,Christine Figge,Ina Kramer,Bettina M Willie,Laia Albiol,Sara Checa,Alexander Büttner

doi:10.1038/s41598-020-79098-0

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.

Highlights

Loss-of-function mutations in the Sost gene lead to high bone mass phenotypes
We recently showed female Sost knockout (KO) mice had a significantly greater load-induced cortical and trabecular bone formation response compared to female littermate control (LC) m ice[10,11]
In vivo loading was applied to the tibiae of young and older male Sost KO and LC mice to engender a gauge strain of ~ 900 με at the midshaft, the same target strain as our previous female loading s tudy[10]

Summary

Introduction

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. We have previously shown a net gain in trabecular bone volume fracture and trabecular thickness could be achieved with loading in Sost KO adult female mice, due to reduced resorption, which was not the case in males[11] It is unknown how Wnt signaling is affected during loading under Sost inhibition in male mice, since all of the aforementioned studies were performed in females and our single study in males did not examine gene-level changes in the trabecular bone. We observed that the cortical bone formation response to loading was reduced at maturation in both female LC and Sost KO mice coincident with agedependent expression of Wnt target genes in female Sost KO and LC mice as well as Sost gene expression in LC mice[10] It remains unclear if male Sost KO and LC mice have age-related changes in mechanoresponse similar to what has been reported in female wild-type m ice[30,31,32,33]. This knowledge is especially relevant considering that men suffer from age-related bone loss and have fragility fractures and would benefit from sclerostin inhibition[34]

Objectives

Results

Conclusion