Abstract
Mechanical unloading simultaneously induces muscle and bone loss, but its mechanisms are not fully understood. The interactions between skeletal muscle and bone have been recently noted. Although canonical wingless-related integration site (Wnt)/β-catenin signaling is crucial for bone metabolism, its roles in the muscle and bone interactions have remained unknown. Here, we performed comprehensive DNA microarray analyses to clarify humoral factors linking muscle to bone in response to mechanical unloading and hypergravity with 3 g in mice. We identified Dickkopf (Dkk) 2, a Wnt/β-catenin signaling inhibitor, as a gene whose expression was increased by hindlimb unloading (HU) and reduced by hypergravity in the soleus muscle of mice. HU significantly elevated serum Dkk2 levels and Dkk2 mRNA levels in the soleus muscle of mice whereas hypergravity significantly decreased those Dkk2 levels. In the simple regression analyses, serum Dkk2 levels were negatively and positively related to trabecular bone mineral density and mRNA levels of receptor activator of nuclear factor-kappa B ligand (RANKL) in the tibia of mice, respectively. Moreover, shear stress significantly suppressed Dkk2 mRNA levels in C2C12 cells, and cyclooxygenase inhibitors significantly antagonized the effects of shear stress on Dkk2 expression. On the other hand, Dkk2 suppressed the mRNA levels of osteogenic genes, alkaline phosphatase activity and mineralization, and it increased RANKL mRNA levels in mouse osteoblasts. In conclusion, we showed that muscle and serum Dkk2 levels are positively and negatively regulated during mechanical unloading and hypergravity in mice, respectively. An increase in Dkk2 expression in the skeletal muscle might contribute to disuse- and microgravity-induced bone and muscle loss.
Highlights
Sarcopenia is a pivotal disease concept linked to physical frailty and highly comorbid with osteoporosis in the elderly people worldwide [1]
The importance of wingless-related integration site (Wnt)/β-catenin signaling inhibitors, such as sclerostin, Dkks and secreted frizzled related proteins (Sfrps), in regulation of bone metabolism has been demonstrated by numerous studies in humans and genetically modified mice [5,7,8,9,10,11,12,13,14,18]
We showed that trabecular bone mineral density (BMD) was negatively related to serum Dkk2 levels and muscle Dkk2 expression in mice with and without mechanical unloading
Summary
Sarcopenia is a pivotal disease concept linked to physical frailty and highly comorbid with osteoporosis in the elderly people worldwide [1]. Mechanical stress and unloading simultaneously affect skeletal muscle and bone. Previous studies indicated that exercise, mechanical stress and unloading regulate the secretion of myokines affecting bone metabolism [1,2]. Exercise reduces the expression of myostatin, a negative regulator of muscle mass and bone metabolism, in the skeletal muscle in humans and mice [2]. Irisin is involved in mechanical unloading-induced trabecular bone loss of mice in our study [4]. These findings suggest that mechanical stress and gravity change influence muscle and bone metabolism through the humoral factors linking muscle to bone. What kinds of humoral factors linking muscle to bone regulated by mechanical stress are important have not been fully understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
