Abstract
Disrupted Wnt signaling in osteoblastic-lineage cells leads to bone formation defect in osteoporosis. However, the factors repressing Wnt signaling are unclear. In our study, we found that Wnt signaling was suppressed persistently in bone marrow-derived mesenchymal stem cells (BMSCs) during osteoporosis. Accordingly, histone acetylation levels on Wnt genes (Wnt1, Wnt6, Wnt10a, and Wnt10b) were declined in BMSCs from OVX mice. By screening the family of histone acetyltransferase, we identified that GCN5 expression increased during osteogenic differentiation of BMSCs, whereas decreased after osteoporosis. Further analysis revealed that GCN5 promoted osteogenic differentiation of BMSCs by increasing acetylation on histone 3 lysine 9 loci on the promoters of Wnt genes. Reduced GCN5 expression suppressed Wnt signaling, resulting in osteogenic defect of BMSCs from OVX mice. Moreover, restoring GCN5 levels recovered BMSC osteogenic differentiation, and attenuated bone loss in OVX mice. Taken together, our study demonstrated that disrupted histone acetylation modification in BMSCs lead to bone formation defect during osteoporosis. The findings also introduced a novel therapeutic target for osteoporosis.
Highlights
Osteoporosis is a common degenerative bone disease in aged population and postmenopausal females[1]
Previous reports showed that decreased levels of Wnt signaling, a key pathway regulating osteogenesis, led to bone formation defect of Bone marrow-derived mesenchymal stem cells (BMSCs) during osteoporosis[12,23]
Dysfunction of BMSCs lead to bone formation defect in osteoporosis[7,8,10,11,31,32]
Summary
Osteoporosis is a common degenerative bone disease in aged population and postmenopausal females[1]. It is characterized by decreased bone density and bone microarchitecture destruction[2]. The fundamental mechanism of osteoporosis is the imbalance between bone formation and resorption[3]. Recent studies of our group and others revealed that osteogenic differentiation capacity of BMSCs was impaired during osteoporosis[5,6,7,8]. Recovering the osteogenic capacities of BMSCs could reduce bone loss in osteoporosis[7,9,10,11], suggesting potential therapeutic strategy for osteoporosis. Understanding the mechanisms of BMSCs dysfunction has become a critical issue in osteoporosis research
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