SPTBN1 Prevents Primary Osteoporosis by Modulating Osteoblasts Proliferation and Differentiation and Blood Vessels Formation in Bone.

Xuejuan Xu,Xiaochun Bai,Xiao Wang,Guoqiang Chen,Meichen Feng,Yanshi Ye,Jiayi Yang,Xingying Chen,Xiaoting Feng,Yuqian Song,Yinhua Zhang,Xu Lin,Hangtian Wu,Jie Shen

doi:10.3389/fcell.2021.653724

Abstract

Osteoporosis is a common systemic skeletal disorder that leads to increased bone fragility and increased risk of fracture. Although βII-Spectrin (SPTBN1) has been reported to be involved in the development of various human cancers, the function and underlying molecular mechanisms of SPTBN1 in primary osteoporosis remain unclear. In this study, we first established a primary osteoporosis mouse model of senile osteoporosis and postmenopausal osteoporosis. The results showed that the expression of SPTBN1 was significantly downregulated in primary osteoporosis mice model compared with the control group. Furthermore, silencing of SPTBN1 led to a decrease in bone density, a small number of trabecular bones, wider gap, decreased blood volume fraction and number of blood vessels, as well as downregulation of runt-related transcription factor 2 (Runx2), Osterix (Osx), Osteocalcin (Ocn), and vascular endothelial growth factor (VEGF) in primary osteoporosis mice model compared with the control group. Besides, the silencing of SPTBN1 inhibited the growth and induced apoptosis of mouse pre-osteoblast MC3T3-E1 cells compared with the negative control group. Moreover, the silencing of SPTBN1 significantly increased the expression of TGF-β, Cxcl9, and the phosphorylation level STAT1 and Smad3 in MC3T3-E1 cells compared with the control group. As expected, overexpression of SPTBN1 reversed the effect of SPTBN1 silencing in the progression of primary osteoporosis both in vitro and in vivo. Taken together, these results suggested that SPTBN1 suppressed primary osteoporosis by facilitating the proliferation, differentiation, and inhibition of apoptosis in osteoblasts via the TGF-β/Smad3 and STAT1/Cxcl9 pathways. Besides, overexpression of SPTBN1 promoted the formation of blood vessels in bone by regulating the expression of VEGF. This study, therefore, provided SPTBN1 as a novel therapeutic target for osteoporosis.

Highlights

Osteoporosis is a skeletal disorder characterized by compromised bone strength and predisposes a person to an increased risk of fracture, and is becoming an increasingly serious health challenge worldwide (Aspray and Hill, 2019)
The representative photomicrographs of H&E staining are shown in Figure 1F, indicating that there was a significant increase in adipose tissue and fracture tendency in the OVX group compared with the sham group
The results showed that the mean density of SPTBN1 positive cells was significantly decreased both in the OVX group and senile group compared with the respective control groups (Figure 1G)

Summary

Introduction

Osteoporosis is a skeletal disorder characterized by compromised bone strength and predisposes a person to an increased risk of fracture, and is becoming an increasingly serious health challenge worldwide (Aspray and Hill, 2019). Wang et al (2009) conducted a two-stage case-control association study with 1046 patients with the non-traumatic vertebra, hip, or distal radius fractures and 2303 healthy controls, and indicated that SPTBN1 was a susceptibility genetic loci for osteoporotic fracture in postmenopausal Chinese women (Wang et al, 2012). Our recent system-level study based on genome-wide association studies of osteoporosis indicated that SPTBN1 associated with BMD in females (Chen et al, 2016). These reports suggest that SPTBN1 may contribute to the progression of osteoporosis. The specific functions and mechanisms of SPTBN1 in osteoporosis have not been reported

Methods

Results

Conclusion