Connexin 43 Channels in Osteocytes Regulate Bone Responses to Mechanical Unloading.

Dezhi Zhao,Huiyun Xu,Jean X Jiang,Hui Yang,Ruofei Liu,Meng Chen,Guobin Li,Peng Shang

doi:10.3389/fphys.2020.00299

Abstract

Connexin (Cx) 43 forms gap junctions and hemichannels that mediate communication between osteocytes and adjacent cells or the extracellular environment in bone, respectively. To investigate the role of each channel type in response to mechanical unloading, two transgenic mouse models overexpressing dominant-negative Cx43 predominantly in osteocytes driven by a 10 kb dentin matrix protein 1 (Dmp1) promoter were generated. The R76W mutation resulted in gap junction inhibition and enhancement of hemichannels, whereas the Δ130–136 mutation inhibited both gap junctions and hemichannels. Both mutations led to cortical bone loss with increased endocortical osteoclast activity during unloading. Increased periosteal osteoclasts with decreased apoptotic osteocytes were observed only in R76W mice. These findings indicated that inhibiting osteocytic Cx43 channels promotes bone loss induced by unloading, mainly in the cortical area; moreover, hemichannels protect osteocytes against apoptosis and promote periosteal bone remodeling, whereas gap junctions modulate endocortical osteoclast activity in response to unloading.

Highlights

IntroductionMechanical unloading caused by microgravity during long space flight leads to bone mineral density (BMD) loss at a rate of 0.5– 1.5% per month that is only partly restored 1 year after return to Earth (Lang et al, 2006)
Bone structure adapts to the mechanical environment
Hindlimb unloading for 4 weeks resulted in a significant loss of femoral distal metaphysis trabecular bone in all mice, which confirmed that the unloading model was established (Figure 1F). μCT analysis revealed a decrease in bone volume to trabecular volume (BV/TV) (Figure 1A) and Tb.N (Figure 1B) and increase in structure model index (SMI) (Figure 1C) and Tb.Sp (Figure 1D)

Summary

Introduction

Mechanical unloading caused by microgravity during long space flight leads to bone mineral density (BMD) loss at a rate of 0.5– 1.5% per month that is only partly restored 1 year after return to Earth (Lang et al, 2006). This phenomenon is caused by the absence of normal mechanical stimulation at zero gravity, which results in inadequate anabolic signaling for bone formation and increased bone resorption (Lin et al, 2009; Jing et al, 2014).

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