Connexin hemichannels with prostaglandin release in anabolic function of bone to mechanical loading.

Dezhi Zhao,Sumin Gu,Huiyun Xu,Manuel A Riquelme,Teja Guda,Jean X Jiang,Chao Tu

doi:10.7554/elife.74365

Abstract

Mechanical stimulation, such as physical exercise, is essential for bone formation and health. Here, we demonstrate the critical role of osteocytic Cx43 hemichannels in anabolic function of bone in response to mechanical loading. Two transgenic mouse models, R76W and Δ130-136, expressing dominant-negative Cx43 mutants in osteocytes were adopted. Mechanical loading of tibial bone increased cortical bone mass and mechanical properties in wild-type and gap junction-impaired R76W mice through increased PGE2, endosteal osteoblast activity, and decreased sclerostin. These anabolic responses were impeded in gap junction/hemichannel-impaired Δ130-136 mice and accompanied by increased endosteal osteoclast activity. Specific inhibition of Cx43 hemichannels by Cx43(M1) antibody suppressed PGE2 secretion and impeded loading-induced endosteal osteoblast activity, bone formation and anabolic gene expression. PGE2 administration rescued the osteogenic response to mechanical loading impeded by impaired hemichannels. Together, osteocytic Cx43 hemichannels could be a potential new therapeutic target for treating bone loss and osteoporosis.

Highlights

Bone as a mechanosensitive tissue is adaptive to mechanical stimuli, which are essential for bone homeostasis, formation, and remodeling (Bonewald, 2011)
Bone tissue sections around the tibial midshaft region showed that tibial loading increased Evans blue (EB) dye uptake in the osteocytes of WT and R76W mice, but not in the osteocytes of Δ130–136 mice (Figure 1—figure supplement 2a,b)
We observed that unlike WT and R76W mice, Δ130–136 mice, with inhibited osteocytic Cx43 hemichannels, attenuated anabolic bone responses to mechanical loading in both trabecular and Figure 7 continued on page

Summary

Introduction

Bone as a mechanosensitive tissue is adaptive to mechanical stimuli, which are essential for bone homeostasis, formation, and remodeling (Bonewald, 2011). Reduced mechanical stimulation leads to bone loss and elevated risk of fracture (Lang et al, 2004), while enhanced mechanical stimulation, such as physical exercise, has positive, anabolic impacts on bone tissue, even following a prolonged cessation of stimulation (Erlandson et al, 2012; Warden et al, 2007). The osteocytes embedded in the bone mineral matrix comprise over 90–95% of all bone cells and are thought to be a major mechanoreceptor in the adult skeleton (Bonewald, 2011). Osteocytes detect the mechanical loading- induced alterations of the bone matrix microenvironment and translate them into biological responses

Methods

Results

Conclusion