Abstract

The skeleton adapts to mechanical loading to promote bone formation and remodeling. While most bone cells are involved in mechanosensing, it is well accepted that osteocytes are the principal mechanosensory cells. The osteocyte cell body and processes are surrounded by a fluid-filled space, forming an extensive lacuno-canalicular network. The flow of interstitial fluid is a major stress-related factor that transmits mechanical stimulation to bone cells. The long dendritic processes of osteocytes form a gap junction channel network connecting not only neighboring osteocytes, but also cells on the bone surface, such as osteoblasts and osteoclasts. Mechanosensitive osteocytes also form hemichannels that mediate the communication between the cytoplasmic and extracellular microenvironment. This paper will discuss recent research progress regarding connexin (Cx)-forming gap junctions and hemichannels in osteocytes, osteoblasts, and other bone cells, including those richly expressing Cx43. We will then cover the recent progress regarding the regulation of these channels by mechanical loading and the role of integrins and signals in mediating Cx43 channels, and bone cell function and viability. Finally, we will summarize the recent studies regarding bone responses to mechanical unloading in Cx43 transgenic mouse models. The osteocyte has been perceived as the center of bone remodeling, and connexin channels enriched in osteocytes are a likely major player in meditating the function of bone. Based on numerous studies, connexin channels may present as a potential new therapeutic target in the treatment of bone loss and osteoporosis. This review will primarily focus on Cx43, with some discussion in other connexins expressed in bone cells.

Highlights

  • Gap junctions serve as a conduit for signal transduction between bone cells, which allow metabolic and electric coupling for an efficient response to extracellular stimuli

  • The lack of specific tools to discriminate the role of gap junctions, hemichannels, and channel/hemichannel-independent functions limits the interpretation of the phenotypes associated with connexin genetic deletion animal studies

  • The specific role of gap junction channels and hemichannels formed by Cx43 was identified using two transgenic mouse models driven by a 10 kb DMP-1 promoter (Figure 1) and expressing two dominant-negative Cx43 mutants [18]

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Summary

Introduction

Gap junctions serve as a conduit for signal transduction between bone cells, which allow metabolic and electric coupling for an efficient response to extracellular stimuli. The specific role of gap junction channels and hemichannels formed by Cx43 was identified using two transgenic mouse models driven by a 10 kb DMP-1 promoter (Figure 1) and expressing two dominant-negative Cx43 mutants [18]. An enhanced anabolic response to mechanical loading has been observed on the periosteal surface in mice lacking Cx43 in mature osteoblasts and osteocytes (Cx43fl/fl;OCN-Cre) [12].

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