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.

Connexin-containing gap junctions mediate the direct exchange of small molecules between cells, thus promoting cell–cell communication. Connexins (Cxs) have been widely studied as key tumor-suppressors. However, certain Cx subtypes, such as Cx43 and Cx26, are overexpressed in metastatic tumor lesions. Cyclic adenosine monophosphate (cAMP) signaling regulates Cx expression and function via transcriptional control and phosphorylation. cAMP also passes through gap junction channels between adjacent cells, regulating cell cycle progression, particularly in cancer cell populations. Low levels of cAMP are sufficient to activate key effectors. The present review evaluates the mechanisms underlying Cx regulation by cAMP signaling and the role of gap junctions in cancer progression and metastasis. A deeper understanding of these processes might facilitate the development of novel anticancer drugs.