Roles of gap junctions and hemichannels in bone cell functions and in signal transmission of mechanical stress

Abstract

Gap junctions formed by connexins (Cx) play an important role in transmitting signals between bone cells such as osteoblasts and osteoclasts, cells responsible for bone formation and bone remodeling, respectively. Gap junction intercellular communication (GJIC) has been demonstrated to mediate the process of osteoblast differentiation and bone formation. Furthermore, GJIC propagates Ca2+ signaling, conveys anabolic effects of hormones and growth factors, and regulates gene transcription of osteoblast differentiation markers. GJIC is also implicated to regulate osteoclast formation, survival and apoptosis. Compared with other bone cells, the most abundant type are osteocytes, which express large amounts of connexins. Mechanosensing osteocytes connect and form gap junctions with themselves and other cells only through the tips of their dendritic processes, a relatively small percent of the total cell surface area compared to other cells. Recent studies show that in addition to gap junctions, osteoblasts and osteocytes express functional hemichannels, the un-opposed halves of gap junction channels. Hemichannels are localized at the cell surface and function independently of gap junctions. Hemichannels in osteocytes mediate the immediate release of prostaglandins in response to mechanical stress. The major challenges remaining in the field are how the functions of these two types of channels are coordinated in bone cells and what the asserted, distinct effects of these channels are on bone formation and remodeling processes, and on conveying signals elicited by mechanical loading.

Figure 1

Model diagram for the role of hemichannels under fluid flow shear stress in osteocytes. Hemichannels are expressed on the plasma membrane away from cell-cell junction regions. (A) In the absence of mechanical stress, hemichannels remain closed, whereas gap junctions are kept open. (B) Fluid flow shear stress induces the opening of hemichannels (upper panel). PGE₂, possibly ATP and other responding physiological factors are released into canaliculi to mediate biological responses elicited by mechanical stress (lower panel).