Gap junctions and hemichannels in signal transmission, function and development of bone

Abstract

Gap junctional intercellular communication (GJIC) mediated by connexins, in particular connexin 43 (Cx43), plays important roles in regulating signal transmission among different bone cells and thereby regulates development, differentiation, modeling and remodeling of the bone. GJIC regulates osteoblast formation, differentiation, survival and apoptosis. Osteoclast formation and resorptive ability are also reported to be modulated by GJIC. Furthermore, osteocytes utilize GJIC to coordinate bone remodeling in response to anabolic factors and mechanical loading. Apart from gap junctions, connexins also form hemichannels, which are localized on the cell surface and function independently of the gap junction channels. Both these channels mediate the transfer of molecules smaller than 1.2kDa including small ions, metabolites, ATP, prostaglandin and IP(3). The biological importance of the communication mediated by connexin-forming channels in bone development is revealed by the low bone mass and osteoblast dysfunction in the Cx43-null mice and the skeletal malformations observed in occulodentodigital dysplasia (ODDD) caused by mutations in the Cx43 gene. The current review summarizes the role of gap junctions and hemichannels in regulating signaling, function and development of bone cells. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.

Figure 1. Gap junctions and hemichannels contribute to the maintenance of bone integrity and function by allowing the exchange of bone modulators through the bone cell network

(A). Schematic representation of the bone cell network containing the gap junctions (GJ) and hemichannels (HC). The osteocytes embedded in the bone matrix with their long dendritic processes (blue) make connections with the osteoblasts (green) and the osteoclasts (brown) through the gap junctions (pink). Presence of GJ is also shown in the bone marrow stromal cells (BMSCs). The HC on the osteocytic cell body interacts with the extracellular environment. (B). Upper panel shows that gap junction channels are stimulated by several factors like fluid flow (mechanical stimulation), PTH (hormonal stimulation) or PNS, IL1β (chemical stimulation), which results in increased activity of gap junctions. These molecules are signaled across the two communicating cells to regulate several cellular functions of the bone cells. Lower panel shows that hemichannels can open upon stimulation by fluid flow, calcium and bisphosphonates, and release PGE₂, ATP, NAD and calcium to the external environment leading to activation of several signaling pathways.