Functional Roles of Connexins and Gap Junctions in Osteo-Chondral Cellular Components

Abstract

Gap junctions (GJs) formed by connexins (Cxs) play an important role in the intercellular communication within most body tissues. In this paper, we focus on GJs and Cxs present in skeletal tissues. Cx43 is the most expressed connexin, participating in the formation of both GJs for intercellular communication and hemichannels (HCs) for communication with the external environment. Through GJs in long dendritic-like cytoplasmic processes, osteocytes embedded in deep lacunae are able to form a functional syncytium not only with neighboring osteocytes but also with bone cells located at the bone surface, despite the surrounding mineralized matrix. The functional syncytium allows a coordinated cell activity through the wide propagation of calcium waves, nutrients and anabolic and/or catabolic factors. Acting as mechanosensors, osteocytes are able to transduce mechanical stimuli into biological signals that spread through the syncytium to orchestrate bone remodeling. The fundamental role of Cxs and GJs is confirmed by a plethora of investigations that have highlighted how up- and downregulation of Cxs and GJs critically influence skeletal development and cartilage functions. A better knowledge of GJ and Cx mechanisms in physiological and pathological conditions might help in developing therapeutic approaches aimed at the treatment of human skeletal system disorders.

Keywords: Cx43; Gap junctions; bone; cartilage; chondrocytes; connexins; homeostasis; mesenchymal stem cells; osteoblasts; osteoclasts; osteocytes.

Figure 1

Schematic representation of gap junctions and hemichannels in bone cells.

Figure 2

Schematic representation of Cx43 gap junctions and hemichannels in bone cells. Through gap junctions located in their long dendritic processes, osteocytes embedded in the deep lacunae are able to make connections with each other and with other bone cells such as osteoblasts and osteoclasts, in spite of the surrounding mineralized matrix. The resulting “functional syncytium” allows diffuse intercellular propagation of metabolites, second messengers and Ca⁺⁺ waves. Through hemichannels, osteocytes may sense a variety of extracellular cues (mechanic stimuli, biochemical signals (hormones, growth factors, cytokines)), or release signaling molecules (PGE₂, ATP, NAD⁺) into the external environment.