Shifting paradigms on the role of connexin43 in the skeletal response to mechanical load.

Gap junctions (GJs) are membrane-spanning channels that allow for the movement of small molecules across cell membranes. Connexin43 (Cx43) is the predominant GJ protein in bone. In vitro studies suggest that gap junctional intercellular communication (GJIC) sensitizes bone cells to mechanical signals. Additionally, mechanical signals detected by osteocytes are communicated to osteoblasts via GJIC, and osteocytic Cx43 hemichannels release anabolic factors, such as PGE2 and ATP, in response to mechanical load. These findings and others have led to near consensus among researchers in the field that GJIC, hemichannels or connexins facilitate the anabolic response of bone to mechanical load and, in their absence, bone would be less sensitive to load. However, recent in vivo evidence suggests the opposite is true. Studies from our laboratory and others demonstrate that Cx43-deficient mice have an increased anabolic response to mechanical load and are protected against the catabolic effects of mechanical unloading. These developments suggest a paradigm shift in our understanding of connexins, GJIC, and mechanotransduction in bone. That is, inhibiting bone cell Cx43 expression or GJIC has a beneficial effect on bone's response to its mechanical environment, preserving bone during unloading and enhancing its formation during loading. Here, we review literature in support of this hypothesis and suggest a mechanism by which Cx43, through interaction with WNT/β-catenin signaling, moderates both arms of bone remodeling.