Shifting Paradigms on the Role of Connexin43 in the Skeletal Response to Mechanical Load

Abstract

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 PGE 2 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/b-catenin signaling, moderates both arms of bone remodeling.

Connexin 43 Modulates Osteogenic Differentiation of Bone Marrow Stromal Cells Through GSK-3beta/Beta-Catenin Signaling Pathways

“…However, it is noteworthy the effects of Cx43 deficiency in different contexts involves diverse interactions of Cx43 with the Wnt/beta-catenin pathway [63]. In contrast, Cx43-deficient ulnae and Cx43-silenced MLO-Y4 osteocyte-like cells elevate basal beta-catenin protein levels to respond to mechanical forces, and is accompanied by increases in the levels of the beta-catenin/Wnt target genes axin 2 and Sfrp4 [64].…”

Complex trait genetics: mapping, correlation and causation

“…Wnt signalling is essential for maintaining bone density and the homeostasis in connective tissue [210][211][212]. Our finding adds evidence on the link of these disorders to corneal thinning.…”

Does Defective Bone Lead to Defective Muscle?

“…These in vitro results were interpreted to mean that the opening of gap junctions and hemichannels is essential for bone formation in response to load. (27) This certainly appears to be the case for normal loading of the skeleton, loads that are generally less than the experimental anabolic loads. However, the finding that these mice have a greater response to experimental anabolic loading suggests that under these conditions, Cx43 may put a "brake" on this response.…”

“…Mice lacking Cx43 in osteoblasts/osteocytes have defective, reduced bone under normal conditions but have a greater anabolic response to anabolic loading compared to controls (for review see Lloyd and colleagues. (27) Direct anabolic loading of bone can increase bone mass independent of muscle loading. (28) Because these mice have a greater anabolic bone response to mechanical loading, would loading the bone of these mice reverse the muscle phenotype?…”