Connexin hemichannels with prostaglandin release in anabolic function of bone to mechanical loading

Abstract

Mechanical stimulation, such as physical exercise, is essential for bone formation and health. Here, we demonstrate the critical role of osteocytic Cx43 hemichannels in anabolic function of bone in response to mechanical loading. Two transgenic mouse models, R76W and Δ130–136, expressing dominant-negative Cx43 mutants in osteocytes were adopted. Mechanical loading of tibial bone increased cortical bone mass and mechanical properties in wild-type and gap junction-impaired R76W mice through increased PGE2, endosteal osteoblast activity, and decreased sclerostin. These anabolic responses were impeded in gap junction/hemichannel-impaired Δ130–136 mice and accompanied by increased endosteal osteoclast activity. Specific inhibition of Cx43 hemichannels by Cx43(M1) antibody suppressed PGE2 secretion and impeded loading-induced endosteal osteoblast activity, bone formation and anabolic gene expression. PGE2 administration rescued the osteogenic response to mechanical loading impeded by impaired hemichannels. Together, osteocytic Cx43 hemichannels could be a potential new therapeutic target for treating bone loss and osteoporosis.

Connexin and Pannexin Large-Pore Channels in Microcirculation and Neurovascular Coupling Function

“…Cxs hemichannels also promote ion permeation (i.e., Ca 2+ ) [6,9,15,[28][29][30] and molecule release (ATP, D-serine, prostaglandins, nitric oxide, etc.) to the milieu, playing a vital role in cell function activity [15,[31][32][33][34][35]. (A) Ribbon and surface representations of the Cx46 GJ channel viewed from the lateral side.…”

Connexin 43 hemichannels regulate mitochondrial ATP generation, mobilization, and mitochondrial homeostasis against oxidative stress

“…HC opening is stimulated by many factors like low extracellular Ca 2+ concentration, oxidative stress, mechanical signals, and extracellular alkalinization ( Burra and Jiang, 2011 ; Decrock et al, 2011 ; Francis et al, 1999 ; Gault et al, 2014 ; Kar et al, 2012 ; Leithe et al, 2018 ; Schalper et al, 2010 ). The opening of Cx43 HCs also exhibits a positive impact on cells, especially in bone osteocytes ( Kar et al, 2013 ; Zhao et al, 2022 ).…”

“…Osteocytes are the most abundant cell in bone, occupying 90–95% of adult total bone cells ( Bonewald, 2011 ). Cx43 HCs, richly present in osteocytes, prominently mediate the anabolic action of mechanical loading and regulate the response to mechanical loading and oxidative stress ( Cherian et al, 2003 ; Hua et al, 2021 ; Zhao et al, 2022 ). Oxidative stress causes apoptosis, further affecting the normal function of the osteocytic network.…”

Connexin 43 Hemichannels Regulate Mitochondrial ATP Generation, Mobilization, and Mitochondrial Homeostasis against Oxidative Stress

“…Osteocytes are the most abundant cell in bone, occupying 90-95% of adult total bone cells (Bonewald, 2011). Cx43 HCs, richly present in osteocytes, prominently mediate anabolic action of mechanical loading and regulate the response to mechanical loading and oxidative stress (Cherian et al, 2003; Hua et al, 2021; Zhao et al ., 2022). Oxidative stress causes apoptosis, further affecting the normal function of the osteocytic network.…”

“…HC opening is stimulated by many factors like low extracellular Ca 2+ concentration, oxidative stress, mechanical signals, and extracellular alkalinization (Burra and Jiang, 2011; Decrock et al, 2011; Francis et al, 1999; Gault et al, 2014; Kar et al, 2012; Leithe et al, 2018; Schalper et al, 2010). The opening of Cx43 HCs also exhibits a positive impact on cells, especially in bone osteocytes (Kar et al, 2013; Zhao et al, 2022). Connexin 43 (Cx43) is the most ubiquitous expressed Cx in different cell types such as endothelial cells, cardiomyocytes, astrocytes, etc.…”