Activation of connexin hemichannels enhances mechanosensitivity and anabolism in disused and aged bone
Dezhi Zhao, Chao Tu, Lidan Zhang, Teja Guda, Sumin Gu, Jean X. Jiang
Dezhi Zhao, Chao Tu, Lidan Zhang, Teja Guda, Sumin Gu, Jean X. Jiang
View: Text | PDF
Research Article Bone biology

Activation of connexin hemichannels enhances mechanosensitivity and anabolism in disused and aged bone

Abstract

Mechanical loading, essential for bone health, promotes bone formation and remodeling. However, the positive response diminishes in cases of disuse and aging, leading to bone loss and an increased fracture risk. This study demonstrates that activating hemichannels (HCs) using a connexin 43 (Cx43) antibody, Cx43(M2), in bone osteocytes revitalizes aging and disused bones. Using a hindlimb suspension (HLS) disuse model and a tibial mechanical loading model, we found that Cx43(M2) inhibited bone loss and osteocyte apoptosis induced by unloading in 16-week-old adult mice. Additionally, it enhanced bone mass in response to tibial loading in 22-month-old aged mice. The HC opening released bone anabolic factor prostaglandin E2 (PGE2) and suppressed catabolic factor sclerostin (SOST). This suppressed the increase of cortical bone formation and reduction of bone resorption during unloading and promoted trabecular and cortical bone formation during loading. Cx43(M2)-induced HC opening, coupled with PGE2 release, effectively rescued unloading-induced bone loss and restored the diminished anabolic response of aged bones to mechanical loading. Activating HCs with the Cx43 antibody holds promise as a de novo therapeutic approach, as it can overcome the limitations of existing treatment regimens for treating bone loss and osteoporosis associated with aging and disuse.

Authors

Dezhi Zhao, Chao Tu, Lidan Zhang, Teja Guda, Sumin Gu, Jean X. Jiang

×

Figure 8

Model illustrating the effect of enhanced HCs via the Cx43(M2) antibody on osteocyte responses to mechanical loading in disused and aged bones.

Options: View larger image (or click on image) Download as PowerPoint
Model illustrating the effect of enhanced HCs via the Cx43(M2) antibody ...
Enhanced Cx43 HC activity releases PGE2 (9), leading to a reduction of SOST expression in osteocytes during both mechanical loading and unloading. Aging is associated with a decline in osteocytic Cx43 levels and reduced responsiveness of Cx43 HCs to mechanical loading. Activation of osteocytic Cx43 HCs using the Cx43(M2) antibody increases PGE2 levels and suppresses SOST expression, resulting in increased endosteal osteoblast activity and bone formation, while simultaneously decreasing endosteal osteoclast activity in aged mice under mechanical loading conditions. During periods of disuse, apoptotic osteocytes release higher levels of RANKL, which induces osteoclast differentiation and recruitment. Activating HCs with the Cx43(M2) antibody raises extracellular PGE2 levels. This increase in PGE2 suppresses SOST, thereby enhancing endosteal bone formation and preventing osteocyte apoptosis and RANKL expression in osteocytes. Consequently, reduced endosteal osteoclast activity leads to decreased bone resorption.