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

Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas, USA.Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas, USA. · pubmed

Paper

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.

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Research summary

The paper addresses a mechanism related to bone health, specifically focusing on the activation of connexin hemichannels to enhance mechanosensitivity and anabolic responses in aging and disused bones. This research is relevant to longevity as it explores potential therapeutic approaches to mitigate bone loss associated with aging, which is a significant concern in the context of age-related diseases. However, while the findings are solid and contribute to the understanding of bone metabolism, the impact is limited as it primarily addresses a specific aspect of bone health rather than broader mechanisms of aging or lifespan extension.

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