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
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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

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Figure 1

Cx43(M2) antibody enhances HC opening in osteocytes under both tibia loading and unloading in vivo.

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Cx43(M2) antibody enhances HC opening in osteocytes under both tibia loa...
To assess the effects of Cx43(M2) on HCs in osteocytes, EB dye uptake was evaluated in 16-week-old male mice after 28-day HLS or in 22-month-old male mice after a single round tibia loading. (A) Representative fluorescence images of EB dye uptake in middiaphyseal cortical bone for both control and HLS unloaded tibias, in the absence or presence of Cx43(M2). White arrowheads indicate EB+ osteocytes. Scale bar: 20 μm. (B and C) Quantitation of EB fluorescence intensity and the ratio changes over control in osteocytes. n = 3–4 per group. (D) Representative fluorescence images of EB dye uptake in 37% diaphyseal cortical bone for both loaded and contralateral tibias, in the absence or presence of Cx43(M2). White arrowheads indicate EB+ osteocytes. Scale bar: 20 μm. (E and F) Quantitation of EB fluorescence intensity and the ratio changes over contralateral control in osteocytes. n = 3 per group. Data are presented as mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001. Statistical analysis was performed using the paired Student’s t test for loaded and contralateral tibias (B and E), unpaired Student’s t test for the ratio changes of EB dye uptake (C and F), and 2-way ANOVA with Tukey test for differences among groups (B and E).