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 3

Enhanced Cx43 HC activity by Cx43(M2) inhibits osteocyte apoptosis and osteoclastogenesis in 16-week-old male tibias induced by 28-day mechanical unloading.

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Enhanced Cx43 HC activity by Cx43(M2) inhibits osteocyte apoptosis and o...
(A) Representative images of H&E staining on middiaphyseal cortical bone for both control and HLS tibias of vehicle- and Cx43(M2)-treated mice. Black arrowheads indicate empty lacunae. n = 5–6 per group. Scale bar: 80 μm. (B) Quantification of empty lacunae in middiaphyseal cortical bone. (C) Representative images of TUNEL staining of apoptotic osteocytes in both control and HLS tibias of vehicle- and Cx43(M2)-treated mice. White arrowheads indicate TUNEL+ osteocytes. n = 4 per group. Scale bar: 120 μm. (D and E) Representative RANKL immunohistostaining and quantification of RANKL+ osteocytes in middiaphyseal cortical bone for both control and HLS tibias of vehicle- and Cx43(M2)-treated mice. Black arrowheads indicated RANKL+ osteocytes. n = 4 per group. Scale bar: 40 μm. (F) Representative images of TRAP+ osteoclasts (black arrows) on the endosteal surface for both control and HLS tibias of vehicle- and Cx43(M2)-treated mice. (G and H) Quantification of TRAP+ osteoclast surface per bone perimeter (Oc.S/BS) on endosteal surfaces (G) and periosteal surfaces of middiaphyseal cortical bone (H). n = 4–6 per group. Scale bar: 40 μm. Data are expressed as mean ± SD. *P < 0.05; ***P < 0.001. Statistical analysis was performed using 2-way ANOVA with Tukey test for differences among groups (B, E, G, and H). Ps, periosteal surface; Ec, endosteal surface.