Connexin 43 hemichannels protect bone loss during estrogen deficiency
Open accessAbstract
Estrogen deficiency in postmenopausal women is a major cause of bone loss, resulting in osteopenia, osteoporosis, and a high risk for bone fracture. Connexin 43 (Cx43) hemichannels (HCs) in osteocytes play an important role in osteocyte viability, bone formation, and remodeling. We showed here that estrogen deficiency reduced Cx43 expression and HC function. To determine if functional HCs protect osteocytes and bone loss during estrogen deficiency, we adopted an ovariectomy model in wild-type (WT) and two transgenic Cx43 mice: R76W (dominant-negative mutant inhibiting only gap junction channels) and Cx43 Δ130–136 (dominant-negative mutant compromising both gap junction channels and HCs). The bone mineral density (BMD), bone structure, and histomorphometric changes of cortical and trabecular bones after ovariectomy were investigated. Our results showed that the Δ130–136 transgenic cohort had greatly decreased vertebral trabecular bone mass compared to WT and R76W mice, associated with a significant increase in the number of apoptotic osteocyte and empty lacunae. Moreover, osteoclast surfaces in trabecular and cortical bones were increased after ovariectomy in the R76W and WT mice, respectively, but not in ∆130–136 mice. These data demonstrate that impairment of Cx43 HCs in osteocytes accelerates vertebral trabecular bone loss and increase in osteocyte apoptosis, and further suggest that Cx43 HCs in osteocytes protect trabecular bone against catabolic effects due to estrogen deficiency.
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In addition to its effects on bone remodeling, estrogen regulates mechanotransduction in osteocytes by affecting FFSS, Wnt/β-catenin expression, and Cx43 expression.
“In addition to its effects on bone remodeling, estrogen regulates mechanotransduction in osteocytes by affecting FFSS,95 Wnt/β-catenin expression,96 and Cx43 expression.97”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [97]
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“showed that Cx43 could protect bone loss during estrogen deficiency.(33) In summary, our study demonstrated the role of N-cadherin in TGF-β1-mediated cell–cell communication in osteoblast lineage.”
BackgroundEstrogen depletion on In vivo osteocyte calcium signaling responses to mechanical loading
Lewis, K. J., Zuckerman, P. C., Boorman-Padgett, J. F., Basta‐Pljakic, J., Louie, J., Stephen, S. J., Spray, D. C., Thi, M. M., Şeref-Ferlengez, Z., Majeska, R. J., et al. (2021) · Bone · doi:10.1016/j.bone.2021.116072 · Cited by 28 · see citing works
In Sickness and in Health: The Oxygen Reactive Species and the Bone
Reis, J. D. C., & Ramos, A. M. (2021) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2021.745911 · Cited by 30 · see citing works
“, 2021) and protects the trabecular bone against catabolic effects associated with estrogen deficiency (Ma et al., 2019).”
BackgroundHighly-purified rapidly expanding clones, RECs, are superior for functional-mitochondrial transfer
Yang, J., Liu, L., Oda, Y., Wada, K., Ago, M., Matsuda, S., Hattori, M., Goto, T., Kawashima, Y., Matsuzaki, Y., et al. (2023) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03274-y · Cited by 24 · see citing works
“The downregulated expression of Cx43 also reduced the proportion of microtubules in astrocytoma cells [43], suggesting that Cx43 has a role in stabilizing cell membrane microtubules in tumor cells.”
BackgroundLi, G., Zhang, L., Lu, Z., Yang, B., Yang, H., Shang, P., Jiang, J. X., Wang, D., & Xu, H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113506 · Cited by 21 · see citing works
“Many in vitro studies also have demonstrated that Cx43 HCs can protect osteocytes from cell death and inhibition of HCs with anti-Cx43 E2 antibody in osteocytes accelerates H2O2-induced apoptosis [16,36], suggestive of a protective role of Cx43 HCs for osteocyte”
BackgroundInfluentialSelf-citationConnexin 43 Hemichannels Regulate Osteoblast to Osteocyte Differentiation
Hua, R., Gu, S., & Jiang, J. X. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.892229 · Cited by 21 · see citing works
“We also showed that functional HCs protect osteocytes against catabolic effects during estrogen deficiency (Ma et al., 2019).”
BackgroundMethodSelf-citationXu, J., Cao, B., Li, C., & Li, G. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1218206 · Cited by 14 · see citing works
“Studies have shown that Connexin 43 half-channels (Cx43 HCs) demonstrate protective effects on bone cells and can inhibit bone loss in estrogendeficient mice following ovariectomy (100).”
BackgroundZhao, D., Tu, C., Zhang, L., Guda, T., Gu, S., & Jiang, J. X. (2024) · JCI Insight · doi:10.1172/jci.insight.177557 · Cited by 12 · see citing works
“Con-sistently, a similar load-induced increase in trabecular osteoclasts was also found in ovariectomized mice (53) that had reduced Cx43 HC function in osteocytes (54).”
Self-citationGlucocorticoids Alter Bone Microvascular Barrier via MAPK/Connexin43 Mechanisms
Lee, E.-J., Lialios, P.-P., Curtis, M., Williams, J., Kim, Y., Salipante, P., Hudson, S. D., Esch, M. B., Levi, M., Kitlinska, J., et al. (2025) · Advanced Healthcare Materials · doi:10.1002/adhm.202404302 · Cited by 12 · see citing works
Osteocytic Connexin Hemichannels Modulate Oxidative Bone Microenvironment and Breast Cancer Growth
Tian, Y., Riquelme, M. A., Tu, C., Quan, Y., Liu, X., Sun, L., & Jiang, J. X. (2021) · Cancers · doi:10.3390/cancers13246343 · Cited by 12 · see citing works
Self-citationYuze, M., Hu, J., Lv, J., Cheng, X., Tianwen, X., & Junqiang, Z. (2025) · Frontiers in Physiology · doi:10.3389/fphys.2025.1629273 · Cited by 11 · see citing works
“They found that impairment of Cx43 hemichannels in osteocytes caused by estrogen deficiency accelerates vertebral trabecular bone loss and increases osteocyte apoptosis (Ma et al., 2019).”
Extracellular Cysteines Are Critical to Form Functional Cx46 Hemichannels
Fernández-Olivares, A., Durán-Jara, E., Verdugo, D. A., Fiori, M. C., Altenberg, G. A., Stehberg, J., Alfaro, I. E., Calderón, J. F., & Retamal, M. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137252 · Cited by 10 · see citing works
“Due to their permeability to second messengers and metabolites, hemichannels participate in relevant physiological functions, such as the formation of short-term memory [13], memory consolidation [14], gliotransmitter release [15], retina function [16], bone-hormone response and healing [17,18], neuronal-network activ…”
BackgroundPan, T., Liu, F., Hao, X., Wang, S., Wasi, M., Song, J. H., Lewis, V. O., Lin, P. P., Moon, B. S., Bird, J. E., et al. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217009 · Cited by 8 · see citing works
Hua, R., Truong, V. A., Fajardo, R. J., Guda, T., Gu, S., & Jiang, J. X. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114363 · Cited by 8 · see citing works
“However, when calibrated by the cross-section, Δ130–136 mice showed significantly decreased material properties. addition, we observed increased apoptotic osteocytes and empty lacunae in Δ130–136 mice, 24,28 further compromising bone quality.”
BackgroundMethodSelf-citationDevelopment of a potent embryonic chick lens model for studying congenital cataracts in vivo
Li, Z., Gu, S., Quan, Y., Varadaraj, K., & Jiang, J. X. (2021) · Communications Biology · doi:10.1038/s42003-021-01849-0 · Cited by 8 · see citing works
Self-citationMisiakiewicz-Has, K., Pilutin, A., & Wiszniewska, B. (2021) · Reproductive Biology · doi:10.1016/j.repbio.2021.100562 · Cited by 8 · see citing works
Xu, J., Lei, M., & Xu, D. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1683183 · Cited by 6 · see citing works
Yang, J., Cong, N., Shi, D., Chen, S., Zhang, Z., & Zhao, P. (2024) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2024.118366 · Cited by 6 · see citing works
Connexin43 in Musculoskeletal System: New Targets for Development and Disease Progression
An, S., Zheng, S., Cai, Z., Chen, S., Wang, C., Li, Y., & Deng, Z. (2022) · Aging and Disease · doi:10.14336/ad.2022.0421 · Cited by 6 · see citing works
Chen, J. H., Shen, C., Oh, H., & Park, J. H. (2021) · Endocrine · doi:10.1007/s12020-021-02664-7 · Cited by 5 · see citing works
Connexin 43 in the function and homeostasis of osteocytes: a narrative review
Ma, L., Wang, W., Xu, G., Li, H., Liu, F., Shao, H., Zhang, X., Ma, Y., Li, G., Li, H. Y., et al. (2024) · Annals of Joint · doi:10.21037/aoj-23-65 · Cited by 5 · see citing works
“The shear stress induced by fluid flow stimulates intercellular communication mediated by intercellular connectivity in osteoblast-like MLO-Y4 cells and increases the expression of Cx43 (73).”
Self-citationThe potential effects of whole grain-enriched diet on preventing osteoporosis
Zhang, J., Zheng, M., Yu, Y., Wang, J., & Sun, B. (2024) · Food Science and Technology Research · doi:10.3136/fstr.fstr-d-24-00024 · Cited by 4 · see citing works
Uspenskaya, Y. A., Malinovskaya, N. A., & Salmina, A. B. (2022) · Cell and Tissue Biology · doi:10.1134/s1990519x22020109 · Cited by 2 · see citing works
“The expression of Cx43 in the osteocyte network has been reported to promote the survival of osteocytes (Ma et al., 2019).”
BackgroundPei, S., Wasi, M., Wang, S., Chu, T., Guerra, R. M., & Wang, L. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-96123-3.00010-5 · Cited by 2 · see citing works
Role of Cx43 on the Bone Cell Generation, Function, and Survival
Plotkin, L. I., Asad, I., Kritikos, A. E., & Sanz, N. (2023) · Bioelectricity · doi:10.1089/bioe.2023.0028 · Cited by 1 · see citing works
“32 Indeed, addition of 17 b -estradiol to MLO-Y4 cell cultures results in increased Cx43 expression when compared to a nonsupplemented group.”
Cellular and Molecular Biology in Bone Remodeling
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Bone Cell Communication Through Gap Junctions
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Osterix Facilitates Osteocytic Communication by Targeting Connexin43Preprint
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“Gap junction communication, facilitated by connexin channels, is critical for bone cells to perform their functions(Ma et al., 2019).”
BackgroundInfluentialOsterix Facilitates Osteocytic Communication by Targeting Connexin43Preprint
Wu, Z., Chen, Q., Gao, Q., Liang, M., Zhou, Y., Zhu, L., Wang, J., Shen, Y., Jing, J., Xie, J., et al. (2024) · eLife · doi:10.7554/elife.102453.1
Osterix Facilitates Osteocytic Communication by Targeting Connexin43Preprint
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Yuan, H., Gu, J., Chen, W., Wu, J., Ma, Y., Jiang, Y., & Huang, Z. (2026) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2026.108292
Peng, D.-C., Liang, C.-T., Li, Y.-X., Tan, J.-Q., Jiang, K.-L., Song, Z.-Y., Guo, X.-Y., & Wang, H.-K. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1927444
“Both clinical specimens and osteoporotic animal models exhibit decreased skeletal Cx43 expression (11, 12); however, the precise signaling cascade linking Cx43 loss to impaired osteoblast differentiation under osteoporosis remains unclear.”
Intercellular communication networks in the osteoporotic bone microenvironment
Li, Y., Liu, X., Feng, X., Li, X., & Yin, H. (2026) · Connective Tissue Research · doi:10.1080/03008207.2026.2752398
- Authors
- Ma, L., Hua, R., Tian, Y., Cheng, H., Fajardo, R. J., Pearson, J. J., Guda, T., Shropshire, D. B., Gu, S., & Jiang, J. X.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- The University of Texas at San Antonio (US)
- Corresponding author
- Jiang, Jean X.
- Venue
- Bone Research
- Published
- 2019-04-22
- Volume
- 7
- Issue
- 1
- Pages
- 11-11
- ISSN
- 2095-4700 (ISSN-L)
- 2095-6231
- PMC
- PMC6476886
- OpenAlex
- W2938005757
- Cited by
- 48
- References
- 77
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 9 · 2023: 7 · 2022: 8 · 2021: 12 · 2020: 5 · 2019: 1
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Bone Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (AR072020; CA196214)
- Welch Foundation (AQ-1507)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- connexin 43, hemichannels, estrogen deficiency, postmenopausal bone loss, osteocytes, osteocyte apoptosis, ovariectomy, trabecular bone, cortical bone, osteoclast surface, bone mineral density, gap junctions, osteoporosis
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