Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43
Open accessAbstract
Connexin43 (Cx43) is involved in bone development, but its role in adult bone homeostasis remains unknown. To overcome the postnatal lethality of Cx43 null mutation, we generated mice with selective osteoblast ablation of Cx43, obtained using a Cx43fl allele and a 2.3-kb fragment of the α1(I) collagen promoter to drive Cre in osteoblasts (ColCre). Conditionally osteoblast-deleted ColCre;Cx43–/fl mice show no malformations at birth, but develop low peak bone mass and remain osteopenic with age, exhibiting reduced bone formation and defective osteoblast function. By both radiodensitometry and histology, bone mineral content increased rapidly and progressively in adult Cx43+/fl mice after subcutaneous injection of parathyroid hormone (PTH), an effect significantly attenuated in ColCre;Cx43–/fl mice, with Cx43–/fl exhibiting an intermediate response. Attenuation of PTH anabolic action was associated with failure to increase mineral apposition rate in response to PTH in ColCre;Cx43–/fl, despite an increased osteoblast number, suggesting a functional defect in Cx43-deficient bone-forming cells. In conclusion, lack of Cx43 in osteoblasts leads to suboptimal acquisition of peak bone mass, and hinders the bone anabolic effect of PTH. Cx43 represents a potential target for modulation of bone anabolism.
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FFSS induces the disruption of the FAK-integrin complex, thereby inhibiting HDAC4/5, a negative regulator of SOST expression in osteocytes modulated by PTH treatment.
“Recently, Sato et al.20,44 showed that FFSS induces the disruption of the FAK-integrin complex, thereby inhibiting histone deacetylase 4/5 (HDAC4/5), a negative regulator of SOST expression in osteocytes45 modulated by parathyroid hormone (PTH) treatment.46”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [20]
Conditional knockout of Cx43 in osteoblasts and osteocytes in mice led to various degrees of osteopenia depending on the differentiation state in which the deletion was induced, suggesting that functional Cx43 in osteoblasts and osteocytes is essential for normal bone mass acquisition and maintenance.
“Conditional knockout of Cx43 in osteoblasts and osteocytes in mice led to various degrees of osteopenia depending on the differentiation state in which the deletion was induced,20,21 suggesting that functional Cx43 in osteoblasts and osteocytes is essential for normal bone mass acquisition and maintenance.”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [20]
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- Authors
- Chung, D. J., Castro, C. H. M., Watkins, M., Stains, J. P., Chung, M. Y., Szejnfeld, V. L., Willecke, K., Theis, M., & Civitelli, R.
- Affiliations
- Chonnam National University (KR)
- Division of Bone and Mineral Diseases, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, USA
- Washington University in St. Louis (US)
- Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo, Brasil
- University of Bonn (DE)
- Corresponding author
- Civitelli, Roberto
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2006-10-15
- Volume
- 119
- Issue
- 20
- Pages
- 4187-4198
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2092039312
- Cited by
- 169
- References
- 59
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 4 · 2020: 9 · 2019: 7 · 2018: 5 · 2017: 10 · 2016: 15 · 2015: 8 · 2014: 10 · 2013: 15 · 2012: 13
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- green
- americanae.aecid.es
- Licence
- other-oa
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- Americanae (AECID Library) (submittedVersion, other-oa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056341)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR041255)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- connexin 43, osteoblasts, parathyroid hormone, peak bone mass, bone formation, osteopenia, bone homeostasis, conditional knockout mice, Cre-loxP system
- MeSH terms
- Animals, Bone and Bones, Mice, Transgenic, Osteoblasts, Osteogenesis, Parathyroid Hormone, Phenotype, Blotting, Western, Bone Density, Gene Deletion, Gap Junctions, Connexin 43, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Cell Proliferation, Mice
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