Loss of the auxiliary α 2 δ 1 voltage-sensitive calcium channel subunit impairs bone formation and anabolic responses to mechanical loading.

Autor:	Kelly MM; Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, United States.; College of Osteopathic Medicine, Marian University, Indianapolis, IN 46222, United States., Sharma K; Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, United States.; College of Osteopathic Medicine, Marian University, Indianapolis, IN 46222, United States., Wright CS; Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, United States.; Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN 46202, United States., Yi X; Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, United States.; Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN 46202, United States., Reyes Fernandez PC; Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, United States.; Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN 46202, United States., Gegg AT; Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, United States., Gorrell TA; Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, United States., Noonan ML; Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, United States., Baghdady A; College of Osteopathic Medicine, Marian University, Indianapolis, IN 46222, United States., Sieger JA; College of Osteopathic Medicine, Marian University, Indianapolis, IN 46222, United States., Dolphin AC; Department of Neuroscience, Physiology and Pharmacology, University College of London, Gower Street, London WC1E 6BT, United Kingdom., Warden SJ; Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, United States.; Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN 46202, United States.; La Trobe Sport and Exercise Medicine Research Centre, La Trobe University, Melbourne Victoria 3086, DX 211319, Australia., Deosthale P; Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN 46202, United States.; Department of Anatomy, Cell Biology, & Physiology, Indiana University, Indianapolis, IN 46202, United States., Plotkin LI; Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN 46202, United States.; Department of Anatomy, Cell Biology, & Physiology, Indiana University, Indianapolis, IN 46202, United States., Sankar U; Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN 46202, United States.; Department of Anatomy, Cell Biology, & Physiology, Indiana University, Indianapolis, IN 46202, United States., Hum JM; College of Osteopathic Medicine, Marian University, Indianapolis, IN 46222, United States.; Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN 46202, United States., Robling AG; Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN 46202, United States.; Department of Anatomy, Cell Biology, & Physiology, Indiana University, Indianapolis, IN 46202, United States., Farach-Carson MC; Department of Diagnostic & Biomedical Sciences, University of Texas Health Science Center at Houston School of Dentistry, Houston, TX 77054, United States., Thompson WR; Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, United States.; College of Osteopathic Medicine, Marian University, Indianapolis, IN 46222, United States.; Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN 46202, United States.; Department of Anatomy, Cell Biology, & Physiology, Indiana University, Indianapolis, IN 46202, United States.
Jazyk:	angličtina
Zdroj:	JBMR plus [JBMR Plus] 2024 Jan 10; Vol. 8 (2), pp. ziad008. Date of Electronic Publication: 2024 Jan 10 (Print Publication: 2024).
DOI:	10.1093/jbmrpl/ziad008
Abstrakt:	Voltage-sensitive calcium channels (VSCCs) influence bone structure and function, including anabolic responses to mechanical loading. While the pore-forming (α 1 ) subunit of VSCCs allows Ca 2+ influx, auxiliary subunits regulate the biophysical properties of the pore. The α 2 δ 1 subunit influences gating kinetics of the α 1 pore and enables mechanically induced signaling in osteocytes; however, the skeletal function of α 2 δ 1 in vivo remains unknown. In this work, we examined the skeletal consequences of deleting Cacna2d1 , the gene encoding α 2 δ 1 . Dual-energy X-ray absorptiometry and microcomputed tomography imaging demonstrated that deletion of α 2 δ 1 diminished bone mineral content and density in both male and female C57BL/6 mice. Structural differences manifested in both trabecular and cortical bone for males, while the absence of α 2 δ 1 affected only cortical bone in female mice. Deletion of α 2 δ 1 impaired skeletal mechanical properties in both sexes, as measured by three-point bending to failure. While no changes in osteoblast number or activity were found for either sex, male mice displayed a significant increase in osteoclast number, accompanied by increased eroded bone surface and upregulation of genes that regulate osteoclast differentiation. Deletion of α 2 δ 1 also rendered the skeleton insensitive to exogenous mechanical loading in males. While previous work demonstrates that VSCCs are essential for anabolic responses to mechanical loading, the mechanism by which these channels sense and respond to force remained unclear. Our data demonstrate that the α 2 δ 1 auxiliary VSCC subunit functions to maintain baseline bone mass and strength through regulation of osteoclast activity and also provides skeletal mechanotransduction in male mice. These data reveal a molecular player in our understanding of the mechanisms by which VSCCs influence skeletal adaptation. Competing Interests: None declared. (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)
Databáze:	MEDLINE
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