The CaV1.2 L-type calcium channel regulates bone homeostasis in the middle and inner ear

Chike Cao, Aaron B. Oswald, Brian A. Fabella, Yinshi Ren, Ramona Rodriguiz, George Trainor, Matthew B. Greenblatt, Matthew J. Hilton, Geoffrey S. Pitt

Research output: Contribution to journalArticle

Abstract

Bone remodeling of the auditory ossicles and the otic capsule is highly restricted and tightly controlled by the osteoprotegerin (OPG)/receptor activator of nuclear factor kappa-Β ligand (RANKL)/receptor activator of nuclear factor kappa-Β (RANK) system. In these bony structures, a pathological decrease in OPG expression stimulates osteoclast differentiation and excessive resorption followed by accrual of sclerotic bone, ultimately resulting in the development of otosclerosis, a leading cause of deafness in adults. Understanding the signaling pathways involved in maintaining OPG expression in the ear would shed light on the pathophysiology of otosclerosis and other ear bone-related diseases. We and others previously demonstrated that Ca2+ signaling through the L-type CaV1.2 Ca2+ channel positively regulates OPG expression and secretion in long bone osteoblasts and their precursor cells in vitro and in vivo. Whether CaV1.2 regulates OPG expression in ear bones has not been investigated. We drove expression of a gain-of-function CaV1.2 mutant channel (CaV1.2TS) using Col2a1-Cre, which we found to target osteochondral/osteoblast progenitors in the auditory ossicles and the otic capsule. Col2a1-Cre;CaV1.2TS mice displayed osteopetrosis of these bones shown by μCT 3D reconstruction, histological analysis, and lack of bone sculpting, findings similar to phenotypes seen in mice with an osteoclast defect. Consistent with those observations, we found that Col2a1-Cre;CaV1.2TS mutant mice showed reduced osteoclasts in the otic capsule, upregulated mRNA expression of Opg and Opg/Rankl ratio, and increased mRNA expression of osteoblast differentiation marker genes in the otic capsule, suggesting both an anti-catabolic and anabolic effect of CaV1.2TS mutant channel contributed to the observed morphological changes of the ear bones. Further, we found that Col2a1-Cre;CaV1.2TS mice experienced hearing loss and displayed defects of body balance in behavior tests, confirming that the CaV1.2-dependent Ca2+ influx affects bone structure in the ear and consequent hearing and vestibular functions. Together, these data support our hypothesis that Ca2+ influx through CaV1.2TS promotes OPG expression from osteoblasts, thereby affecting bone modeling/remodeling in the auditory ossicles and the otic capsule. These data provide insight into potential pathological mechanisms underlying perturbed OPG expression and otosclerosis.

Original languageEnglish (US)
Pages (from-to)160-168
Number of pages9
JournalBone
Volume125
DOIs
StatePublished - Aug 2019
Externally publishedYes

Fingerprint

L-Type Calcium Channels
Middle Ear
Inner Ear
Osteoprotegerin
Ear
Homeostasis
Bone and Bones
Ear Ossicles
Capsules
Osteoblasts
Otosclerosis
Osteoclasts
Bone Remodeling
L-type calcium channel alpha(1C)
Osteopetrosis
Anabolic Agents
kappa Opioid Receptor
Messenger RNA
Bone Diseases
Differentiation Antigens

Keywords

  • Ca1.2
  • Ca signaling
  • Osteoclast
  • Osteoprotegerin
  • Otosclerosis

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

Cite this

Cao, C., Oswald, A. B., Fabella, B. A., Ren, Y., Rodriguiz, R., Trainor, G., ... Pitt, G. S. (2019). The CaV1.2 L-type calcium channel regulates bone homeostasis in the middle and inner ear. Bone, 125, 160-168. https://doi.org/10.1016/j.bone.2019.05.024

The CaV1.2 L-type calcium channel regulates bone homeostasis in the middle and inner ear. / Cao, Chike; Oswald, Aaron B.; Fabella, Brian A.; Ren, Yinshi; Rodriguiz, Ramona; Trainor, George; Greenblatt, Matthew B.; Hilton, Matthew J.; Pitt, Geoffrey S.

In: Bone, Vol. 125, 08.2019, p. 160-168.

Research output: Contribution to journalArticle

Cao, C, Oswald, AB, Fabella, BA, Ren, Y, Rodriguiz, R, Trainor, G, Greenblatt, MB, Hilton, MJ & Pitt, GS 2019, 'The CaV1.2 L-type calcium channel regulates bone homeostasis in the middle and inner ear', Bone, vol. 125, pp. 160-168. https://doi.org/10.1016/j.bone.2019.05.024
Cao, Chike ; Oswald, Aaron B. ; Fabella, Brian A. ; Ren, Yinshi ; Rodriguiz, Ramona ; Trainor, George ; Greenblatt, Matthew B. ; Hilton, Matthew J. ; Pitt, Geoffrey S. / The CaV1.2 L-type calcium channel regulates bone homeostasis in the middle and inner ear. In: Bone. 2019 ; Vol. 125. pp. 160-168.
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