title: Parallel mechanisms suppress cochlear bone remodeling to protect hearing.
abstract: Bone remodeling, a combination of bone resorption and formation, requires precise regulation of cellular and molecular signaling to maintain proper bone quality. Whereas osteoblasts deposit and osteoclasts resorb bone matrix, osteocytes both dynamically resorb and replace perilacunar bone matrix. Osteocytes secrete proteases like matrix metalloproteinase-13 (MMP13) to maintain the material quality of bone matrix through perilacunar remodeling (PLR). Deregulated bone remodeling impairs bone quality and can compromise hearing since the auditory transduction mechanism is within bone. Understanding the mechanisms regulating cochlear bone provides unique ways to assess bone quality independent of other aspects that contribute to bone mechanical behavior. Cochlear bone is singular in its regulation of remodeling by expressing high levels of osteoprotegerin. Since cochlear bone expresses a key PLR enzyme, MMP13, we examined whether cochlear bone relies on, or is protected from, osteocyte-mediated PLR to maintain hearing and bone quality using a mouse model lacking MMP13 (MMP13(-/-)). We investigated the canalicular network, collagen organization, lacunar volume via micro-computed tomography, and dynamic histomorphometry. Despite finding defects in these hallmarks of PLR in MMP13(-/-) long bones, cochlear bone revealed no differences in these markers, nor hearing loss as measured by auditory brainstem response (ABR) or distortion product oto-acoustic emissions (DPOAEs), between wild type and MMP13(-/-) mice. Dynamic histomorphometry revealed abundant PLR by tibial osteocytes, but near absence in cochlear bone. Cochlear suppression of PLR corresponds to repression of several key PLR genes in the cochlea relative to long bones. These data suggest that cochlear bone uniquely maintains bone quality and hearing independent of MMP13-mediated osteocytic PLR. Furthermore, the cochlea employs parallel mechanisms to inhibit remodeling by osteoclasts and osteoblasts, and by osteocytes, to protect hearing. Understanding the cellular and molecular mechanisms that confer site-specific control of bone remodeling has the potential to elucidate new pathways that are deregulated in skeletal disease.
authors.affiliation: Department of Orthopaedic Surgery, University of California, San Francisco, United States.
authors.forename: Emmanuel J
authors.initials: EJ
authors.lastname: Jáuregui
authors.affiliation: Department of Otolaryngology-Head & Neck Surgery, University of California, San Francisco, United States.
authors.forename: Omar
authors.initials: O
authors.lastname: Akil
authors.affiliation: Department of Orthopaedic Surgery, University of California, San Francisco, United States; Materials Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA, United States.
authors.forename: Claire
authors.initials: C
authors.lastname: Acevedo
authors.affiliation: Department of Orthopaedic Surgery, University of California, San Francisco, United States.
authors.forename: Faith
authors.initials: F
authors.lastname: Hall-Glenn
authors.affiliation: Department of Otorhinolaryngology, University of Oklahoma Health Sciences Center, United States.
authors.forename: Betty S
authors.initials: BS
authors.lastname: Tsai
authors.affiliation: Materials Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA, United States.
authors.forename: Hrishikesh A
authors.initials: HA
authors.lastname: Bale
authors.affiliation: Department of Orthopaedic Surgery, University of California, San Francisco, United States.
authors.forename: Ellen
authors.initials: E
authors.lastname: Liebenberg
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, United States.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Humphrey
authors.affiliation: Materials Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA, United States.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Ritchie
authors.affiliation: Department of Otolaryngology-Head & Neck Surgery, University of California, San Francisco, United States.
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Lustig
authors.affiliation: Department of Orthopaedic Surgery, University of California, San Francisco, United States; Department of Otolaryngology-Head & Neck Surgery, University of California, San Francisco, United States. Electronic address: tamara.alliston@ucsf.edu.
authors.forename: Tamara
authors.initials: T
authors.lastname: Alliston
mesh_terms: D000818:Animals; D016723:Bone Remodeling / Q000502:physiology*; D003051:Cochlea / Q000033:anatomy & histology / Q000502:physiology*; D006309:Hearing / Q000502:physiology*; D053509:Matrix Metalloproteinase 13 / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D055114:X-Ray Microtomography
chemical_list: D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse
keywords: Bone matrix; Bone remodeling; Collagen; Matrix mineralization; Mouse model; Osteocytes; Perilacunar remodeling