title: Tissue-specific calibration of extracellular matrix material properties by transforming growth factor-β and Runx2 in bone is required for hearing.
abstract: Physical cues, such as extracellular matrix stiffness, direct cell differentiation and support tissue-specific function. Perturbation of these cues underlies diverse pathologies, including osteoarthritis, cardiovascular disease and cancer. However, the molecular mechanisms that establish tissue-specific material properties and link them to healthy tissue function are unknown. We show that Runx2, a key lineage-specific transcription factor, regulates the material properties of bone matrix through the same transforming growth factor-β (TGFβ)-responsive pathway that controls osteoblast differentiation. Deregulated TGFβ or Runx2 function compromises the distinctly hard cochlear bone matrix and causes hearing loss, as seen in human cleidocranial dysplasia. In Runx2+/⁻ mice, inhibition of TGFβ signalling rescues both the material properties of the defective matrix, and hearing. This study elucidates the unknown cause of hearing loss in cleidocranial dysplasia, and demonstrates that a molecular pathway controlling cell differentiation also defines material properties of extracellular matrix. Furthermore, our results suggest that the careful regulation of these properties is essential for healthy tissue function.
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University of California at San Francisco, San Francisco, California 94143, USA.
authors.forename: Jolie L
authors.initials: JL
authors.lastname: Chang
authors.forename: Delia S
authors.initials: DS
authors.lastname: Brauer
authors.forename: Jacob
authors.initials: J
authors.lastname: Johnson
authors.forename: Carol G
authors.initials: CG
authors.lastname: Chen
authors.forename: Omar
authors.initials: O
authors.lastname: Akil
authors.forename: Guive
authors.initials: G
authors.lastname: Balooch
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Humphrey
authors.forename: Emily N
authors.initials: EN
authors.lastname: Chin
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Porter
authors.forename: Kristin
authors.initials: K
authors.lastname: Butcher
authors.forename: Robert O
authors.initials: RO
authors.lastname: Ritchie
authors.forename: Richard A
authors.initials: RA
authors.lastname: Schneider
authors.forename: Anil
authors.initials: A
authors.lastname: Lalwani
authors.forename: Rik
authors.initials: R
authors.lastname: Derynck
authors.forename: Grayson W
authors.initials: GW
authors.lastname: Marshall
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Marshall
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lustig
authors.forename: Tamara
authors.initials: T
authors.lastname: Alliston
mesh_terms: D000818:Animals; D001844:Bone Conduction; D001846:Bone Development / Q000502:physiology; D001857:Bone Matrix / Q000378:metabolism*; D002454:Cell Differentiation; D002973:Cleidocranial Dysplasia / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D004195:Disease Models, Animal; D055119:Elastic Modulus; D005109:Extracellular Matrix / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta