Tissue-specific calibration of extracellular matrix material properties by transforming growth factor-β and Runx2 in bone is required for hearing.
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.
Chang
Jolie L
JL
Department of Otolaryngology, Head and Neck Surgery, University of California at San Francisco, San Francisco, California 94143, USA.
Brauer
Delia S
DS
Johnson
Jacob
J
Chen
Carol G
CG
Akil
Omar
O
Balooch
Guive
G
Humphrey
Mary Beth
MB
Chin
Emily N
EN
Porter
Alexandra E
AE
Butcher
Kristin
K
Ritchie
Robert O
RO
Schneider
Richard A
RA
Lalwani
Anil
A
Derynck
Rik
R
Marshall
Grayson W
GW
Marshall
Sally J
SJ
Lustig
Lawrence
L
Alliston
Tamara
T
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*
D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta