Tissue-specific calibration of extracellular matrix material properties by transforming growth factor-β and Runx2 in bone is required for hearing

Department of Otolaryngology, Head and Neck Surgery, University of California at San Francisco, San Francisco, California 94143, USA.
EMBO Reports (Impact Factor: 9.06). 10/2010; 11(10):765-71. DOI: 10.1038/embor.2010.135
Source: PubMed


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.

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    • "Therefore, patients with CCD should be evaluated routinely by an otolaryngologist and should undergo complete audiological testing.[14] Deregulated transforming growth factor-b (TGFb) or RUNX2 function compromises the distinctly hard cochlear bone matrix and causes hearing loss in CCD.[15] Management for the patient with CCD is quite challenging. The earlier the treatment is initiated, the better is the prognosis.[16] "
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    ABSTRACT: Cleidocranial dysplasia is an inherited skeletal anomaly that affects primarily the skull, clavicle, and dentition, which can occur spontaneously, but most are inherited in autosomal dominant mode. The skull findings are brachycephaly, delayed or failed closure of the fontanelles, presence of open skull sutures and multiple wormian bones with pronounced frontal bossing. The syndrome is notable for aplasia or hypoplasia of the clavicles. The neck appears long and narrow and the shoulders markedly droop. Oral manifestations exhibit a hypoplastic maxilla with high-arched palate. Crowding of teeth is produced by retention of deciduous teeth, delayed eruption of permanent teeth, and the presence of a large number of unerupted supernumerary teeth. We report a case of CCD in a 12-year-old girl who presented with an unaesthetic facial appearance, unerupted permanent dentition with hearing loss.
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