Dataset Information

Tissue-specific calibration of extracellular matrix material properties by transforming growth factor-? 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-? (TGF?)-responsive pathway that controls osteoblast differentiation. Deregulated TGF? 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 TGF? 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.

SUBMITTER: Chang JL

PROVIDER: S-EPMC2948188 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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

Chang Jolie L JL 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

EMBO reports 20100917 10

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 ...[more]

PMID: 20847738

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Project description:One possibility for the disproportionate increase in fracture risk with aging relative to the decrease in bone mass is an accumulation of changes to the bone matrix which deleteriously affect fracture resistance. In order to effectively develop new targets for osteoporosis, a preclinical model of the age-related loss in fracture resistance needs to be established beyond known age-related decreases in bone mineral density and bone volume fraction. To that end, we examined long bones of male and female BALB/c mice at 6-mo. and 20-mo. of age and assessed whether material and matrix properties of cortical bone significantly differed between the age groups. The second moment of area of the diaphysis (minimum and maximum principals for femur and radius, respectively) as measured by ex vivo micro-computed tomography (μCT) was higher at 20-mo. than at 6-mo. for both males and females, but ultimate moment as measured by three-point bending tests did not decrease with age. Cortical thickness was lower with age for males, but higher for old females. Partially accounting for differences in structure, material estimates of yield, ultimate stress, and toughness (left femur) were 12.6%, 11.1%, and 40.9% lower, respectively, with age for both sexes. The ability of the cortical bone to resist crack growth (right femur) was also 18.1% less for the old than for the young adult mice. These decreases in material properties were not due to changes in intracortical porosity as pore number decreased with age. Rather, age-related alterations in the matrix were observed for both sexes: enzymatic and non-enzymatic crosslinks by high performance liquid chromatography increased (femur), volume fraction of bound water by 1H-nuclear magnetic resonance relaxometry decreased (femur), cortical tissue mineral density by μCT increased (femur and radius), and an Amide I sub-peak ratio I1670/I1640 by Raman spectroscopy increased (tibia). Overall, there are multiple matrix changes to potentially target that could prevent the age-related decrease in fracture resistance observed in BALB/c mouse.

Dataset Information

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

Publications

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

Similar Datasets

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