In:
Molecular Biology of the Cell, American Society for Cell Biology (ASCB), Vol. 30, No. 1 ( 2019-01), p. 17-29
Kurzfassung:
An activating bone morphogenetic proteins (BMP) type I receptor ACVR1 (ACVR1 R206H ) mutation enhances BMP pathway signaling and causes the rare genetic disorder of heterotopic (extraskeletal) bone formation fibrodysplasia ossificans progressiva. Heterotopic ossification frequently occurs following injury as cells aberrantly differentiate during tissue repair. Biomechanical signals from the tissue microenvironment and cellular responses to these physical cues, such as stiffness and rigidity, are important determinants of cell differentiation and are modulated by BMP signaling. We used an Acvr1 R206H/+ mouse model of injury-induced heterotopic ossification to examine the fibroproliferative tissue preceding heterotopic bone and identified pathologic stiffening at this stage of repair. In response to microenvironment stiffness, in vitro assays showed that Acvr1 R206H/+ cells inappropriately sense their environment, responding to soft substrates with a spread morphology similar to wild-type cells on stiff substrates and to cells undergoing osteoblastogenesis. Increased activation of RhoA and its downstream effectors demonstrated increased mechanosignaling. Nuclear localization of the pro-osteoblastic factor RUNX2 on soft and stiff substrates suggests a predisposition to this cell fate. Our data support that increased BMP signaling in Acvr1 R206H/+ cells alters the tissue microenvironment and results in misinterpretation of the tissue microenvironment through altered sensitivity to mechanical stimuli that lowers the threshold for commitment to chondro/osteogenic lineages.
Materialart:
Online-Ressource
ISSN:
1059-1524
,
1939-4586
DOI:
10.1091/mbc.E18-05-0311
Sprache:
Englisch
Verlag:
American Society for Cell Biology (ASCB)
Publikationsdatum:
2019
ZDB Id:
1474922-1
SSG:
12
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