Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 30, Issue 1, Pages 17-29Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E18-05-0311
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Funding
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Building Interdisciplinary Research Teams (BIRT) Award from the National Institutes of Health (NIH) [3R01-AR041916-15S1]
- NIH [R01-AR071399, R01-EB008722]
- International Fibrodysplasia Ossificans Progressiva Association
- Center for Research in FOP and Related Disorders
- Ian Cali Endowment for FOP Research
- Whitney Weldon Endowment for FOP Research
- Cali-Weldon Professorship of FOP Research
- NIH NIAMS [F31 AR069982-01A1]
- National Science Foundation Graduate Research Fellowship [DGE-0822]
- Penn Center for Musculoskeletal Disorders [P30 AR069619]
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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.
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