The Cellular and molecular Basis of FOP Lesions

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DESCRIPTION (provided by applicant): Altered Mechanotransduction in FOP Progenitor Cells Abstract Rare genetic disorders, although directly impacting relatively small segments of the population, are caused by mutations in genes with such critical importance that changes in their functions are rarely tolerated, providing unique insight into fundamental cellular mechanisms. One such disease, fibrodysplasia ossificans progressiva (FOP) is caused by misregulated control of cell fate decisions that lead to congenital skeletal malformations and progressive disabling extra-skeletal (heterotopic) endochondral ossification. We determined that all familial and sporadic cases of classic FOP carry the same heterozygous mutation in ACVR1/ALK2 (R206H; c.617G>A), a cell surface receptor that mediates signal transduction of bone morphogenetic proteins (BMPs). Our data show that ACVR1 R206H activates the BMP pathway, at least in part, through mildly activating BMP- independent signaling. Commitment and differentiation of progenitor cells are regulated by signals from the tissue microenvironment that direct cell fate to specific lineages, including BMPs that are established regulators of early development and cell differentiation. However, cells exist in vivo in a mechanical environment, experiencing local microenvironments of varying elasticity/stiffness and dynamic mechanical signals (such as tensile deformation) through physiologic activities. These mechanical signals can also direct cell fate decisions, and are mediated through some of the same pathways that transmit signals from classical soluble factors/cytokines. We propose that the R206H ACVR1 receptor mutation enhances progenitor cells to be more responsive to interactions with molecular and mechanical modulators of cell differentiation, and that in patients this enhanced sensitivity can trigger and/or mediate active episodes of endochondral bone formation. We hypothesize that enhanced BMP signaling by the ACVR1 R206H mutation alters the normal cell differentiation "set-point" of mesenchymal stem cells, increasing the sensitivity of these cells to microenvironmental mechanical cues that modulate cell fate decisions. A new multi-disciplinary team of investigators will work together on this BIRT proposal to accomplish two specific aims. Aim 1: To investigate the chondrogenic response of Acvr1R206H mutant cells to static mechanical forces and altered cell mechanics in the cell microenvironment. This Aim will examine differences in the internal cellular contractile machinery in cells with and without the Acvr1R206H mutation, and their response to changes in the elasticity (substrate stiffness) of the niche. Aim 2: To investigate the chondrogenic response of Acvr1R206H mutant cells to active mechanical forces (cell deformation) from the cell microenvironment. This Aim will examine the interactions of the ACVR1 R206H mutation with externally applied mechanical forces that alter cell shape (tensile deformation of the niche). The proposed highly innovative investigations will be conducted by a new and synergistic, multi- disciplinary, and interactive research team in order to identify regulatory mechanisms controlling cell differentiation and provide the foundation for establishing a new and innovative multidisciplinary research program.