Research ArticleBone

A self-amplifying loop of YAP and SHH drives formation and expansion of heterotopic ossification

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Science Translational Medicine  23 Jun 2021:
Vol. 13, Issue 599, eabb2233
DOI: 10.1126/scitranslmed.abb2233

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Understanding heterotopic ossification

Heterotopic ossification (HO), a condition where bone forms in nonskeletal tissues, is a common complication after soft tissue injury or surgery that remains incompletely understood, and treatment options are limited. Here, Cong and colleagues dissected out the molecular mechanisms of HO, finding that a positive feedback loop of YAP–Sonic hedgehog (SHH) signaling drove HO formation in several different mouse models of the disease. Pharmacological inhibition of YAP ameliorated HO expansion in both genetic and acquired HO murine models, suggesting that such inhibition may prevent or reduce HO expansion in humans.


Heterotopic ossification (HO) occurs as a common complication after injury or in genetic disorders. The mechanisms underlying HO remain incompletely understood, and there are no approved prophylactic or secondary treatments available. Here, we identify a self-amplifying, self-propagating loop of Yes-associated protein (YAP)–Sonic hedgehog (SHH) as a core molecular mechanism underlying diverse forms of HO. In mouse models of progressive osseous heteroplasia (POH), a disease caused by null mutations in GNAS, we found that Gnas−/− mesenchymal cells secreted SHH, which induced osteoblast differentiation of the surrounding wild-type cells. We further showed that loss of Gnas led to activation of YAP transcription activity, which directly drove Shh expression. Secreted SHH further induced YAP activation, Shh expression, and osteoblast differentiation in surrounding wild-type cells. This self-propagating positive feedback loop was both necessary and sufficient for HO expansion and could act independently of Gnas in fibrodysplasia ossificans progressiva (FOP), another genetic HO, and nonhereditary HO mouse models. Genetic or pharmacological inhibition of YAP or SHH abolished HO in POH and FOP and acquired HO mouse models without affecting normal bone homeostasis, providing a previously unrecognized therapeutic rationale to prevent, reduce, and shrink HO.

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