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

Abstract

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.

Self-amplifying loop of NF-κB and periostin initiated by PIEZO1 accelerates mechano-induced senescence of nucleus pulposus cells and intervertebral disc degeneration

“…Targeting dCas9-KRAB to putative enhancers or promoters recruits the H3K9 methyltransferase SET domain bifurcated histone lysine methyltransferase 1 (SETDB1), which increases local H3K9me3 binding and represses target gene expression. 33 As expected, dCas9-KRAB guided by sgRNA targeting the NF-kB p65 binding site in the POSTN promoter greatly reduced POSTN expression under TNF-a treatment (Figure 2M). In addition, we generated a luciferase reporter construct driven by the POSTN promoter (Figure S2B) and performed a dual-luciferase reporter assay.…”

Human osteoprogenitor cells obtained from traumatic heterotopic ossification samples showed enhanced osteogenic differentiation potential and ERK/hedgehog signaling than that from normal bone

“…Interestingly, rather than independently exerting their effects, the ERK and hedgehog signaling pathway displayed crosstalk between each other in HO‐ops upon osteogenic induction. The significance of hedgehog signaling pathway in trauma‐induced osteogenic milieu has also been confirmed in transgenic murine models by several scholars 31,32 . Likewise, in a study by Tu et al, ERK signaling has also been suggested to involved in the murine soft tissues HO formation downstream of Connexin 43 33 .…”

“…The significance of hedgehog signaling pathway in trauma-induced osteogenic milieu has also been confirmed in transgenic murine models by several scholars. 31,32 Likewise, in a study by Tu et al, ERK signaling has also been suggested to involved in the murine soft tissues HO formation downstream of Connexin 43. 33 Since ERK is also a master regulator highly linked to inflammation, targeting ERK signaling could reach a synergistic beneficial effect on wound healing.…”

“…Since ERK is also a master regulator highly linked to inflammation, targeting ERK signaling could reach a synergistic beneficial effect on wound healing 34 . Analogously, as hedgehog signaling is not required for orthotopic skeletal development, it serves as a preferable therapeutic target as well 31 …”

Gnas Loss Causes Chondrocyte Fate Conversion in Cranial Suture Formation

“…Loss-of-function mutations in the GNAS gene cause progressive osseous heteroplasia (POH) (OMIM #166350), Albright hereditary osteodystrophy (AHO, OMIM #103580), or pseudo-pseudohypoparathyroidism (PPHP, OMIM #612 463) (Shore et al 2002), three rare autosomal dominant disorders. Loss of GNAS is characterized by progressive heterotopic ossification (HO) in extraskeletal soft tissue (Cong et al 2021). Although only a few clinical craniosynostosis cases due to loss of GNAS have been reported, infantile lethal cerebral infarction after surgery was documented (Leclercq et al 2018).…”