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- Title
Primary cilia mediate skeletogenic BMP and Hedgehog signaling in heterotopic ossification.
- Authors
He, Kai; Jiang, Heng; Li, Weijun; Toutounchi, Saman; Huang, Yan; Wu, Jianfeng; Ma, Xiaoyu; Baehr, Wolfgang; Pignolo, Robert J.; Ling, Kun; Zhou, Xuhui; Wang, Haitao; Hu, Jinghua
- Abstract
Heterotopic ossification (HO), defined as the formation of extraskeletal bone in muscle and soft tissues, is a diverse pathological process caused by either genetic mutations or inciting trauma. Fibrodysplasia ossificans progressiva (FOP) is a genetic form of HO caused by mutations in the bone morphogenetic protein (BMP) type I receptor gene activin A receptor type 1 (ACVR1). These mutations make ACVR1 hypersensitive to BMP and responsive to activin A. Hedgehog (Hh) signaling also contributes to HO development. However, the exact pathophysiology of how skeletogenic cells contribute to endochondral ossification in FOP remains unknown. Here, we showed that the wild-type or FOP-mutant ACVR1 localized in the cilia of stem cells from human exfoliated deciduous teeth with key FOP signaling components, including activin A receptor type 2A/2B, SMAD family member 1/5, and FK506-binding protein 12kD. Cilia suppression by deletion of intraflagellar transport 88 or ADP ribosylation factor like GTPase 3 effectively inhibited pathological BMP and Hh signaling, subdued aberrant chondro-osteogenic differentiation in primary mouse or human FOP cells, and diminished in vivo extraskeletal ossification in Acvr1Q207D, Sox2-Cre; Acvr1R206H/+ FOP mice and in burn tenotomy–treated wild-type mice. Our results provide a rationale for early and localized suppression of cilia in affected tissues after injury as a therapeutic strategy against either genetic or acquired HO. Editor's summary: Heterotopic ossification (HO) is ectopic bone formation common in fibrodysplasia ossificans progressiva (FOP). Cellular mechanisms of HO are not fully understood. He et al. found that inhibiting cilia formation on stem cells prevented HO in vitro and in mice. Genetically inhibiting two regulators of cilia formation, ADP ribosylation factor like GTPase 3 (ARL3) or intraflagellar transport 88, blocked HO in stem cells from exfoliated deciduous teeth from patients with FOP. Inhibiting these two genes in different mouse models of FOP resulted in decreased HO. Inhibiting Arl3 with a small interfering RNA treatment also reduced HO in a burn tenotomy model in wild-type mice. These data suggest that suppressing stem cell cilia could be a therapeutic approach to treat HO. —Brandon Berry
- Subjects
HEDGEHOG signaling proteins; HETEROTOPIC ossification; BONE morphogenetic proteins; CILIA &; ciliary motion; ACTIVIN receptors; FIBRODYSPLASIA ossificans progressiva
- Publication
Science Translational Medicine, 2024, Vol 16, Issue 757, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abn3486