NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification

Barruet, Emilie; Morales, Blanca M.; Cain, Corey J.; Ton, Amy N.; Wentworth, Kelly; Chan, Tea V.; Moody, Tania; Haks, Mariëlle C.; Ottenhoff, Tom H. M.; Hellman, Judith; Nakamura, Mary C.; Hsiao, Edward C.

doi:10.1172/jci.insight.122958

Cited by 81 publications

(100 citation statements)

References 114 publications

(119 reference statements)

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“…The inflammatory nature of flare-ups in FOP is clinically obvious and well-described (41). In FOP patients without clinically evident HO, increased serum levels of cytokines, including IL3-, IL-7, IL-8, and IL-10, suggest a persistent proinflammatory state (42). So-called "inflammaging" refers to the chronic, sterile, low-grade inflammation which develops as part of normal aging, and is thought to contribute to the pathogenesis of multiple age-related diseases (43).…”

Section: Segmental Progeroid Features Of Fopmentioning

confidence: 99%

Fibrodysplasia Ossificans Progressiva (FOP): A Segmental Progeroid Syndrome

2020

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Segmental progeroid syndromes are commonly represented by genetic conditions which recapitulate aspects of physiological aging by similar, disparate, or unknown mechanisms. Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by mutations in the gene for ACVR1/ALK2 encoding Activin A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor, and results in the formation of extra-skeletal ossification and a constellation of others features, many of which resemble accelerated aging. The median estimated lifespan of individuals with FOP is approximately 56 years of age. Characteristics of precocious aging in FOP include both those that are related to dysregulated BMP signaling as well as those secondary to early immobilization. Progeroid features that may primarily be associated with mutations in ACVR1 include osteoarthritis, hearing loss, alopecia, subcutaneous lipodystrophy, myelination defects, heightened inflammation, menstrual abnormalities, and perhaps nephrolithiasis. Progeroid features that may secondarily be related to immobilization from progressive heterotopic ossification include decreased vital capacity, osteoporosis, fractures, sarcopenia, and predisposition to respiratory infections. Some manifestations of precocious aging may be attributed to both primary and secondary effects of FOP. At the level of lesion formation in FOP, soft tissue injury resulting in hypoxia, cell damage, and inflammation may lead to the accumulation of senescent cells as in aged tissue. Production of Activin A, platelet-derived growth factor, metalloproteinases, interleukin 6, and other inflammatory cytokines as part of the senescence-associated secretory phenotype could conceivably mediate the initial signaling cascade that results in the intense fibroproliferative response as well as the tissue-resident stem cell reprogramming leading up to ectopic endochondral bone formation. Consideration of FOP as a segmental progeroid syndrome offers a unique perspective into potential mechanisms of normal aging and may also provide insight for identification of new targets for therapeutic interventions in FOP.

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Section: Segmental Progeroid Features Of Fopmentioning

confidence: 99%

Fibrodysplasia Ossificans Progressiva (FOP): A Segmental Progeroid Syndrome

2020

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“…In FOP, muscle tissue differentiates into bone following trivial injury, resulting in the formation of mature bone at multiple extra-skeletal sites. ACVR1 mutations may produce a more severe phenotype, compared with loss-of-function mutations in SMAD9 reported here, since ACVR1 also activates non-SMAD dependent BMP signalling cascades such as the NF-κB and p38 MAP kinase (p38MAPK) pathways, which are upregulated in FOP ACVR1 R206H monocytes 46 .…”

Section: Discussionmentioning

confidence: 71%

A rare SMAD9 mutation identifies the BMP signalling pathway as a potential osteoanabolic target

Gregson

Bergen

et al. 2019

Preprint

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To identify targets for novel anabolic medicines for osteoporosis, we recruited a large cohort with unexplained high bone mass (HBM). Exome sequencing identified a rare (minor allele frequency 0.0014) missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in an autosomal dominant family. The same mutation was identified in another two unrelated individuals with HBM. In-silico protein modelling predicts the mutation severely disrupts the MH1 DNA-binding domain of SMAD9. Affected individuals have bone mineral density [BMD] Z-Scores +3 to +5, with increased volumetric cortical and trabecular BMD, increased cortical thickness, and low/normal bone turnover. Fractures and nerve compressions are not seen. Both genome-wide, and gene-based association testing of heel estimated-BMD in >362,924 UK-Biobank British subjects showed strong associations with SMAD9 (PGWAS=6x10 -16 ; PGENE =8×10 -17 ). Smad9 is highly expressed in murine osteocytes and zebrafish bone tissue. Our findings support SMAD9 as a novel HBM gene, and a potential novel osteoanabolic target.

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“…(58) Such examples of diverse phenotypes arising from mutations in differing exons of the same gene are well recognized, eg, differing mutations in FBN1 (Fibrillin 1) can cause Marfan syndrome (with associated tall stature) (OMIM#154700), acromicric dysplasias (with short stature) (OMIM#102370), or stiff skin syndrome (OMIM#184900). (64) Given the benign phenotype observed in c.65T>C, p.Leu22Pro SMAD9 carriers, our findings suggest that SMAD9 is worth consideration as a drug target for osteoporosis. A rare SMAD6 mutation has been associated with susceptibility to nonsyndromic midline craniosynostosis 7 (OMIM#617439), but only in the context of co-inheritance of a common variant in BMP2 strongly associated with this condition, a rare example of two locus inheritance.…”

Section: Discussionmentioning

confidence: 71%

“…ACVR1 mutations may produce a more severe phenotype, compared with loss-of-function mutations in SMAD9 reported here, since ACVR1 also activates non-SMAD-dependent BMP signaling cascades, such as the NF-κB and p38 MAP kinase (p38MAPK) pathways, which are upregulated in FOP ACVR1 R206H monocytes. (64) Given the benign phenotype observed in c.65T>C, p.Leu22Pro SMAD9 carriers, our findings suggest that SMAD9 is worth consideration as a drug target for osteoporosis. Our zebrafish studies suggest that Smad9 is expressed in pre-osteoblasts, consistent with the profile of an anabolic target capable of stimulating new bone formation through recruitment of early osteoblast progenitors.…”

Section: Discussionmentioning

confidence: 71%

A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD-Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis

Gregson

Bergen

Leo

et al. 2019

Journal of Bone and Mineral Research

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Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA‐binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z‐scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome‐wide and gene‐based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (PGWAS = 6 × 10−16; PGENE = 8 × 10−17). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone–derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)‐dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss‐of‐function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

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NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification

Cited by 81 publications

References 114 publications

Fibrodysplasia Ossificans Progressiva (FOP): A Segmental Progeroid Syndrome

Fibrodysplasia Ossificans Progressiva (FOP): A Segmental Progeroid Syndrome

A rare SMAD9 mutation identifies the BMP signalling pathway as a potential osteoanabolic target

A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD-Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis

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