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Cited by 44Bone health and osteoporosis researchBone Metabolism and DiseasesConnective tissue disorders research

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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Gregson, Celia L, Bergen, Dylan J. M., Leo, Paul, Sessions, Richard B, Wheeler, Lawrie, Hartley, April, Youlten, Scott, Croucher, Peter I +14 more·2020·Journal of Bone and Mineral Research
DOI 10.1002/jbmr.3875PMC PMC7004081
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Abstract

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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Authors
Gregson, C. L., Bergen, D. J. M., Leo, P., Sessions, R. B., Wheeler, L., Hartley, A., Youlten, S., Croucher, P. I., McInerney-Leo, A. M., Fraser, W., Tang, J. C., Anderson, L., Marshall, M., Sergot, L., Paternoster, L., Davey Smith, G., The AOGC Consortium, Brown, M. A., Hammond, C., Kemp, J. P., Tobias, J. H., & Duncan, E. L.
Affiliations
  • University of Bristol (GB)
  • Translational Research Institute (AU)
  • Garvan Institute of Medical Research (AU)
  • University of East Anglia (GB)
  • Severn School of Radiology, Severn Deanery Bristol UK
  • Medical Research Council Integrative Epidemiology Unit, Population Health Sciences Bristol Medical School, University of Bristol Bristol UK
  • The University of Queensland (AU)
  • Musculoskeletal Research Unit, Translational Health Sciences Bristol Medical School, University of Bristol Bristol UK
Corresponding author
Gregson, Celia L
ORCID
Venue
Journal of Bone and Mineral Research
Publisher
Oxford University Press (OUP)
Published
2019-09-16
Volume
35
Issue
1
Pages
92-105
ISSN
  • 0884-0431 (ISSN-L)
  • 1523-4681
DOI
10.1002/jbmr.3875
PMC
PMC7004081
OpenAlex
W2973985024
Cited by
44
References
71
Citations by year
2026: 7 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 6 · 2021: 13 · 2020: 8
FWCI
7.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Bone and Mineral Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (publishedVersion, cc-by)
  • Explore Bristol Research (publishedVersion, other-oa)
  • UEA Digital Repository (University of East Anglia) (acceptedVersion)
  • Bristol Research (University of Bristol) (acceptedVersion, other-oa)
  • QUT ePrints (Queensland University of Technology) (submittedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Funders
  • Arthritis Research UK (19476, 20000, 21211, 21937)
  • British Geriatrics Society
  • FP7 Health (247642)
  • Harold Hyam Wingate Foundation (DMMTF-180208, DMMTF‐180208)
  • Medical Research Council (MC_UU_12013/4)
  • National Health and Medical Research Council (1032571, 511132, GNT1158758)
  • University of Queensland (UQFEL1718945)
  • Wellcome Trust (080280/Z/06/Z, 101123, 20378/Z/16/Z, 204813/Z/16/Z)
  • NIHR (5163)
  • Medical Research Council Canada (MC_UU_12013/4)
Topics
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
Keywords
SMAD9, high bone mass, osteoporosis, anabolic therapy, BMP signaling, missense mutations, loss-of-function mutations, bone mineral density, osteocytes, genetic association, autosomal dominant inheritance
MeSH terms
Animals, Bone and Bones, Humans, Mutation, Osteoporosis, Zebrafish, Signal Transduction, Mice, Smad8 Protein

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