University of Oulu

Nilsson, K.H., Henning, P., El Shahawy, M. et al. RSPO3 is important for trabecular bone and fracture risk in mice and humans. Nat Commun 12, 4923 (2021).

RSPO3 is important for trabecular bone and fracture risk in mice and humans

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Author: Nilsson, Karin H.1; Henning, Petra1; Shahawy, Maha El1,2;
Organizations: 1Univ Gothenburg, Sahlgrenska Acad, Inst Med, Sahlgrenska Osteoporosis Ctr,Ctr Bone & Arthrit R, Gothenburg, Sweden.
2Minia Univ, Dept Oral Biol, Fac Dent, Al Minya, Egypt.
3Univ Southern Denmark, Dept Clin Res, Odense, Denmark.
4Odense Univ Hosp, Dept Pathol, Odense, Denmark.
5Odense Univ Hosp, Dept Endocrinol, Odense, Denmark.
6Univ Oulu, Inst Canc Res & Translat Med, Dept Anat & Cell Biol, Fac Med, Oulu, Finland.
7Univ Fed Goias, Fac Dent, Innovat Biomat Lab, Goiania, Brazil.
8Univ Ulm, Inst Comparat Mol Endocrinol CME, Ulm, Germany.
9Sahlgrens Univ Hosp, Dept Geriatr Med, Reg Vastra Gotaland, Molndal, Sweden.
10Australian Catholic Univ, Mary MacKillop Inst Hlth Res, Melbourne, Vic, Australia.
11Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden.
12Fimlab Labs, Dept Clin Chem, Tampere, Finland.
13Tampere Univ, Fac Med & Hlth Technol, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland.
14Univ Bristol, Bristol Med Sch, Musculoskeletal Res Unit, Translat Hlth Sci & Med Res Council Integrat Epid, Bristol, Avon, England.
15McGill Univ, Lady Davis Inst, Jewish Gen Hosp, Dept Med,Ctr Clin Epidemiol, Montreal, PQ, Canada.
16McGill Univ, Dept Human Genet, Montreal, PQ, Canada.
17Sahlgrens Univ Hosp, Dept Drug Treatment, Reg Vastra Gotaland, Gothenburg, Sweden.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.6 MB)
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Language: English
Published: Springer Nature, 2021
Publish Date: 2021-09-13


With increasing age of the population, countries across the globe are facing a substantial increase in osteoporotic fractures. Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here we show that the fracture reducing allele at the RSPO3 locus associate with increased RSPO3 expression both at the mRNA and protein levels, increased trabecular bone mineral density and reduced risk mainly of distal forearm fractures in humans. We also demonstrate that RSPO3 is expressed in osteoprogenitor cells and osteoblasts and that osteoblast-derived RSPO3 is the principal source of RSPO3 in bone and an important regulator of vertebral trabecular bone mass and bone strength in adult mice. Mechanistic studies revealed that RSPO3 in a cell-autonomous manner increases osteoblast proliferation and differentiation. In conclusion, RSPO3 regulates vertebral trabecular bone mass and bone strength in mice and fracture risk in humans.

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Series: Nature communications
ISSN: 2041-1723
ISSN-E: 2041-1723
ISSN-L: 2041-1723
Volume: 12
Issue: 1
Article number: 4923
DOI: 10.1038/s41467-021-25124-2
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: Open access funding provided by University of Gothenburg. This study was supported by the Swedish Research Council, the Swedish Foundation of Strategic Research, the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement in Gothenburg, the IngaBritt and Arne Lundberg Foundation, the Torsten and Ragnar Söderberg’s Foundation, the Knut and Alice Wallenberg Foundation, the Novo Nordisk Foundation, and the Adlerbertska Research Foundation. The Richards research group is supported by the Canadian Institutes of Health Research (CIHR: 365825; 409511), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation, the NIH Foundation, Cancer Research UK, Genome Québec, the Public Health Agency of Canada and the Fonds de Recherche Québec Santé (FRQS). J.B.R. is supported by a FRQS Clinical Research Scholarship. Support from Calcul Québec and Compute Canada is acknowledged. TwinsUK is funded by the Welcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. These funding agencies had no role in the design, implementation or interpretation of this study. T.L.’s group has been financially supported by the Academy of Finland: grants 3322098, 286284, 117787; Competitive State Research Financing of the Expert Responsibility area of Tampere (grant X51001); Tampere University Hospital Supporting Foundation and Finnish Society of Clinical Chemistry.
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