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

Karin H Nilsson, Petra Henning, Maha El Shahawy, Maria Nethander, Thomas L Andersen, Charlotte Ejersted, Jianyao Wu, Karin L Gustafsson, Antti Koskela, Juha Tuukkanen, Pedro P C Souza, Jan Tuckermann, Mattias Lorentzon, Linda Engstrom Ruud, Terho Lehtimaki, Jonathan H Tobias, Sirui Zhou, Ulf H Lerner, J Brent Richards, Sofia Moverare-SkrticClaes Ohlsson

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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.
Original languageEnglish
Article number4923
Number of pages18
JournalNature Communications
Issue number1
Early online date13 Aug 2021
Publication statusPublished - Dec 2021

Bibliographical note

Funding Information:
J.B.R. has served as an advisor to GlaxoSmithKline and Deerfield Capital. He has received investigator-initiated grant funding from Eli Lilly, GlaxoSmithKline and Biogen for projects unrelated to this paper. M.L. has received lecture fees from Amgen, Astellas, Lilly, Meda, Renapharma, UCB Pharma, and consulting fees from Amgen, Radius Health, UCB Pharma, Renapharma, and Consilient Health. The other authors declare no competing interests.

Funding Information:
We thank Anna Westerlund and Ulrika Björklund at the University of Gothenburg for excellent technical assistance. Single cell data analysis was performed by Sanna Abra-hamsson from the Bioinformatics Core Facility at the Sahlgrenska Academy. We thank Jian Q Feng from the Department of Biomedical Sciences at the Texas A&M University for providing the Dmp1-cre mice. 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.

Publisher Copyright:
© 2021, The Author(s).


  • bone
  • osteoblasts


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