RSPO3 is important for trabecular bone and fracture risk in mice and humans.
Animals
Bone Density
Cancellous Bone
/ injuries
Cell Differentiation
/ genetics
Cell Proliferation
/ genetics
Cells, Cultured
Fractures, Bone
/ genetics
Genetic Predisposition to Disease
/ genetics
Humans
Mendelian Randomization Analysis
/ methods
Mice, Knockout
Mice, Transgenic
Osteoblasts
/ cytology
Polymorphism, Single Nucleotide
Risk Factors
Thrombospondins
/ deficiency
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 08 2021
13 08 2021
Historique:
received:
21
01
2021
accepted:
19
07
2021
entrez:
14
8
2021
pubmed:
15
8
2021
medline:
31
8
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34389713
doi: 10.1038/s41467-021-25124-2
pii: 10.1038/s41467-021-25124-2
pmc: PMC8363747
doi:
Substances chimiques
R-spondin3 protein, mouse
0
RSPO3 protein, human
0
Thrombospondins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4923Subventions
Organisme : CIHR
ID : 365825
Pays : Canada
Organisme : CIHR
ID : 409511
Pays : Canada
Organisme : Cancer Research UK
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
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