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

Karin H. Nilsson; Petra Henning; Maha El Shahawy; Maria Nethander; Thomas Levin Andersen; Charlotte Ejersted; Jianyao Wu; Karin L. Gustafsson; Antti Koskela; Juha Tuukkanen; Pedro P.C. Souza; Jan Tuckermann; Mattias Lorentzon; Linda Engström Ruud; Terho Lehtimäki; Jon H. Tobias; Sirui Zhou; Ulf H. Lerner; J. Brent Richards; Sofia Movérare-Skrtic; Claes Ohlsson

doi:10.1038/s41467-021-25124-2

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

Karin H. Nilsson, Petra Henning, Maha El Shahawy, Maria Nethander, Thomas Levin Andersen, Charlotte Ejersted, Jianyao Wu, Karin L. Gustafsson, Antti Koskela, Juha Tuukkanen, Pedro P.C. Souza, Jan Tuckermann, Mattias Lorentzon, Linda Engström Ruud, Terho Lehtimäki, Jon H. Tobias, Sirui Zhou, Ulf H. Lerner, J. Brent Richards, Sofia Movérare-Skrtic^*Claes Ohlsson

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

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 language	English
Article number	4923
Journal	Nature Communications
Volume	12
Number of pages	18
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-021-25124-2
Publication status	Published - 13. Aug 2021

Bibliographical note

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

Keywords

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

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10.1038/s41467-021-25124-2Licence: CC BY

Open Access VersionFinal published version, 2.57 MBLicence: CC BY

Cite this

Nilsson, K. H., Henning, P., Shahawy, M. E., Nethander, M., Andersen, T. L., Ejersted, C., Wu, J., Gustafsson, K. L., Koskela, A., Tuukkanen, J., Souza, P. P. C., Tuckermann, J., Lorentzon, M., Ruud, L. E., Lehtimäki, T., Tobias, J. H., Zhou, S., Lerner, U. H., Richards, J. B., ... Ohlsson, C. (2021). RSPO3 is important for trabecular bone and fracture risk in mice and humans. Nature Communications, 12, Article 4923. https://doi.org/10.1038/s41467-021-25124-2

@article{9aee8f52b2c247719dc72cac68d025d9,

title = "RSPO3 is important for trabecular bone and fracture risk in mice and humans",

abstract = "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.",

keywords = "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",

author = "Nilsson, {Karin H.} and Petra Henning and Shahawy, {Maha El} and Maria Nethander and Andersen, {Thomas Levin} and Charlotte Ejersted and Jianyao Wu and Gustafsson, {Karin L.} and Antti Koskela and Juha Tuukkanen and Souza, {Pedro P.C.} and Jan Tuckermann and Mattias Lorentzon and Ruud, {Linda Engstr{\"o}m} and Terho Lehtim{\"a}ki and Tobias, {Jon H.} and Sirui Zhou and Lerner, {Ulf H.} and Richards, {J. Brent} and Sofia Mov{\'e}rare-Skrtic and Claes Ohlsson",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = aug,

day = "13",

doi = "10.1038/s41467-021-25124-2",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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Nilsson, KH, Henning, P, Shahawy, ME, Nethander, M, Andersen, TL, Ejersted, C, Wu, J, Gustafsson, KL, Koskela, A, Tuukkanen, J, Souza, PPC, Tuckermann, J, Lorentzon, M, Ruud, LE, Lehtimäki, T, Tobias, JH, Zhou, S, Lerner, UH, Richards, JB, Movérare-Skrtic, S & Ohlsson, C 2021, 'RSPO3 is important for trabecular bone and fracture risk in mice and humans', Nature Communications, vol. 12, 4923. https://doi.org/10.1038/s41467-021-25124-2

TY - JOUR

T1 - RSPO3 is important for trabecular bone and fracture risk in mice and humans

AU - Nilsson, Karin H.

AU - Henning, Petra

AU - Shahawy, Maha El

AU - Nethander, Maria

AU - Andersen, Thomas Levin

AU - Ejersted, Charlotte

AU - Wu, Jianyao

AU - Gustafsson, Karin L.

AU - Koskela, Antti

AU - Tuukkanen, Juha

AU - Souza, Pedro P.C.

AU - Tuckermann, Jan

AU - Lorentzon, Mattias

AU - Ruud, Linda Engström

AU - Lehtimäki, Terho

AU - Tobias, Jon H.

AU - Zhou, Sirui

AU - Lerner, Ulf H.

AU - Richards, J. Brent

AU - Movérare-Skrtic, Sofia

AU - Ohlsson, Claes

PY - 2021/8/13

Y1 - 2021/8/13

N2 - 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.

AB - 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.

KW - Animals

KW - Bone Density

KW - Cancellous Bone/injuries

KW - Cell Differentiation/genetics

KW - Cell Proliferation/genetics

KW - Cells, Cultured

KW - Fractures, Bone/genetics

KW - Genetic Predisposition to Disease/genetics

KW - Humans

KW - Mendelian Randomization Analysis/methods

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Osteoblasts/cytology

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

KW - Thrombospondins/deficiency

U2 - 10.1038/s41467-021-25124-2

DO - 10.1038/s41467-021-25124-2

M3 - Journal article

C2 - 34389713

AN - SCOPUS:85112714444

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

M1 - 4923

ER -

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

Abstract

Bibliographical note

Keywords

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