An additional Lrp4 high bone mass mutation mitigates the sost-knockout phenotype in mice by increasing bone remodeling
Pathogenic variants disrupting the binding between sclerostin (encoded by SOST) and its receptor LRP4 have previously been described to cause sclerosteosis, a rare high bone mass disorder. The sclerostin-LRP4 complex inhibits canonical WNT signaling, a key pathway regulating osteoblastic bone formation and a promising therapeutic target for common bone disorders, such as osteoporosis. In the current study, we crossed mice deficient for Sost (Sost(-/-)) with our p.Arg1170Gln Lrp4 knock-in (Lrp4(KI/KI)) mouse model to create double mutant Sost(-/-);Lrp4(KI/KI) mice. We compared the phenotype of Sost(-/-) mice with that of Sost(-/-);Lrp4(KI/KI) mice, to investigate a possible synergistic effect of the disease-causing p.Arg1170Trp variant in Lrp4 on Sost deficiency. Interestingly, presence of Lrp4(KI) alleles partially mitigated the Sost(-/-) phenotype. Cellular and dynamic histomorphometry did not reveal mechanistic insights into the observed phenotypic differences. We therefore determined the molecular effect of the Lrp4(KI) allele by performing bulk RNA sequencing on Lrp4(KI/KI) primary osteoblasts. Unexpectedly, mostly genes related to bone resorption or remodeling (Acp5, Rankl, Mmp9) were upregulated in Lrp4(KI/KI) primary osteoblasts. Verification of these markers in Lrp4(KI/KI), Sost(-/-) and Sost(-/-);Lrp4(KI/KI) mice revealed that sclerostin deficiency counteracts this Lrp4(KI/KI) effect in Sost(-/-);Lrp4(KI/KI) mice. We therefore hypothesize that models with two inactivating Lrp4(KI) alleles rather activate bone remodeling, with a net gain in bone mass, whereas sclerostin deficiency has more robust anabolic effects on bone formation. Moreover, these effects of sclerostin and Lrp4 are stronger in female mice, contributing to a more severe phenotype than in males and more detectable phenotypic differences among different genotypes.
Source (journal)
Calcified tissue international. - New York, N.Y., 1979, currens
New york : Springer , 2023
0171-967X [print]
1432-0827 [online]
(2023) , p. 1-11
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The author-created version that incorporates referee comments and is the accepted for publication version Available from 05.06.2024
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Project info
Study on the role of LRP4 in the regulation of Wnt signaling and bone formation.
Evaluation of the role of LRP4 in the regulation of Wnt/Bcatenin dependent Wnt signalling and bone formation.
Systems biology for the functional validation of genetic determinants of skeletal diseases (SYBIL).
Systems biology for the functional validation of genetic determinants of skeletal diseases (SYBIL).
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Publications with a UAntwerp address
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Web of Science
Creation 09.01.2024
Last edited 12.02.2024
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