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Lrp5 functions in bone to regulate bone mass

Abstract

The human skeleton is affected by mutations in low-density lipoprotein receptor-related protein 5 (LRP5). To understand how LRP5 influences bone properties, we generated mice with osteocyte-specific expression of inducible Lrp5 mutations that cause high and low bone mass phenotypes in humans. We found that bone properties in these mice were comparable to bone properties in mice with inherited mutations. We also induced an Lrp5 mutation in cells that form the appendicular skeleton but not in cells that form the axial skeleton; we observed that bone properties were altered in the limb but not in the spine. These data indicate that Lrp5 signaling functions locally, and they suggest that increasing LRP5 signaling in mature bone cells may be a strategy for treating human disorders associated with low bone mass, such as osteoporosis.

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Figure 1: Generation and characterization of HBM-causing Lrp5 knock-in mice.
Figure 2: Effect of activating Lrp5 NeoR-containing HBM alleles.
Figure 3: Generation and characterization of mice with a conditional knockout allele of Lrp5.
Figure 4: Effect of Lrp5 genotype on 5HT concentration and on Tph1 expression.
Figure 5: Bone mass in WT and Tph1−/− mice.
Figure 6: Bone mass after pharmacologic inhibition of Tph1 activity.

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Acknowledgements

We thank members of our laboratories for technical support: B. Newby, K. Kurek and E. Boyden for assistance with the HBM mouse studies; G. Zhou for assistance with histomorphometry; M. Niedecker and E. Kleinschmidt for assistance with radiography; the Case Transgenic and Targeting Facility; K. Sisson and P. Swiatek of the Van Andel Research Institute Mouse Germline Modification Core; B. Eagleson and the staff of the Van Andel Research Institute Vivarium; J. Bardenhagen, J. Greer, S. Jeter-Jones, J. Liu, M.K. Shadoan, D.D. Smith, W. Xiong and A. Yu of Lexicon Pharmaceuticals; and F. Bourgondien, R. Zhang and S. Yeh of Merck Sharp & Dohme Research Laboratories. This work was supported by the following grants: US National Institutes of Health (NIH) grant AR53237 (to A.G.R.); Public Health Service Career Development Award (UL 1RR025761-02) (to P.J.N.); NIH grant (GM74241) and a Leukemia and Lymphoma Society Scholarship (both to X.H.); NIH grant AR053293 and Van Andel Research Institute funds (to B.O.W.). M.L.W. is an investigator with the Howard Hughes Medical Institute.

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Authors

Contributions

Y.C. created and did studies on the mice with the Lrp5 HBM alleles and measured serum serotonin levels by competitive ELISA. P.J.N. did radiographic imaging and biomechanical testing on the mice with HBM-associated alleles. B.T.M. contributed to the serotonin and Tph1 qRT-PCR measurements in HBM-causing and Lrp5 knockout mice. C.R.Z. did multiple studies using the conditional Lrp5 knockout mice. N.A. studied the Tph1−/− mice, and with S.M. measured whole blood serotonin levels from HBM-causing and Lrp5-knockout mice by HPLC. D.R.R. generated the conditional Lrp5 knockout strain and Z.Z. participated in conditional inactivation of this allele using different Cre transgenes. C.M.J. carried out the Prrx1-Cre experiments. R.B., F.M. and Q.M.Y. organized studies on Lrp5- and Tph -knockout mice, and also organized the mouse pharmacology experiment. H.G. and J.A.G. organized the rat pharmacology experiment. R.A.C., X.H., M.B., D.R.P., Q.L., B.Z., B.O.W., A.G.R. and M.L.W. designed experiments and provided reagents and financial support. M.L.W. prepared the first draft of the manuscript. All co-authors contributed detailed methods and results, and revised and approved the manuscript.

Corresponding author

Correspondence to Matthew L Warman.

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Competing interests

Employees of Lexicon Pharmaceuticals (R.B., Q.L., F.M., D.R.P., Q.M.Y. and B.Z.) and Merck Sharp & Dohme Research Laboratories (H.G. and J.A.G.) have received compensation in the form of salary and stock options.

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Cui, Y., Niziolek, P., MacDonald, B. et al. Lrp5 functions in bone to regulate bone mass. Nat Med 17, 684–691 (2011). https://doi.org/10.1038/nm.2388

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