@article{bb4a23c4a32d40c39e0ec710052a3d3a,
title = "Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGF-RANKL signaling",
abstract = "Skeletal health relies on architectural integrity and sufficient bone mass, which are maintained through a tightly regulated equilibrium of bone resorption by osteoclasts and bone formation by osteoblasts. Genetic studies have linked the gene coding for low-density lipoprotein receptor-related protein1 (Lrp1) to bone traits but whether these associations are based on a causal molecular relationship is unknown. Here, we show that Lrp1 in osteoblasts is a novel regulator of osteoclast activity and bone mass. Mice lacking Lrp1 specifically in the osteoblast lineage displayed normal osteoblast function but severe osteoporosis due to highly increased osteoclast numbers and bone resorption. Osteoblast Lrp1 limited receptor activator of NF-κB ligand (RANKL) expression in vivo and in vitro through attenuation of platelet-derived growth factor (PDGF-BB) signaling. In co-culture, Lrp1-deficient osteoblasts stimulated osteoclastogenesis in a PDGFRβ-dependent manner and in vivo treatment with the PDGFR tyrosine kinase inhibitor imatinib mesylate limited RANKL production and led to complete remission of the osteoporotic phenotype. These results identify osteoblast Lrp1 as a key regulator of osteoblast-to-osteoclast communication and bone mass through a PDGF-RANKL signaling axis in osteoblasts and open perspectives to further explore the potential of PDGF signaling inhibitors in counteracting bone loss as well as to evaluate the importance of functional LRP1 gene variants in the control of bone mass in humans.",
author = "Alexander Bartelt and Friederike Behler-Janbeck and Beil, {F. Timo} and Till Koehne and Brigitte M{\"u}ller and Tobias Schmidt and Markus Heine and Laura Ochs and Tayfun Yilmaz and Martin Dietrich and Tuckermann, {Jan P.} and Michael Amling and Joachim Herz and Thorsten Schinke and Joerg Heeren and Andreas Niemeier",
note = "Funding Information: We thank Walter Tauscher, Gudrun Arndt, Birgit Henkel, Marianne Flato, Philip Missberger, Mona Neven, Olga Winter, Andrea Japke, and Sandra Ehret for excellent technical assistance. We are grateful to Ulrike Beisiegel for continuous support. We apologize to colleagues whose work we could not cite due to space limitations. This work was supported by Deutsche Forschungsgemeinschaft grants to A.N. (Ni637/2-3), J.Hee. (GRK1459), to J.P.T. (Tu220/6-1, 6-2, Collaborative Research Centre 1149 {\textquoteleft}Trauma{\textquoteright} (INST 40/492-1)) as well as to M.A. and T.S. (AM103/15-2 and Schi504/5-2 within the FOR793), the Bundesministerium f{\"u}r Bildung und Forschung projects A Network on Clinics and Pathophysiology of Osteophytes and Ancylosis, Metabolic Impact on Joint and Bone Diseases (ANCYLOSS 01EC1002B, METARTHROS) to A.N. and Tailored Magnetic Nanoparticles for Cancer Targeting project (TOMCAT 01EZ0824) to M.H., a Postdoctoral Fellowship Award from the European Atherosclerosis Society to A.B., and the Boehringer Ingelheim Foundation to J.P.T. J.Her. was the recipient of a Wolfgang Paul Award by the Humboldt Foundation and is supported by NIH grant R37-HL63762, the Ted Nash Longlife Foundation, the BrightFocus Foundation and the Consortium for Frontotemporal Dementia Research. Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41413-017-0006-3",
language = "English (US)",
volume = "6",
journal = "Bone Research",
issn = "2095-4700",
publisher = "Nature Publishing Group",
number = "1",
}