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Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGF–RANKL signaling

Bone Research 2018年第1期6卷 50-59页

作者： Alexander Bartelt friederike behler-janbeck F.Timo Beil Till Koehne Brigitte Müller Tobias Schmidt Markus Heine Laura Ochs Tayfun Yilmaz Martin Dietrich Jan P.Tuckermann Michael Amling Joachim Herz Thorsten Schinke Joerg Heeren Andreas Niemeier Department of Orthopaedics University Medical Center Hamburg-EppendorfMartinistr.5220246 HamburgGermany Department of Biochemistry and Molecular Cell Biology University Medical Center Hamburg-EppendorfMartinistr.5220246 HamburgGermany Department of Osteology and Biomechanics University Medical Center Hamburg-EppendorfMartinistr5220246 HamburgGermany Department of Orthodontics University Medical Center Hamburg-EppendorfMartinistr52 20246 HamburgGermany Department of Anatomy and Experimental Morphology University Medical Center Hamburg-EppendorfMartinistr.5220246 HamburgGermany Department of Molecular Genetics University of Texas Southwestern Medical CenterDallasTX 75390USA Institute for Comparative Molecular Endocrinology University of UlmUlmGermany Correspondence:Andreas Niemeier Department of Genetics and Complex Diseases&Sabriülker Center Harvard T.H.Chan School of Public Health665 Huntington AvenueBostonMA 02115USA

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 *** 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.

关键词： PDGFRβ RANKL activator receptor imatinib axis gene vivo

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