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. 2018 Oct;33(10):1773-1784.
doi: 10.1002/jbmr.3469. Epub 2018 Jun 12.

LRP1 Suppresses Bone Resorption in Mice by Inhibiting the RANKL-Stimulated NF-κB and p38 Pathways During Osteoclastogenesis

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LRP1 Suppresses Bone Resorption in Mice by Inhibiting the RANKL-Stimulated NF-κB and p38 Pathways During Osteoclastogenesis

Di Lu et al. J Bone Miner Res. .
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Abstract

Single-nucleotide polymorphisms in the LRP1 gene coding sequence are associated with low bone mass, and cell culture studies suggest that LRP1 plays a role in osteoblast proliferation and osteoblast-mediated osteoclastogenesis. However, the in vivo function of LRP1 in bone homeostasis has not been explored. In this work, we studied the osteoclast-specific role of LRP1 in bone homeostasis using a Ctsk-Cre;Lrp1f/f mouse model on the C57BL/6J background. These mice had a dramatically decreased trabecular bone mass with markedly more osteoclasts, while the osteoblast activity was unaffected or slightly increased. The cortical bone parameters were largely unaltered. Upon RANKL treatment, Lrp1-deficient bone marrow monocytes more efficiently differentiated into osteoclasts and showed elevated p65 NFκB and p38 signaling. Consistently, Lrp1-overexpressing Raw264.7 cells were desensitized to RANKL-induced p38 and p65 activation and osteoclastogenesis. Moreover, RANKL treatment led to a sharp decrease of LRP1 protein and RNA in BMMs. Overall, our data suggest that osteoclast-expressed LRP1 is a crucial regulator of bone mass. It inhibits the NFκB and p38 pathways and lessens the efficiency of RANKL-induced osteoclastogenesis. © 2018 American Society for Bone and Mineral Research.

Keywords: LRP1; OSTEOCLASTOGENESIS; OSTEOPOROSIS; RANKL.

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