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

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
Di LuTao Yang

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 Amer...Continue Reading

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Citations

Oct 3, 2018·International Journal of Molecular Sciences·Kyunghee LeeDaewon Jeong
Jan 11, 2020·Annals of the New York Academy of Sciences·Joseph L RobertsHicham Drissi
Mar 18, 2020·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Ella P DennisMichael D Briggs
Aug 19, 2021·Nature Communications·Sanja ArandjelovicKodi S Ravichandran

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