LRP1 Suppresses Bone Resorption in Mice by Inhibiting the RANKL‐Stimulated NF‐κB and p38 Pathways During Osteoclastogenesis. (12th June 2018)

• Record Type: Journal Article
• Authors: Lu, Di; Li, Jianshuang; Liu, Huadie; Foxa, Gabrielle E; Weaver, Kevin; Li, Jie; Williams, Bart O; Yang, Tao
• Is Part Of: Journal of bone and mineral research. Volume 33:Number 10(2018)
• Page Start: 1773
• Page End: 1784
• Publication Date: 2018-06-12
• Subjects: LRP1 -- OSTEOCLASTOGENESIS -- RANKL -- OSTEOPOROSIS; Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.3469
• Languages: English
• ISSNs: 0884-0431

Abstract

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;Lrp1 f/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.