Journal
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 33, Issue 10, Pages 1773-1784Publisher
WILEY
DOI: 10.1002/jbmr.3469
Keywords
LRP1; OSTEOCLASTOGENESIS; RANKL; OSTEOPOROSIS
Categories
Funding
- Van Andel Research Institute (VARI)
- VARI Faculty Innovation Award
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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 NFB 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 NFB and p38 pathways and lessens the efficiency of RANKL-induced osteoclastogenesis. (c) 2018 American Society for Bone and Mineral Research.
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