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

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


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.


Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / metabolism
  • Bone Resorption / metabolism*
  • Bone Resorption / pathology
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / drug effects
  • Bone and Bones / pathology
  • Cathepsin K / genetics
  • Cell Differentiation / drug effects
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / metabolism
  • NF-kappa B / metabolism*
  • Organ Size / drug effects
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism*
  • Osteogenesis* / drug effects
  • Phenotype
  • RANK Ligand / pharmacology*
  • RAW 264.7 Cells
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Signal Transduction* / drug effects
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • X-Ray Microtomography
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse
  • NF-kappa B
  • RANK Ligand
  • RNA, Messenger
  • Receptors, LDL
  • Tumor Suppressor Proteins
  • p38 Mitogen-Activated Protein Kinases
  • Cathepsin K