Low-density lipoprotein receptor deficiency causes impaired osteoclastogenesis and increased bone mass in mice because of defect in osteoclastic cell-cell fusion

J Biol Chem. 2012 Jun 1;287(23):19229-41. doi: 10.1074/jbc.M111.323600. Epub 2012 Apr 12.

Abstract

Osteoporosis is associated with both atherosclerosis and vascular calcification attributed to hyperlipidemia. However, the cellular and molecular mechanisms explaining the parallel progression of these diseases remain unclear. Here, we used low-density lipoprotein receptor knockout (LDLR(-/-)) mice to elucidate the role of LDLR in regulating the differentiation of osteoclasts, which are responsible for bone resorption. Culturing wild-type osteoclast precursors in medium containing LDL-depleted serum decreased receptor activator of NF-κB ligand (RANKL)-induced osteoclast formation, and this defect was additively rescued by simultaneous treatment with native and oxidized LDLs. Osteoclast precursors constitutively expressed LDLR in a RANKL-independent manner. Osteoclast formation from LDLR(-/-) osteoclast precursors was delayed, and the multinucleated cells formed in culture were smaller and contained fewer nuclei than wild-type cells, implying impaired cell-cell fusion. Despite these findings, RANK signaling, including the activation of Erk and Akt, was normal in LDLR(-/-) preosteoclasts, and RANKL-induced expression of NFATc1 (a master regulator of osteoclastogenesis), cathepsin K, and tartrate-resistant acid phosphatase was equivalent in LDLR-null and wild-type cells. In contrast, the amounts of the osteoclast fusion-related proteins v-ATPase V(0) subunit d2 and dendritic cell-specific transmembrane protein in LDLR(-/-) plasma membranes were reduced when compared with the wild type, suggesting a correlation with impaired cell-cell fusion, which occurs on the plasma membrane. LDLR(-/-) mice consistently exhibited increased bone mass in vivo. This change was accompanied by decreases in bone resorption parameters, with no changes in bone formation parameters. These findings provide a novel mechanism for osteoclast differentiation and improve the understanding of the correlation between osteoclast formation and lipids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Resorption / genetics
  • Bone Resorption / metabolism*
  • Bone Resorption / pathology
  • Bone and Bones / metabolism*
  • Bone and Bones / pathology
  • Cell Differentiation*
  • Cell Fusion
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation / genetics
  • Humans
  • MAP Kinase Signaling System*
  • Mice
  • Mice, Knockout
  • NFATC Transcription Factors / biosynthesis
  • NFATC Transcription Factors / genetics
  • Organ Size
  • Osteoclasts / metabolism*
  • Osteoclasts / pathology
  • Osteoporosis / genetics
  • Osteoporosis / metabolism*
  • Osteoporosis / pathology
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RANK Ligand / genetics
  • RANK Ligand / metabolism
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Vacuolar Proton-Translocating ATPases / genetics
  • Vacuolar Proton-Translocating ATPases / metabolism

Substances

  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • RANK Ligand
  • Receptors, LDL
  • Tnfsf11 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Vacuolar Proton-Translocating ATPases