Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

Lei Xiong, Ji Ung Jung, Haitao Wu, Wen Fang Xia, Jin Xiu Pan, Chengyong Shen, Lin Mei, Wen Cheng Xiong

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Bone mass is maintained by balanced activity of osteoblasts and osteoclasts. Lrp4 (low-density lipoprotein receptor related protein 4) is a member of the LDL receptor family, whose mutations have been identified in patients with high-bone-mass disorders, such as sclerosteosis and van Buchem diseases. However, it remains unknown whether and how Lrp4 regulates bone-mass homeostasis in vivo. Here we provide evidence that Lrp4-null mutation or specific mutation in osteoblast-lineage cells increased cortical and trabecular bone mass, which was associated with elevated bone formation and impaired bone resorption. This phenotype was not observed in osteoclast-selective Lrp4 knockout mice. Mechanistic studies indicate that loss of Lrp4 function in osteoblast-lineage cells increased serum levels of sclerostin, a key factor for bone-mass homeostasis that interacts with Lrp4, but abolished the inhibition of Wnt/β-catenin signaling and osteoblastic differentiation by sclerostin. Concomitantly, sclerostin induction of RANKL (receptor activator of nuclear kappa B ligand) was impaired, leading to a lower ratio of RANKL over OPG (osteoprotegerin) (a key factor for osteoclastogenesis). Taken together, these results support the view for Lrp4 as a receptor of sclerostin to inhibit Wnt/β-catenin signaling and bone formation and identify Lrp4 as a critical player in bonemass homeostasis.

Original languageEnglish (US)
Pages (from-to)3487-3492
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number11
DOIs
StatePublished - Mar 17 2015

Keywords

  • LRP4
  • Osteoblasts
  • Osteoclasts
  • Sclerostin
  • β-catenin

ASJC Scopus subject areas

  • General

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