Olfactomedin-like protein OLFML1 inhibits Hippo signaling and mineralization in osteoblasts

Biochem Biophys Res Commun. 2018 Oct 28;505(2):419-425. doi: 10.1016/j.bbrc.2018.09.112. Epub 2018 Sep 25.


Congenital scoliosis is a lateral curvature of the spine that is due to the presence of vertebral anomalies. Although genetic and environmental factors are involved in the pathogenesis of congenital scoliosis, the specific cause of only a small number of individuals has been identified to date. We identified a de novo missense mutation in the olfactomedin-like 1 (OLFML1) gene by whole-exome sequencing of a patient with congenital scoliosis. Then, we carried out further functional investigation in mice. An assessment of the tissue distribution of Olfml1 revealed it to be prominently expressed in developing skeletal tissues, specifically osteoblasts. Short hairpin RNA-mediated knockdown of Olfml1 in osteoblasts induced the translocation of Yes-associated protein (YAP) transcriptional coactivator from the cytoplasm to the nucleus, which accelerated the Hippo signaling pathway to promote osteoblast mineralization. In contrast, experimentally induced gain of function of Olfml1 retained YAP in the cytoplasm. There appears to exist a novel cell-autonomous mechanism by which osteoblasts avoid excess mineralization through Olfml1. Our results also indicate that mutation of OLFML1 leads to impaired osteoblast differentiation and abnormal development of bone tissue.

Keywords: Congenital scoliosis; Hippo signaling; Olfml1; Osteoblasts; YAP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcification, Physiologic / drug effects*
  • Cell Cycle Proteins
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Extracellular Matrix Proteins / pharmacology
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Glycoproteins / pharmacology
  • Hippo Signaling Pathway
  • Humans
  • Mice
  • Mutation, Missense
  • Nuclear Proteins / metabolism
  • Osteoblasts / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Transport
  • Signal Transduction / drug effects*
  • Tissue Distribution
  • Transcription Factors / metabolism


  • Cell Cycle Proteins
  • Extracellular Matrix Proteins
  • Glycoproteins
  • Nuclear Proteins
  • OLFML1 protein, human
  • Olfml1 protein, mouse
  • Transcription Factors
  • YY1AP1 protein, human
  • olfactomedin
  • Protein Serine-Threonine Kinases