Cbl-PI3K interaction regulates Cathepsin K secretion in osteoclasts

Jungeun Yu, Naga Suresh Adapala, Laura Doherty, Archana Sanjay

Research output: Contribution to journalArticle

Abstract

Effective bone resorption by osteoclasts is critical for balanced bone remodeling. We have previously reported that mice harboring a substitution mutation of tyrosine 737 to phenylalanine in the adapter protein Cbl (CblY737F, YF) have increased bone volume partly due to decreased osteoclast-mediated bone resorption. The CblY737F mutation abrogates interaction between Cbl and the p85 subunit of PI3K. Here, we studied the mechanism for defective resorptive function of YF mutant osteoclasts. The YF osteoclasts had intact actin cytoskeletons and sealing zones. Expression and localization of proteins needed for acidification of the resorptive lacunae were also comparable between the WT and YF osteoclasts. In contrast, secretion of Cathepsin K, a major protease needed to degrade collagen, was diminished in the conditioned media derived from YF osteoclasts. The targeting of Cathepsin K into LAMP2-positive vesicles was also compromised due to decreased number of LAMP2-positive vesicles in YF osteoclasts. Further, we found that in contrast to WT, conditioned media derived from YF osteoclasts promoted increased numbers of alkaline phosphatase positive colonies, and increased expression of osteogenic markers in WT calvarial cultures. Cumulatively, our results suggest that the Cbl-PI3K interaction regulates Cathepsin K secretion required for proper bone resorption, and secretion of factors which promote osteogenesis.

Original languageEnglish (US)
Pages (from-to)376-385
Number of pages10
JournalBone
Volume127
DOIs
StatePublished - Oct 1 2019
Externally publishedYes

Fingerprint

Cathepsin K
Osteoclasts
Phosphatidylinositol 3-Kinases
Bone Resorption
Conditioned Culture Medium
Mutation
Bone Remodeling
Phenylalanine
Actin Cytoskeleton
Osteogenesis
Alkaline Phosphatase
Tyrosine
Proteins
Peptide Hydrolases
Collagen
Bone and Bones

Keywords

  • Cathepsin K
  • LAMP2
  • Osteoclast
  • PI3K and Cbl
  • Vesicular trafficking

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

Cite this

Cbl-PI3K interaction regulates Cathepsin K secretion in osteoclasts. / Yu, Jungeun; Adapala, Naga Suresh; Doherty, Laura; Sanjay, Archana.

In: Bone, Vol. 127, 01.10.2019, p. 376-385.

Research output: Contribution to journalArticle

Yu, Jungeun ; Adapala, Naga Suresh ; Doherty, Laura ; Sanjay, Archana. / Cbl-PI3K interaction regulates Cathepsin K secretion in osteoclasts. In: Bone. 2019 ; Vol. 127. pp. 376-385.
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