A Glanzmann's Mutation in Beta 3 Integrin Specifically Impairs Osteoclast Function

J Clin Invest. 2001 May;107(9):1137-44. doi: 10.1172/JCI12040.

Abstract

Osteoclastic bone resorption requires cell-matrix contact, an event mediated by the alpha v beta 3 integrin. The structural components of the integrin that mediate osteoclast function are, however, not in hand. To address this issue, we generated mice lacking the beta 3 integrin gene, which have dysfunctional osteoclasts. Here, we show the full rescue of beta 3(-/-) osteoclast function following expression of a full-length beta 3 integrin. In contrast, truncated beta 3, lacking a cytoplasmic domain (h beta 3c), is completely ineffective in restoring function to beta 3(-/-) osteoclasts. To identify the components of the beta 3 cytoplasmic domain regulating osteoclast function, we generated six point mutants known, in other circumstances, to mediate beta integrin signaling. Of the six, only the S(752)P substitution, which also characterizes a form of the human bleeding disorder Glanzmann's thrombasthenia, fails to rescue beta 3(-/-) osteoclasts or restore ligand-activated signaling in the form of c-src activation. Interestingly, the double mutation Y(747)F/Y(759)F, which disrupts platelet function, does not affect the osteoclast. Thus similarities and distinctions exist in the mechanisms by which the beta 3 integrin regulates platelets and osteoclasts.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, CD / genetics*
  • Bone Resorption / genetics*
  • Cell Size
  • Cytoskeleton / pathology
  • Integrin beta3
  • Integrins / genetics*
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Osteoclasts / metabolism*
  • Osteoclasts / pathology
  • Platelet Membrane Glycoproteins / genetics*
  • Point Mutation
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Sequence Homology, Amino Acid
  • Stem Cells / metabolism
  • Stem Cells / pathology
  • Thrombasthenia / genetics*

Substances

  • Antigens, CD
  • Integrin beta3
  • Integrins
  • Platelet Membrane Glycoproteins
  • Proto-Oncogene Proteins pp60(c-src)