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Protein-tyrosine phosphatase activity regulates osteoclast formation and function: inhibition by alendronate

A Schmidt1, S J Rutledge, N Endo

  • 1Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486, USA.

Proceedings of the National Academy of Sciences of the United States of America
|April 2, 1996
PubMed

Insights

Alendronate (ALN), an osteoporosis drug, inhibits osteoclast protein-tyrosine phosphatase (PTPepsilon). This suggests PTP activity is a key target for bisphosphonate drugs, impacting bone resorption and osteoclast function.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Alendronate (ALN) is a widely used aminobisphosphonate for treating osteoporosis by inhibiting bone resorption.
  • The precise molecular target of ALN remains unidentified, hindering a complete understanding of its mechanism of action.

Purpose of the Study:

  • To investigate the effect of ALN on osteoclast protein-tyrosine phosphatase (PTPepsilon), a key enzyme in osteoclasts.
  • To determine if PTPepsilon activity is a potential molecular target for bisphosphonate drugs.

Main Methods:

  • Osteoclast-like cells were generated and PTPepsilon expression was analyzed using molecular cloning and RNA blot hybridization.
  • Purified PTPepsilon fusion protein was used to assess inhibition by ALN and other PTP inhibitors (orthovanadate, phenylarsine oxide).
  • In vitro assays evaluated the suppression of osteoclast formation and bone resorption by ALN and other PTP inhibitors.

Main Results:

  • PTPepsilon was found to be highly expressed in osteoclasts.
  • ALN inhibited purified PTPepsilon with an IC50 of 2 microM, and also affected other PTPs like PTPsigma and CD45.
  • ALN, orthovanadate, and phenylarsine oxide suppressed osteoclast formation and bone resorption in vitro.

Conclusions:

  • Tyrosine phosphatase activity is crucial for osteoclast formation and function.
  • PTPepsilon is a putative molecular target of bisphosphonate action, offering insights into ALN's mechanism.

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