Protein-Tyrosine Phosphatase Activity Regulates Osteoclast Formation and Function: Inhibition by Alendronate

Alendronate (ALN), an aminobisphosphonate used in the treatment of osteoporosis, is a potent inhibitor of bone resorption. Its molecular target is still unknown. This study examines the effects of ALN on the activity of osteoclast protein-tyrosine phosphatase (PTP; protein-tyrosine-phosphate phospho...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1996-04, Vol.93 (7), p.3068-3073
Main Authors: Schmidt, Azriel, Rutledge, Su Jane, Endo, Naoto, Opas, Evan E., Tanaka, Hirofumi, Wesolowski, Gregg, Leu, Chih Tai, Huang, Zheng, Ramachandaran, Chidambaram, Rodan, Sevgi B., Rodan, Gideon A.
Format: Article
Language:English
Subjects:
Alendronate
Amino Acid Sequence
Amino acids
Animals
Arsenicals - pharmacology
Bone Marrow Cells
Bone Resorption
Bones
Cell lines
Cloning, Molecular
Coculture Techniques
Diphosphonates - pharmacology
Enzyme Inhibitors - pharmacology
Gene Expression
Giant cells
Isoenzymes - antagonists & inhibitors
Isoenzymes - biosynthesis
Isoenzymes - metabolism
Kinetics
Mice
Molecular Sequence Data
Osteoclasts
Osteoclasts - drug effects
Osteoclasts - enzymology
Osteoclasts - physiology
Osteoporosis
Pharmacology
Phosphatases
Protein Tyrosine Phosphatases - antagonists & inhibitors
Protein Tyrosine Phosphatases - biosynthesis
Protein Tyrosine Phosphatases - metabolism
Rats
Recombinant Fusion Proteins - antagonists & inhibitors
Recombinant Fusion Proteins - biosynthesis
Recombinant Fusion Proteins - metabolism
RNA
Skull - cytology
Vanadates
Vanadates - pharmacology
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Summary:Alendronate (ALN), an aminobisphosphonate used in the treatment of osteoporosis, is a potent inhibitor of bone resorption. Its molecular target is still unknown. This study examines the effects of ALN on the activity of osteoclast protein-tyrosine phosphatase (PTP; protein-tyrosine-phosphate phosphohydrolase, EC 3.1.3.48), called PTPε . Using osteoclast-like cells generated by coculturing mouse bone marrow cells with mouse calvaria osteoblasts, we found by molecular cloning and RNA blot hybridization that PTPε is highly expressed in osteoclastic cells. A purified fusion protein of PTPε expressed in bacteria was inhibited by ALN with an IC50 of 2 μ M. Other PTP inhibitors--orthovanadate and phenylarsine oxide (PAO)--inhibited PTPε with IC50 values of 0.3 μ M and 18 μ M, respectively. ALN and another bisphosphonate, etidronate, also inhibited the activities of other bacterially expressed PTPs such as PTPσ and CD45 (also called leukocyte common antigen). The PTP inhibitors ALN, orthovanadate, and PAO suppressed in vitro formation of multinucleated osteoclasts from osteoclast precursors and in vitro bone resorption by isolated rat osteoclasts (pit formation) with estimated IC50 values of 10 μ M, 3 μ M, and 0.05 μ M, respectively. These findings suggest that tyrosine phosphatase activity plays an important role in osteoclast formation and function and is a putative molecular target of bisphosphonate action.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.93.7.3068