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TRACP as an osteopontin phosphatase.
Göran Andersson1, Barbro Ek-Rylander, Karin Hollberg
1Karolinska Institutet, IMPI, Division of Pathology, Huddinge University Hospital, Huddinge, Sweden.
Summary
Tartrate-resistant acid phosphatase (TRACP) is activated by proteolytic cleavage, with cathepsin K likely activating it in osteoclasts. TRACP dephosphorylates osteopontin, impacting osteoclast function in bone.
Area of Science:
- Biochemistry
- Enzymology
- Cell Biology
Background:
- Tartrate-resistant acid phosphatase (TRACP) is a key enzyme synthesized as a latent proenzyme.
- Proteolytic processing is essential for TRACP to achieve maximal phosphatase activity.
- The enzyme's activity is regulated by its structure, cellular environment, and interactions with ligands.
Purpose of the Study:
- To elucidate the mechanism of TRACP activation and regulation.
- To identify the physiological activators of TRACP.
- To investigate the role of TRACP in bone metabolism, particularly its interaction with osteopontin.
Main Methods:
- Analysis of TRACP proenzyme processing and activation.
- Identification of enzymes involved in TRACP cleavage (cathepsin K and L).
- Investigation of TRACP activity in relation to pH, redox potential, and specific substrates like osteopontin.
Main Results:
- Proteolytic cleavage of a loop domain is crucial for TRACP activation, removing an inhibitory interaction.
- Cathepsin K and L efficiently activate latent TRACP; cathepsin K is proposed as the physiological activator in osteoclasts.
- TRACP dephosphorylates osteopontin (OPN), impairing osteoclast adhesion and migration, suggesting a role as an osteopontin phosphatase in bone.
Conclusions:
- TRACP activation is tightly regulated by proteolytic cleavage and specific cellular conditions (acidic pH, reducing equivalents).
- Cathepsin K is likely the primary physiological activator of TRACP in osteoclasts, with cathepsin L potentially acting in macrophages.
- TRACP plays a significant role in bone resorption by dephosphorylating osteopontin, and may have broader functions regulating OPN bioactivity in various tissues.