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Tartrate-resistant acid phosphatase knockout mice
Alison R Hayman1, Timothy M Cox
1Department of Clinical Veterinary Science, University of Bristol, Langford, United Kingdom.
Abstract:
TRACP is a lysosomal enzyme found in diverse tissues, where it is expressed in dendritic cells as well as osteoclasts and macrophages. To investigate the function of TRACP in vivo, we have generated mice in which the gene-encoding TRACP has been selectively disrupted by targeted homologous recombination in murine embryonic stem cells. Homozygous TRACP "knockout" mice have progressive foreshortening and deformity of the long bones and axial skeleton suggesting a role for TRACP in endochondral ossification. There is increased mineralization reflecting a mild osteopetrosis caused by reduced osteoclast modeling activity. These knockout mice also display an impairment of macrophage function with abnormal immunomodulatory cytokine responses. Superoxide formation and nitrite production were enhanced in stimulated macrophages lacking TRACP as was the secretion of the proinflammatory cytokines TNF-alpha, interleukin (IL)-1beta, and IL-12. TRACP knockout mice showed delayed clearance of the microbial pathogen Staphylococcus aureus after sublethal intraperitoneal inoculation. The macrophages lacking TRACP showed an increase in tartrate-sensitive lysosomal acid phosphatase activity (LAP). The TRACP knockout mice were bred with mice lacking LAP. Mice lacking both TRACP and LAP had even shorter bones than the TRACP single knockouts. Osteopontin, identical to the T-cell cytokine eta-1, accumulated adjacent to actively resorbing osteoclasts suggesting that both phosphatases are important for processing this protein. We propose that TRACP may be an important regulator of osteopontin/eta-1 activity common to both the immune system and skeleton.
Insights
Targeting tartrate-resistant acid phosphatase (TRACP) disrupts skeletal development and impairs macrophage function. TRACP knockout mice exhibit bone deformities and delayed pathogen clearance, highlighting its role in immunity and bone remodeling.
Area of Science:
- Biochemistry
- Immunology
- Skeletal Biology
Background:
- Tartrate-resistant acid phosphatase (TRACP) is a lysosomal enzyme present in osteoclasts, macrophages, and dendritic cells.
- Its precise in vivo function, particularly in skeletal and immune processes, remains incompletely understood.
Purpose of the Study:
- To elucidate the in vivo role of TRACP in skeletal development and macrophage function.
- To investigate the interplay between TRACP, lysosomal acid phosphatase (LAP), and osteopontin.
Main Methods:
- Generation of TRACP-deficient mice using targeted homologous recombination in embryonic stem cells.
- Phenotypic analysis of TRACP knockout mice, including skeletal morphology, bone mineralization, and macrophage function assays.
- Assessment of immune responses, cytokine profiles, and microbial pathogen clearance.
- Cross-breeding TRACP knockout mice with LAP-deficient mice.
Main Results:
- TRACP knockout mice displayed progressive skeletal deformities, including foreshortened long bones and axial skeleton, indicative of impaired endochondral ossification.
- Mild osteopetrosis was observed due to reduced osteoclast modeling activity and increased mineralization.
- Macrophages lacking TRACP showed enhanced superoxide and nitrite production, increased pro-inflammatory cytokine secretion (TNF-alpha, IL-1beta, IL-12), and impaired clearance of Staphylococcus aureus.
- Mice lacking both TRACP and LAP exhibited more severe skeletal defects than TRACP single knockouts, with accumulation of osteopontin near osteoclasts.
Conclusions:
- TRACP is crucial for normal skeletal development, specifically endochondral ossification and osteoclast modeling.
- TRACP plays a significant role in macrophage function, influencing cytokine responses and pathogen clearance.
- TRACP, along with LAP, is important for osteopontin processing, suggesting a shared regulatory role in both skeletal and immune systems.
