THE PURPLE ACID phosphatases (PAP) are a diverse group of metalloenzymes that have a high degree of homology in their active site structure and possess a dinuclear Fe-Fe or Fe-Zn center critical to enzymatic activity. The clinically relevant enzyme in man, and the homologous enzymes in rodents are more commonly known as tartrate-resistant acid phosphatases (TRACP) because of their resistance to L( ) tartaric acid. TRACP is important to the community of physicians and scientists interested in bone disease and bone metabolism because it is the best-known marker for bone-resorbing osteoclasts and their precursors. In fact, in the parlance of bone researchers, the phrase “TRACP-positive multinuclear cells” is almost universally accepted as a definitive description for osteoclasts. Recently, with the development of specific immunoassays for serum TRACP, it is emerging as a new and clinically relevant biomarker for osteoclastic activity and bone resorption rate. Despite over 50 years of history and over 30 years of investigation, the physiologic function of TRACP in osteoclasts, macrophages, and other TRACP-expressing cells still eludes us to a great degree. Because interest in TRACP as a key player in bone metabolism and immune responses is now rapidly increasing, we convened a small group of researchers with noted special expertise in TRACP/PAP to share and discuss recent advances made. The first “Progress on TRACP/PAP” Symposium, co-sponsored by the Research Service of the VA Medical Center, Louisville, Kentucky, and SBA-Sciences, Suomen Bioanalytiikka Oy, Turku, Finland, was held during the 23rd Annual Meeting of ASBMR in Phoenix, Arizona. Eight speakers reviewed their latest work relating to TRACP/PAP and discussed areas needing further work and exploration. Jussi Halleen opened the symposium on behalf of SBA-Sciences, which commercialized a method known as “BoneTRAP,” an immunoassay specifically detecting osteoclast-derived TRACP 5b activity from human serum. Dr Halleen described the scientific background and accumulated clinical data using the BoneTRAP assay. The data strongly suggest that serum TRACP 5b is a specific and sensitive marker of bone resorption. Lung Yam then provided a foundation for the remainder of the meeting by presenting his personalized, historical perspective of 30 years of research and clinical experience with TRACP as a cell marker for osteoclasts, macrophages, and hairy cell leukemia. KH William Lau followed with a review of his work with fluoride-sensitive TRACP in osteoblasts that may be central to understanding the anabolic effects of fluoride on bone. Bruce Averill then reviewed his recent findings with proteolytic activation of PAP, explaining how post-translational processing allows the dinuclear iron center to assume the mixed valency state associated with maximal activity. Ian Cassady reviewed how the TRACP promoter is regulated by two independently acting but synergistic, transcription factors, PU.1 and MiTF, and showed some evidence suggesting these factors may work in a tissue-specific manner. Alison Hayman described the abnormal skeletal and immune phenotypes resulting from targeted disruption of TRACP in mice, confirming that TRACP plays key roles in normal function of both systems. Jussi Halleen presented provocative evidence for a role of TRACP in generating intracellular reactive oxygen species in osteoclasts. Such a function could be involved in further destruction of bone matrix degradation products by the osteoclast during their transcytosis from the ruffled border to a functional secretory domain in the basolateral membrane and in antigen processing by macrophages. Karin Hollberg reviewed considerable data from the laboratory of Goran Andersson, supporting the hypothesis that a major function of TRACP is dephosphorylation of osteopontin and bone sialoprotein in the resorption lacunae. Such a function could regulate osteoclastic attachment to, migration across, and release from the bone surface. Anthony Janckila concluded by reviewing recent experience using TRACP immunoassays for activity and protein, suggesting a diseasespecific expression of separate TRACP isoforms. From this work in rheumatoid arthritis and end-stage renal disease, he proposed that TRACP 5a may have clinical significance in diseases of chronic inflammation, while TRACP 5b was further validated as a specific and sensitive marker for bone resorption. The authors have no conflict of interest.
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Jul 21, 2020
Ming-Zhi Huang + 5
Open Access
