Proteolytic processing and polarized secretion of tartrate-resistant acid phosphatase is altered in a subpopulation of metaphyseal osteoclasts in cathepsin K-deficient mice

Bone ◽  
2007 ◽  
Vol 41 (5) ◽  
pp. 820-832 ◽  
Author(s):  
Serhan Zenger ◽  
Karin Hollberg ◽  
Jenny Ljusberg ◽  
Maria Norgård ◽  
Barbro Ek-Rylander ◽  
...  
Keyword(s):  
Acid Phosphatase ◽  
Cathepsin K ◽  
Proteolytic Processing ◽  
Tartrate Resistant Acid Phosphatase ◽  
Polarized Secretion ◽  
Deficient Mice

scholarly journals Cathepsin K regulates localization and secretion of Tartrate-Resistant Acid Phosphatase (TRAP) in TRAP-overexpressing MDA-MB-231 breast cancer cells

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Anja Reithmeier ◽  
Maria Norgård ◽  
Barbro Ek-Rylander ◽  
Tuomas Näreoja ◽  
Göran Andersson
Keyword(s):  
Breast Cancer ◽  
Acid Phosphatase ◽  
Cancer Cells ◽  
Phosphatase Activity ◽  
Breast Cancer Cells ◽  
Cathepsin K ◽  
Proteolytic Processing ◽  
Migration And Invasion ◽  
Tartrate Resistant Acid Phosphatase ◽  
Trap 5B

Abstract Background Tartrate–resistant acid phosphatase (TRAP/ ACP5) belongs to the binuclear metallophosphatase family and is present in two isoforms. The primary translation product is an uncleaved TRAP 5a isoform with low phosphatase activity. TRAP 5a can be post-translationally processed to a cleaved TRAP 5b isoform with high phosphatase activity by e.g. cysteine proteinases, such as Cathepsin K (CtsK). The relevance of the phosphatase activity of TRAP 5b has been demonstrated for proliferation, migration and invasion of cancer cells. TRAP-overexpressing MDA-MB-231 breast cancer cells displayed higher levels of TRAP 5a and efficient processing of TRAP 5a to TRAP 5b protein, but no changes in levels of CtsK when compared to mock-transfected cells. In TRAP-overexpressing cells colocalization of TRAP 5a and proCtsK was augmented, providing a plausible mechanism for generation of TRAP 5b. CtsK expression has been associated with cancer progression and has been pharmacologically targeted in several clinical studies. Results In the current study, CtsK inhibition with MK-0822/Odanacatib did not abrogate the formation of TRAP 5b, but reversibly increased the intracellular levels of a N-terminal fragment of TRAP 5b and reduced secretion of TRAP 5a reversibly. However, MK-0822 treatment neither altered intracellular TRAP activity nor TRAP-dependent cell migration, suggesting involvement of additional proteases in proteolytic processing of TRAP 5a. Notwithstanding, CtsK was shown to be colocalized with TRAP and to be involved in the regulation of secretion of TRAP 5a in a breast cancer cell line, while it still was not essential for processing of TRAP 5a to TRAP 5b isoform. Conclusion In cancer cells multiple proteases are involved in cleaving TRAP 5a to high-activity phosphatase TRAP 5b. However, CtsK-inhibiting treatment was able to reduce secretion TRAP 5a from TRAP-overexpressing cancer cells.

scholarly journals Directed differentiation of hematopoietic precursors and functional osteoclasts from human ES and iPS cells

Blood ◽  
2010 ◽  
Vol 115 (14) ◽  
pp. 2769-2776 ◽  
Author(s):  
Agamemnon E. Grigoriadis ◽  
Marion Kennedy ◽  
Aline Bozec ◽  
Fiona Brunton ◽  
Gudrun Stenbeck ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acid Phosphatase ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Cathepsin K ◽  
Embryoid Bodies ◽  
Tartrate Resistant Acid Phosphatase ◽  
Αvβ3 Integrin ◽  
Directed Differentiation ◽  
Induced Pluripotent

Abstract The directed differentiation of human pluripotent stem cells offers the unique opportunity to generate a broad spectrum of human cell types and tissues for transplantation, drug discovery, and studying disease mechanisms. Here, we report the stepwise generation of bone-resorbing osteoclasts from human embryonic and induced pluripotent stem cells. Generation of a primitive streak-like population in embryoid bodies, followed by specification to hematopoiesis and myelopoiesis by vascular endothelial growth factor and hematopoietic cytokines in serum-free media, yielded a precursor population enriched for cells expressing the monocyte-macrophage lineage markers CD14, CD18, CD11b, and CD115. When plated in monolayer culture in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand (RANKL), these precursors formed large, multinucleated osteoclasts that expressed tartrate-resistant acid phosphatase and were capable of resorption. No tartrate-resistant acid phosphatase-positive multinucleated cells or resorption pits were observed in the absence of RANKL. Molecular analyses confirmed the expression of the osteoclast marker genes NFATc1, cathepsin K, and calcitonin receptor in a RANKL-dependent manner, and confocal microscopy demonstrated the coexpression of the αvβ3 integrin, cathepsin K and F-actin rings characteristic of active osteoclasts. Generating hematopoietic and osteoclast populations from human embryonic and induced pluripotent stem cells will be invaluable for understanding embryonic bone development and postnatal bone disease.

Overlapping functions of lysosomal acid phosphatase (LAP) and tartrate-resistant acid phosphatase (Acp5) revealed by doubly deficient mice

Development ◽  
2001 ◽  
Vol 128 (23) ◽  
pp. 4899-4910
Author(s):  
Anke Suter ◽  
Vincent Everts ◽  
Alan Boyde ◽  
Sheila J. Jones ◽  
Renate Lüllmann-Rauch ◽  
...  
Keyword(s):  
Acid Phosphatase ◽  
Tartrate Resistant Acid Phosphatase ◽  
Arylsulfatase A ◽  
Acid Phosphatases ◽  
Lysosomal Storage ◽  
Lysosomal Acid ◽  
Biochemical Analyses ◽  
Filamentous Material ◽  
Gait Disturbances ◽  
Deficient Mice

To date, two lysosomal acid phosphatases are known to be expressed in cells of the monocyte/phagocyte lineage: the ubiquitously expressed lysosomal acid phosphatase (LAP) and the tartrate-resistant acid phosphatase-type 5 (Acp5). Deficiency of either acid phosphatase results in relatively mild phenotypes, suggesting that these enzymes may be capable of mutual complementation. This prompted us to generate LAP/Acp5 doubly deficient mice. LAP/Acp5 doubly deficient mice are viable and fertile but display marked alterations in soft and mineralised tissues. They are characterised by a progressive hepatosplenomegaly, gait disturbances and exaggerated foreshortening of long bones. Histologically, these animals are distinguished by an excessive lysosomal storage in macrophages of the liver, spleen, bone marrow, kidney and by altered growth plates. Microscopic analyses showed an accumulation of osteopontin adjacent to actively resorbing osteoclasts of Acp5- and LAP/Acp5-deficient mice. In osteoclasts of phosphatase-deficient mice, vacuoles were frequently found which contained fine filamentous material. The vacuoles in Acp5- and LAP/Acp5 doubly-deficient osteoclasts also contained crystallite-like features, as well as osteopontin, suggesting that Acp5 is important for processing of this protein. This is further supported by biochemical analyses that demonstrate strongly reduced dephosphorylation of osteopontin incubated with LAP/Acp5-deficient bone extracts. Fibroblasts derived from LAP/Acp5 deficient embryos were still able to dephosphorylate mannose 6-phosphate residues of endocytosed arylsulfatase A. We conclude that for several substrates LAP and Acp5 can substitute for each other and that these acid phosphatases are essential for processing of non-collagenous proteins, including osteopontin, by osteoclasts.

Increased cathepsin K and tartrate-resistant acid phosphatase expression in bone of streptozotocin-induced diabetic rats

Bone ◽  
2007 ◽  
Vol 41 (6) ◽  
pp. 1045-1050 ◽  
Author(s):  
Mamiko Hie ◽  
Masumi Shimono ◽  
Kayoko Fujii ◽  
Ikuyo Tsukamoto
Keyword(s):  
Acid Phosphatase ◽  
Cathepsin K ◽  
Diabetic Rats ◽  
Tartrate Resistant Acid Phosphatase
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