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1 Zentrum Biochemie und Molekulare Zellbiologie, Abt. Biochemie II, Universität Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany
2 Department of Cell Biology, AMC, Meibergdreef 15, 1105 AZ Amsterdam, and Department of Periodontology, ACTA, University of Amsterdam The Netherlands
3 Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK
4 Anatomisches Institut, Christian Albrechts Universität Kiel, 24118 Kiel, Germany
5 Department of Medicine, University of Cambridge, Level 5, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK; Wellcome Trust, Institute of Cancer and Developmental Biology; and Department of Genetics, University of Cambridge CB2 1QR, UK
*Author for correspondence (e-mail: psaftig{at}gwdg.de)
Accepted August 31, 2001
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.
Key words: Bone resorption, Kupffer cells, Osteoclasts, Macrophages, Lysosomal storage, Osteopontin, Mouse
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