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Mycobacterium tuberculosis chaperonin 10 stimulates bone resorption: A potential contributory factor in Pott's disease

Meghji, S; White, PA; Nair, SP; Reddi, K; Heron, K; Henderson, B; Zaliani, A; Fossati, G; Mascagni, P; Hunt, JF; et al. Meghji, S; White, PA; Nair, SP; Reddi, K; Heron, K; Henderson, B; Zaliani, A; Fossati, G; Mascagni, P; Hunt, JF; Roberts, MM; Coates, AR (1997) Mycobacterium tuberculosis chaperonin 10 stimulates bone resorption: A potential contributory factor in Pott's disease. JOURNAL OF EXPERIMENTAL MEDICINE, 186 (8). 1241 - 1246. ISSN 0022-1007 https://doi.org/10.1084/jem.186.8.1241
SGUL Authors: Coates, Anthony Robert Milnes

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Abstract

Pott's disease (spinal tuberculosis), a condition characterized by massive resorption of the spinal vertebrae, is one of the most striking pathologies resulting from local infection with Mycobacterium tuberculosis (Mt; Boachie-Adjei, O., and R.G. Squillante. 1996. Orthop. Clin. North Am. 27:95–103). The pathogenesis of Pott's disease is not established. Here we report for the first time that a protein, identified by a monoclonal antibody to be the Mt heat shock protein (Baird, P.N., L.M. Hall, and A.R.M. Coates. 1989. J. Gen. Microbiol. 135:931–939) chaperonin (cpn) 10, is responsible for the osteolytic activity of this bacterium. Recombinant Mt cpn10 is a potent stimulator of bone resorption in bone explant cultures and induces osteoclast recruitment, while inhibiting the proliferation of an osteoblast bone–forming cell line. Furthermore, we have found that synthetic peptides corresponding to sequences within the flexible loop and sequence 65–70 of Mt cpn10 may comprise a single conformational unit which encompasses its potent bone-resorbing activity. Our findings suggest that Mt cpn10 may be a valuable pharmacological target for the clinical therapy of vertebral tuberculosis and possibly other bone diseases. Tuberculosis is epidemic, accounting for 7% of the annual worldwide death toll (1). Tuberculous infections of bone, particularly of the spinal vertebrae (Pott's disease), are still common in the third world (2). It is not known how Mycobacterium tuberculosis (Mt)1 infections of bone cause bone breakdown. Healthy bone is maintained by a dynamic equilibrium between the mesenchymal bone matrix–forming osteoblast cell lineage and the myeloid bone– resorbing osteoclast cell lineage (3). Mt infection of the spine obviously alters this dynamic equilibrium, resulting in the net loss of the extracellular matrix of vertebral bone and collapse of the vertebrae. Whether this loss of bone matrix is the result of the direct action of components of Mt, for example, the LPS-like cell surface molecule lipoarabinomannan (LAM) (4), on bone cells, or an indirect activation of inflammatory cells leading to bone cell activation, is not established. Evidence is appearing to suggest that molecular chaperones have biological actions in addition to their intracellular protein–folding activity (5). For example, chaperonin (cpn)10 has been found to be an essential growth and immunosuppressive factor in early pregnancy (6), and cpn60 induces cytokine synthesis (7) and resorption of bone (8). In this study we have established that the bone resorbing activity of Mt is due to cpn10 which is as active as the most potent osteolytic cytokine, IL-1 (9, 10). Mt cpn10 also appears to induce the recruitment of osteoclasts in calvaria, and it is notable that calvarial bone resorption induced by this cpn can be completely blocked by the osteoclast-inhibiting hormone, calcitonin (11). Mt cpn10 was also found to inhibit the proliferation of cultured osteoblasts. Using a series of NH2- and COOH-terminal truncated peptides, we have identified sites in Mt cpn10 responsible for the osteolytic activity of this molecular chaperone. We have identified the flexible loop of Mt cpn10 and the sequence 65–70 as regions most probably responsible for the bone-modulating bioactivity of this molecule.

Item Type: Article
Additional Information: © The Rockefeller University Press RUP grants the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode.
Keywords: Amino Acid Sequence, Animals, Bone Resorption, Calcium, Cell Line, Chaperonin 10, Dose-Response Relationship, Drug, Growth Inhibitors, Humans, Mice, Models, Molecular, Molecular Sequence Data, Mycobacterium tuberculosis, Organ Culture Techniques, Osteoblasts, Peptide Fragments, Peptide Mapping, Recombinant Proteins, Skull, Sonication, Tuberculosis, Spinal, Science & Technology, Life Sciences & Biomedicine, Immunology, Medicine, Research & Experimental, Research & Experimental Medicine, IMMUNOLOGY, MEDICINE, RESEARCH & EXPERIMENTAL, ACTINOBACILLUS-ACTINOMYCETEMCOMITANS, MONOCLONAL-ANTIBODIES, PROTEIN, GROES, LYMPHOCYTES, OSTEOCLASTS, SEQUENCE, Immunology, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: JOURNAL OF EXPERIMENTAL MEDICINE
ISSN: 0022-1007
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Dates:
DateEvent
20 October 1997Published
Web of Science ID: WOS:A1997YC95000008
URI: http://openaccess.sgul.ac.uk/id/eprint/107190
Publisher's version: https://doi.org/10.1084/jem.186.8.1241

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