two homologous chaperonin 60 proteins of Mycobacterium tuberculosis have distinct effects on monocyte differentiation into osteoclasts

• Published in: Cellular microbiology Vol. 10; no. 10; pp. 2091 - 2104
• Main Authors: Winrow, Vivienne R, Mesher, Jon, Meghji, Sajeda, Morris, Christopher J, Maguire, Maria, Fox, Simon, Coates, Anthony R.M, Tormay, Peter, Blake, David R, Henderson, Brian
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.10.2008; Blackwell Publishing Ltd; Hindawi Limited
• Subjects: Animals; Bacterial Proteins - metabolism; Bone Regeneration; Cell Differentiation; Cell Line; Chaperonin 60 - metabolism; Mice; Monocytes - microbiology; Mycobacterium tuberculosis; Mycobacterium tuberculosis - physiology; Organ Culture Techniques; Osteoclasts - microbiology
• ISSN: 1462-5814; 1462-5822
• DOI: 10.1111/j.1462-5822.2008.01193.x

Mycobacterium tuberculosis produces two homologous chaperonin (Cpn)60 proteins, Cpn60.1 and Cpn60.2 (Hsp65). Both proteins stimulate human and murine monocyte cytokine synthesis but, unlike Cpn60 proteins from other microbial species, fail to stimulate the breakdown of cultured murine bone. Here, we have examined the mechanism of action of these proteins on bone remodelling and osteoclastogenesis, induced in vitro in murine calvarial explants and the murine monocyte cell line RAW264.7. Additionally, we have determined their effect on bone remodelling in vivo in an animal model of arthritis. Recombinant Cpn60.1 but not Cpn60.2 inhibited bone breakdown both in vitro, in murine calvaria and in vivo, in experimental arthritis. Analysis of the mechanism of action of Cpn60.1 suggests that this protein works by directly blocking the synthesis of the key osteoclast transcription factor, nuclear factor of activated T cells c1. The detection of circulating immunoreactive intact Cpn60.1 in a small number of patients with tuberculosis but not in healthy controls further suggests that the skeleton may be affected in patients with tuberculosis. Taken together, these findings reveal that M. tuberculosis Cpn60.1 is a potent and novel inhibitor of osteoclastogenesis both in vitro and in vivo and a potential cure for bone-resorptive diseases like osteoporosis.