Joint erosion in RA: interactions between TNF-alpha, IL-1, and RANKL regulate osteoclasts

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Ann Rheum Dis. 2004 Apr;63(4):354-9.

Joint erosion in rheumatoid arthritis: interactions between tumour

necrosis factor alpha, interleukin 1, and receptor activator of nuclear

factor kappaB ligand (RANKL) regulate osteoclasts.

O' Gradaigh D, Ireland D, Bord S, Compston JE.

Bone Research Group, Department of Medicine, University of Cambridge

School of Clinical Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ,

UK.

BACKGROUND: Osteoclasts, specialised bone resorbing cells regulated by

RANKL and M-CSF, are implicated in rheumatoid joint erosion.

Lymphocyte-monocyte interactions activate bone resorption, this being

attributed to tumour necrosis factor alpha (TNFalpha) and interleukin 1

beta (IL1beta) enhanced osteoblast expression of RANKL. In animal

studies, TNF potently increases osteoclast formation in the presence of

RANKL. RANKL-independent osteoclastogenesis also occurs, though IL1 is

required for resorptive function in most studies. These inflammatory

cytokines have a pivotal role in rheumatoid arthritis, OBJECTIVE: To

study the interactions of TNFalpha and IL1beta with RANKL, particularly

the time course of the interactions and the role of lymphocytes. METHOD:

Cultures of lymphocytes and monocytes (osteoclast precursors) or of

purified CD14(+) cells alone (osteoclast precursors) were exposed to

various combinations of TNFalpha, RANKL, and IL1beta or the inhibitors

osteoprotegerin, IL1 receptor antagonist, or neutralising antibodies to

RANKL or to IL1. Osteoclastogenesis and resorptive activity were

assessed on microscopy of dentine slices. RESULTS: TNFalpha potently

increased osteoclast proliferation/differentiation in the presence of

RANKL. This effect was greatest when RANKL was present before but not

after exposure of osteoclast precursor cells to TNFalpha. The resorptive

activity of osteoclasts generated by TNFalpha in the absence of RANKL

was critically dependent upon IL1, which was expressed by

lymphocyte-monocyte interaction.

CONCLUSION: TNFalpha potently enhances RANKL mediated osteoclast

activity. Interactions between TNFalpha and IL1 also result in

osteoclastic activity independently of RANKL. These findings will inform

therapeutic approaches to the prevention of joint erosion in rheumatoid

arthritis.

PMID: 15020327

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