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Annexin-1 Mediates TNF--Stimulated Matrix Metalloproteinase Secretion from Rheumatoid Arthritis Synovial Fibroblasts¹

Clement E. Tagoe^2,3,*,, Nada Marjanovic^2,*,, Jean Y. Park^*,, Edwin S. Chan^*,, Aryeh M. Abeles^*,, Mukundan Attur^*, Steven B. Abramson^* and Michael H. Pillinger^*,

^* Division of Rheumatology and Division of Clinical Pharmacology, New York University School of Medicine/Hospital for Joint Diseases, New York, NY 10003; New York Harbor Veterans Administration Health Care System, New York, NY 10010; and Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY 10467

Annexins are intracellular molecules implicated in the down-regulation of inflammation. Recently, annexin-1 has also been identified as a secreted molecule, suggesting it may have more complex effects on inflammation than previously appreciated. We studied the role of annexin-1 in mediating MMP-1 secretion from rheumatoid arthritis (RA) synovial fibroblasts (SF) stimulated with TNF-. TNF- induced a biphasic secretion of annexin-1 from RA SF. Early (60 min), cycloheximide-independent secretion from preformed intracellular pools was followed by late (24 h) cycloheximide-inhibitable secretion requiring new protein synthesis. Exogenous annexin-1 N-terminal peptide Ac2-26 stimulated MMP-1 secretion in a dose- (EC₅₀ 25 µM) and time- (8–24 h) dependent manner; full-length annexin-1 had a similar effect. Down-regulation of annexin-1 using small interfering RNA resulted in decreased secretion of both annexin-1 and MMP-1, confirming that annexin-1 mediates TNF--stimulated MMP-1 secretion. Erk, Jnk, and NF-B have been implicated in MMP-1 secretion. Erk, Jnk, and NF-B inhibitors had no effect on annexin-1 secretion stimulated by TNF- but inhibited MMP-1 secretion in response to Ac2-26, indicating that these molecules signal downstream of annexin-1. Annexin-1 stimulation of MMP-1 secretion was inhibited by both a formyl peptide receptor antagonist and pertussis toxin, suggesting that secreted annexin-1 acts via formyl peptide family receptors, most likely FPLR-1. In contrast to its commonly appreciated anti-inflammatory roles, our data indicate that annexin-1 is secreted by RA SF in response to TNF- and acts in an autacoid manner to engage FPRL-1, activate Erk, Jnk, and NF-B, and stimulate MMP-1 secretion.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a research grant from the Arthritis Foundation, New York Chapter.

² C.E.T. and N.M. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Clement E. Tagoe, Division of Rheumatology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467. E-mail address: ctagoe{at}montefiore.org

⁴ Abbreviations used in this paper: RA, rheumatoid arthritis; SF, synovial fibroblasts; MMPs, matrix metalloproteinases; FPR, formyl peptide receptor; FPRL-1, FPR-like 1 receptors; PDTC, pyrollidine dithiocarbamate; OA, osteoarthritis; siRNA, small interfering RNA.