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1
*
Division of Rheumatology, Allergy, and Immunology, University of California at San Diego School of Medicine, La Jolla, CA 92093;
Neurocrine, La Jolla, CA; and
Pharmacia Discovery Research, Skokie, IL 60077
Aggrecanases are key matrix-degrading enzymes that act by cleaving
aggrecan at the Glu373-Ala374 site. While these
fragments have been detected in osteoarthritis (OA) and rheumatoid
arthritis (RA) cartilage and synovial fluid, no information is
available on the regulation or expression of the two key aggrecanases
(aggrecanase-1 and aggrecanase-2) in synovial tissue (ST) or
fibroblast-like synoviocytes (FLS). The aggrecanase-1 gene was
constitutively expressed by both RA and OA FLS. Real-time PCR
demonstrated that TGF-
significantly increased aggrecanase-1 gene
expression in FLS. Aggrecanase-1 induction peaked after 24 h of
TGF- stimulation. The expression of aggrecanase-1 mRNA was
significantly greater in RA ST than in OA or nonarthritis ST.
Aggrecanase-2 mRNA and protein were constitutively produced by
nonarthritis, OA, and RA FLS but were not increased by IL-1, TNF-
,
or TGF-. Furthermore, OA, RA, and nonarthritis ST contained similar
amounts of immunoreactive aggrecanase-2. The major form of the
aggrecanase-2 enzyme was 70 kDa in nonarthritis ST, whereas a processed
53-kDa form was abundant in RA ST. Therefore, aggrecanase-1 and -2 are
differentially regulated in FLS. Both are constitutively expressed, but
aggrecanase-1 is induced by cytokines, especially TGF-. In contrast,
aggrecanase-2 protein may be regulated by a post-translational
mechanism in OA and RA ST. Synovial and FLS production of aggrecanase
can contribute to cartilage degradation in RA and
OA.
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