Deficiency of fibroblast activation protein alpha ameliorates cartilage destruction in inflammatory destructive arthritis.

Abstract

INTRODUCTION:

Inflammatory destructive arthritis, like rheumatoid arthritis (RA), is characterized by invasion of synovial fibroblasts (SF) into the articular cartilage and erosion of the underlying bone, leading to progressive joint destruction. Because fibroblast activation protein alpha (FAP) has been associated with cell migration and cell invasiveness, we studied the function of FAP in joint destruction in RA.

METHODS:

Expression of FAP in synovial tissues and fibroblasts from patients with osteoarthritis (OA) and RA as well as from wild-type and arthritic mice was evaluated by immunohistochemistry, fluorescence microscopy and polymerase chain reaction (PCR). Fibroblast adhesion and migration capacity was assessed using cartilage attachment assays and wound-healing assays, respectively. For in vivo studies, FAP-deficient mice were crossed into the human tumor necrosis factor transgenic mice (hTNFtg), which develop a chronic inflammatory arthritis. Beside clinical assessment, inflammation, cartilage damage, and bone erosion were evaluated by histomorphometric analyses.

RESULTS:

RA synovial tissues demonstrated high expression of FAP whereas in OA samples only marginal expression was detectable. Consistently, a higher expression was detected in arthritis SF compared to non-arthritis OA SF in vitro. FAP-deficiency in hTNFtg mice led to less cartilage degradation despite unaltered inflammation and bone erosion. Accordingly, FAP(-/-) hTNFtg SF demonstrated a lower cartilage adhesion capacity compared to hTNFtg SF in vitro.

CONCLUSIONS:

These data point to a so far unknown role of FAP in the attachment of SF to cartilage, promoting proteoglycan loss and subsequently cartilage degradation in chronic inflammatory arthritis.

• Authors: Stefan Wäldele, Christina Koers-Wunrau, Denise Beckmann, Adelheid Korb-Pap, Corinna Wehmeyer, Thomas Pap, Berno Dankbar
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 17 Pg. 12 (Jan 20 2015) ISSN: 1478-6362 [Electronic] England
• PMID: 25600705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Proteins
• Proteoglycans
• Endopeptidases
• Serine Endopeptidases
• fibroblast activation protein alpha
• Gelatinases

Topics

• Animals
• Arthritis, Rheumatoid (metabolism, pathology, prevention & control)
• Cartilage, Articular (metabolism, pathology)
• Endopeptidases
• Gelatinases (deficiency)
• Humans
• Inflammation (metabolism, pathology, prevention & control)
• Membrane Proteins (deficiency)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Proteoglycans (deficiency)
• Serine Endopeptidases (deficiency)