Serum amyloid A-activating factor-1 (SAF-1) transgenic mice are prone to develop a severe form of inflammation-induced arthritis.
The transcription factor serum amyloid A-activating factor-1 (SAF-1) has been identified as a regulator of a number of cellular genes. To assess the pleiotropic role of SAF-1 in vivo, we generated SAF-1 transgenic mice, in which CMV immediate-early promoter was used to direct expression of the SAF-1 transgene in multiple organs. Our study shows that overexpression of SAF-1 predisposes animals to arthritis. Although SAF-1 transgenic mice do not spontaneously develop arthritis, they develop a severe form of arthritis when challenged with the Lyme disease agent Borrelia burgdorferi, which is known to promote arthritis development in both humans and mice. CMV-SAF-1 transgenic mice, upon B. burgdorferi infection, showed increased joint swelling and synovial inflammation compared with nontransgenic littermates. Immunohistochemical analysis of joint tissues collected 21 days after B. burgdorferi infection revealed colocalization of matrix metalloproteinase-1, a degradative enzyme that destroys type II collagen, a major architectural component of articular cartilage, and SAF-1 in both SAF-1 transgenic and nontransgenic mice. Further analysis by RNase protection assay and Western immunoblot demonstrated the presence of higher levels of matrix metalloproteinase-1 and SAF-1 in the inflamed joints of SAF-1 transgenic mice compared with their levels in nontransgenic mice. Consistent with these findings, reduced levels of proteoglycans were detected in the inflamed joint cartilage of transgenic mice, indicating damage to the cartilage structure. Together these results suggest a role of SAF-1 in the pathogenesis of inflammation-induced arthritis.
Ray
Alpana
A
Department of Veterinary Pathobiology, University of Missouri, Columbia 65211, USA. rayal@missouri.edu
Kumar
Deepak
D
Shakya
Arvind
A
Brown
Charles R
CR
Cook
James L
JL
Ray
Bimal K
BK
D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D002358:Cartilage, Articular / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D011509:Proteoglycans / Q000037:antagonists & inhibitors / Q000378:metabolism; D011817:Rabbits; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D012720:Severity of Illness Index; D014157:Transcription Factors; D015854:Up-Regulation / Q000235:genetics
D004268:DNA-Binding Proteins; D011509:Proteoglycans; D000685:Serum Amyloid A Protein; D014157:Transcription Factors; C076035:c-MYC-associated zinc finger protein; D020781:Matrix Metalloproteinase 1