The role of human HtrA1 in arthritic disease.
Human HtrA1 belongs to a widely conserved family of serine proteases involved in various aspects of protein quality control and cell fate. Although HtrA1 has been implicated in the pathology of several diseases, its precise biological functions remain to be established. Through identification of potential HtrA1 targets, studies presented herein propose that within the context of arthritis pathology HtrA1 contributes to cartilage degradation. Elevated synovial HtrA1 levels were detected in fluids obtained from rheumatoid and osteoarthritis patients, with synovial fibroblasts identified as a major source of secreted HtrA1. Mass spectrometry analysis of potential HtrA1 substrates within synovial fluids identified fibronectin as a candidate target, and treatment of fibronectin with recombinant HtrA1 led to the generation of fibronectin-degradation products that may be involved in cartilage catabolism. Consistently, treatment of synovial fibroblasts with HtrA1 or HtrA1-generated fibronectin fragments resulted in the specific induction of matrix metalloprotease 1 and matrix metalloprotease 3 expression, suggesting that HtrA1 contributes to the destruction of extracellular matrix through both direct and indirect mechanisms.
Grau
Sandra
S
School of Biosciences, Cardiff University, Cardiff CF10 3US, United Kingdom.
Richards
Peter J
PJ
Kerr
Briedgeen
B
Hughes
Clare
C
Caterson
Bruce
B
Williams
Anwen S
AS
Junker
Uwe
U
Jones
Simon A
SA
Clausen
Tim
T
Ehrmann
Michael
M
D001168:Arthritis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002358:Cartilage, Articular / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000201:enzymology / Q000473:pathology; D005347:Fibroblasts / Q000201:enzymology; D005353:Fibronectins / Q000378:metabolism; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D012697:Serine Endopeptidases / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D013379:Substrate Specificity; D013582:Synovial Fluid / Q000201:enzymology; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis / Q000235:genetics
D005353:Fibronectins; D010446:Peptide Fragments; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases; D020782:Matrix Metalloproteinases