Altered collagen turnover in factor VIII-deficient rats with hemophilic arthropathy identifies potential novel serological biomarkers in hemophilia.
Essentials Joint bleeding in hemophilia may induce significant remodeling of the extracellular matrix. Biomarkers of collagen turnover were investigated in a F8-/-rat model of hemophilic arthropathy. Biomarkers of cartilage degradation increased significantly during development of arthropathy. Basement membrane and interstitial matrix turnover changed significantly following hemarthrosis.



Background Hemophilic arthropathy is a severe complication of hemophilia. It is caused by recurrent bleeding into joint cavities, which leads to synovial inflammation, fibrosis, cartilage degradation and bone remodeling. Extracellular matrix remodeling of affected tissues is a hallmark of these pathological processes. Objectives The aim of this study was to use serological biomarkers of collagen turnover to evaluate extracellular matrix remodeling in a factor VIII-deficient rat model of hemophilic arthropathy. Methods F8-/-rats and wild-type littermate controls were subjected to repeated knee bleeds induced by needle puncture on days 0 and 14. Development of arthropathy was confirmed by histology after termination on day 28. Serum samples were collected at baseline and throughout the study and analyzed for biomarkers of collagen turnover, including collagens of the basement membrane (type IV collagen), the interstitial matrix (collagen types III, V and VI) and cartilage (type II collagen). Results In F8-/-rats, induced knee bleeding and subsequent development of arthropathy caused significant alterations in collagen turnover, measured as changes in serological biomarkers of basement membrane turnover, interstitial matrix turnover and cartilage degradation. Biomarkers of type II collagen degradation correlated significantly with cartilage degradation and degree of arthropathy. Hemophilic rats had a 50% higher turnover of the basement membrane than wild-type littermates at baseline. Conclusions Joint bleeding and hemophilic arthropathy cause changes in turnover of extracellular matrix collagens in hemophilic rats. Biomarkers of collagen turnover may be used to monitor joint bleeding and development of blood-induced joint disease in hemophilia.
Nordic Bioscience A/S, Herlev, Denmark.
T
T
Manon-Jensen
Nordic Bioscience A/S, Herlev, Denmark.
M A
MA
Karsdal
Novo Nordisk A/S, Novo Nordisk Park, Maaloev, Denmark.
L N
LN
Nielsen
Novo Nordisk A/S, Novo Nordisk Park, Maaloev, Denmark.
M
M
Kjelgaard-Hansen
Novo Nordisk A/S, Novo Nordisk Park, Maaloev, Denmark.
B
B
Vandahl
Novo Nordisk A/S, Novo Nordisk Park, Maaloev, Denmark.
E H N
EH
Olsen
Novo Nordisk A/S, Novo Nordisk Park, Maaloev, Denmark.
M
M
Enoksson
Novo Nordisk A/S, Novo Nordisk Park, Maaloev, Denmark.
K
K
Roepstorff
D000818:Animals; D015415:Biomarkers / Q000097:blood* / Q000378:metabolism; D016723:Bone Remodeling; D002356:Cartilage / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000737:chemistry*; D024043:Collagen Type II / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005169:Factor VIII / Q000235:genetics*; D005260:Female; D005355:Fibrosis / Q000473:pathology; D006395:Hemarthrosis; D006467:Hemophilia A / Q000097:blood* / Q000150:complications / Q000235:genetics*; D006485:Hemosiderin / Q000737:chemistry; D007249:Inflammation; D007592:Joint Diseases / Q000097:blood* / Q000150:complications / Q000235:genetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D013583:Synovial Membrane / Q000473:pathology
D015415:Biomarkers; D024043:Collagen Type II; D005169:Factor VIII; D003094:Collagen; D006485:Hemosiderin
basement membrane; cartilage; extracellular matrix; hemarthrosis; matrix metalloproteinases