Inhibition of insulin-like growth factor binding protein 5 proteolysis in articular cartilage and joint fluid results in enhanced concentrations of insulin-like growth factor 1 and is associated with improved osteoarthritis.
Arthritis Rheum
; 46(3): 694-703, 2002 Mar.
Article
em En
| MEDLINE
| ID: mdl-11920405
ABSTRACT
OBJECTIVE:
The complement component C1s is present in dog joint fluid in an activated state. Since C1s degrades insulin-like growth factor binding protein 5 (IGFBP-5), we undertook to determine whether inhibiting C1s in joint fluid would result in an increase in the amount of intact IGFBP-5 and IGF-1 in cartilage and joint fluid, and whether C1s inhibition would be associated with a reduction in cartilage destruction during the development of osteoarthritis (OA).METHODS:
Twenty-two dogs were randomized to 3 treatment groups. All dogs underwent anterior cruciate ligament transection and were exercised. Dogs received 1 of 3 treatments buffer alone (controls; n = 6); PB-145, a peptide derived from the sequence of antithrombin III (n = 9); and pentosan polysulfate (PPS; n = 7). PB-145 or saline was injected into the joint space 3 times per week for 3 weeks. PPS was injected intramuscularly weekly for 3 weeks.RESULTS:
Joint histology showed preservation of chondrocytes and a smooth joint surface in the animals treated with PB-145 and PPS. Mankin scoring showed statistically significant reductions in joint destruction with PB-145 and PPS treatments (P < 0.01) compared with buffer control. Mean active collagenase concentrations were decreased by these two treatments. Immunoblotting of joint fluid showed that both treatments increased concentrations of intact IGFBP-5. Direct analysis of IGFBP-3 and IGFBP-5 protease activity showed that IGFBP-5 was degraded more rapidly and that PB-145 and PPS inhibited the degradation of both proteins. Total IGF-1 concentrations in joint fluid were increased 5.6-5.8-fold by these two treatments. Analysis showed that C1s was being activated in joint fluid and that its activation was inhibited by the addition of PB-145 or PPS.CONCLUSION:
The findings suggest that direct inhibition of the serine protease C1s results in increased concentrations of intact IGFBP-5 and that proteolysis of IGFBP-3 is also inhibited, probably by the inhibition of some other protease. This increase in concentrations of intact IGFBP-3 and IGFBP-5 leads to an increase in IGF-1 which is associated with an improvement in joint architecture during the development of OA.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osteoartrite
/
Líquido Sinovial
/
Fator de Crescimento Insulin-Like I
/
Cartilagem Articular
/
Complemento C1s
/
Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Arthritis Rheum
Ano de publicação:
2002
Tipo de documento:
Article
País de afiliação:
Estados Unidos