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.
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.


CONCLUSIONS
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.
Clemmons
David R
DR
Division of Endocrinology, University of North Carolina, Chapel Hill, 27599-7170, USA. endo@med.unc.edu
Busby
Walker H
WH
Garmong
Aaron
A
Schultz
Duane R
DR
Howell
David S
DS
Altman
Roy D
RD
Karr
Robert
R
D000818:Animals; D000990:Antithrombin III / Q000494:pharmacology; D002358:Cartilage, Articular / Q000378:metabolism*; D003173:Complement C1s / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006614:Hindlimb; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D009994:Osmolar Concentration; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology*; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D013582:Synovial Fluid / Q000378:metabolism*
D004791:Enzyme Inhibitors; D018972:Insulin-Like Growth Factor Binding Protein 3; D018975:Insulin-Like Growth Factor Binding Protein 5; C451498:PB 145; D010446:Peptide Fragments; D010426:Pentosan Sulfuric Polyester; D007334:Insulin-Like Growth Factor I; D000990:Antithrombin III; D003173:Complement C1s