Insulin-like growth factor 1-induced interleukin-1 receptor II overrides the activity of interleukin-1 and controls the homeostasis of the extracellular matrix of cartilage.
OBJECTIVE
We examined the effect of the insulin-like growth factor 1 (IGF-1)/IGF receptor I (IGFRI) autocrine/paracrine anabolic pathway on the extracellular matrix (ECM) of human chondrocytes and the mechanism by which IGF-1 reverses the catabolic effects of interleukin-1 (IL-1).


METHODS
Phenotypically stable human articular cartilage cells were obtained from normal cartilage and maintained in culture in alginate beads for 1 week to reach equilibrium of accumulated cell-associated matrix (CAM) compounds. Levels of CAM components aggrecan and type II collagen (CII) and levels of intracellular IGF-1, IL-1alpha, and IL-1beta and their respective plasma membrane-bound receptors IGFRI, IL-1 receptor I (IL-1RI), and the decoy receptor IL-1RII were assayed using flow cytometry to investigate the relationship between the autocrine/paracrine pathways and the homeostasis of ECM molecules in the CAM. The effects of IGF-1 on the expression of IGF-1, IL-1alpha, and IL-1beta and their respective receptor systems, the aggrecan core protein, and CII were determined by flow cytometry.


RESULTS
Cause-effect relationship experiments showed that IGF-1 up-regulates the levels of IGF-1, IGFRI, aggrecan, and CII in the CAM. No effects on the expression of IL-1alpha and IL-1beta and their signaling receptor IL-1RI were observed. However, IGF-1 was able to reverse IL-1beta-mediated degradation of aggrecan and the repression of the aggrecan synthesis rate. Interestingly, levels of aggrecan and CII in the CAM strongly correlated not only with IGF-1, but also with IL-1RII, which acts as a decoy receptor for IL-1alpha and IL-1beta. This suggests that IGF-1 and IL-1RII may cooperate in regulating ECM homeostasis. Additional experiments demonstrated that IGF-1 up-regulated IL-1RII, thereby overriding the catabolic effects of IL-1.


CONCLUSIONS
These findings reveal a new paradigm by which IGF-1 influences chondrocyte metabolism, by reversing the IL-1-mediated catabolic pathway through up-regulation of its decoy receptor.
Wang
Jun
J
Ghent University Hospital, Ghent, Belgium.
Elewaut
Dirk
D
Veys
Eric M
EM
Verbruggen
Gust
G
D053674:Aggrecans; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D024043:Collagen Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D016326:Extracellular Matrix Proteins; D005434:Flow Cytometry; D006133:Growth Substances / Q000494:pharmacology / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000502:physiology*; D007375:Interleukin-1 / Q000502:physiology*; D037181:Lectins, C-Type; D011509:Proteoglycans / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D015854:Up-Regulation
D053674:Aggrecans; D024043:Collagen Type II; D016326:Extracellular Matrix Proteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D037181:Lectins, C-Type; D011509:Proteoglycans; D017472:Receptors, Interleukin-1; C065700:myotrophin