Chondrocyte Regulation by IL-I and IGF-I: Interconnection Between Anabolic and Catabolic Factors
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Articular cartilage functions to reduce the mechanical stresses associated with diarthrodial joint movement, protecting these joints over a lifetime of use. Tissue function is maintained through the balance between synthesis and resorption (i.e., metabolism) of extracellular matrix (ECM) by articular chondrocytes (ACs). Two important hormonal regulators of cartilage metabolism are interleukin-1 (IL-1) and insulin-like growth factor-I (IGF-I). These factors have antagonistic effects on chondrocyte activity, and during the progression of osteoarthritis, IL-1 is thought to promote chondrocyte hyporesponsiveness to IGF-I. To better understand how the anabolic (IGF-I) and catabolic (IL-1) stimuli are linked within articular cartilage, we examined the mechanisms by which IL-1 regulates the IGF-I signaling system of ACs. Equine chondrocytes from non-arthritic stifle joints were multiplied over serial passages, re-differentiated in alginate beads, and stimulated with recombinant equine IL-1b. Chondrocytes were assayed for type I IGF receptor (IGF-IR), IGF binding proteins (IGFBPs), and endogenously-secreted IGF-I. Our experimental findings solidify the significance of IL-1 as a key regulator of IGF-I signaling within articular cartilage, demonstrating that regulation of the IGF-I system occurs through both direct (transcription) and indirect (proteolysis) mechanisms. These results have implications for molecular therapies (e.g., gene transfer) directed at reversing osteoarthritic cartilage deterioration.
The presented research concerns not only cartilage biology but also tissue engineering strategies for cartilage repair. Alginate hydrogel culture has been reported to re-establish chondrocytic phenotype following monolayer expansion, but studies have not addressed effects on the signaling systems responsible for chondrocyte metabolism. We investigated whether chondrocyte culture history influences the IGF-I system and its regulation by IL-1. ACs expanded by serial passaging were either encapsulated in alginate beads or maintained on tissue culture plastic (TCP). Bead and TCP cells were plated at high-density, stimulated with IL-1b, and assayed for expression of IGF-I signaling mediators. Intermediate alginate culture yielded disparate basal levels of IGF-IR and IGFBP-2, which were attributed to differential transcription. The distinct mediator profiles coincided with varied effects of exogenous IL-1b and IGF-I on collagen Ia1 expression and cell growth rate. This study demonstrates that culture strategy impacts the IGF-I system of ACs, likely impacting their capability to mediate cartilage repair.
- Doctoral Dissertations