Chondrocyte Regulation by IL-I and IGF-I: Interconnection Between Anabolic and Catabolic Factors

Type of Document Dissertation
Author Porter, Ryan Michael
URN etd-10302005-194237
Title Chondrocyte Regulation by IL-I and IGF-I: Interconnection Between Anabolic and Catabolic Factors
Degree PhD
Department Chemical Engineering
Advisory Committee
Advisor Name Title
Kimberly F. Williams Committee Chair
Aaron S. Goldstein Committee Member
R. Michael Akers Committee Member
Richey M. Davis Committee Member
Keywords

* articular chondrocytes
* interleukin-1 (IL-1)
* equine
* cell signaling
* insulin-like growth factor-I (IGF-I)
* osteoarthritis

Date of Defense 2005-10-14
Availability unrestricted
Abstract

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.

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