The Role of Transforming Growth Factor Beta (TGF-β) in the Extracellular Matrix Degradation Characteristic of Post-Traumatic Osteoarthritis

Date of Award

6-2013

Degree Type

Thesis

Degree Name

Master of Science (MS)

First Advisor

Marina D'Angelo, PhD

Second Advisor

Christopher Adams, PhD

Third Advisor

Susan Hingley, PhD

Fourth Advisor

Marcus Bell, PhD

Abstract

The loss of articular cartilage over time due to an imbalance in cartilage homeostasis leads to the development of osteoarthritis (OA). Various factors contribute to the pathology of OA including the growth factor, Transforming Growth Factor-β (TGF-β). Stores of latent TGF-β are present in the deeper layers of articular cartilage and the growth factor is activated through the actions of Matrix Metalloprotease-13 (MMP-13). This excess activation of TGF-β has been shown to contribute to the pathology observed in OA. Our lab has developed a new class of therapeutics known as the Extracellular Matrix Protection Factors (ECPFs) that protect cartilage. ECPF -1, in particular, blocks MMP-13's ability to activate TGF-β, but the cellular mechanism that is responsible for this chondroprotection is unknown. It is well documented that inflammatory cytokines play a role in the pathology associated with OA, and that these molecules are regulated, in some part, by TGF-β biology. To test the downstream effects of blocking TGF-β activation on cytokine production, cultured chondrocytes from embryonic avian sterna were treated for 24 hours with ECPF-1 at 250nM, 2.5µM and 5.0µM concentrations and the production of the inflammatory cytokines, IL-1β and TNF-α, were monitored. As expected, activated TGF-β was reduced in response to ECPF-1 treatment. Production of IL-1β and TNF-α demonstrated a statistically significant increase at the 5.0µM concentration of ECPF -1. This increase in inflammatory cytokine production indicates that ECPF-1 might no longer be entirely chondroprotective at the S.Of!M concentration. Future experiments will help to narrow in on the range over which this factor acts as a protective therapeutic agent and to investigate other biochemical factors to determine their role in response to ECPF -1 treatment. This will help to uncover the mechanism of action of ECPF -1 in the protection of the articular cartilage.

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