Date of Award

1-1-2010

Embargo Period

4-22-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biology and Pathobiology

College

College of Graduate Studies

First Advisor

Marian Young

Second Advisor

Keith Kirkwood

Third Advisor

Michael Kern

Fourth Advisor

Maria Trojanowska

Fifth Advisor

Amy Bradshaw

Sixth Advisor

Scott Argraves

Abstract

Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative joint disease, which ultimately results in severe pain, permanent cartilage destruction, and TMJ dysfunction. The extracellular matrix (ECM) micro-environment is critical for maintaining the TMJ mandibular condylar cartilage tissue integrity and is important for regulating chondrocyte activity. The small leucine-rich repeat proteoglycans (SLRPs) are a family of ECM proteins that are highly expressed in cartilage and bone. The goals of this study were to determine the role of two members of the SLRP family, biglycan (Bgn) and fibromodulin (Fmod), in the development of TMJ OA pathology and to identify the early cellular events contributing to the on-set of the disease. In order to understand the biological function of Bgn and Fmod in the mandibular condylar cartilage and their putative role in TMJ OA pathogenesis, mice deficient in Bgn and Fmod (Bgn-10Fmod-1-) were generated. Abnormal post-natal chondrogenesis and age-dependent OA-like phenotype was identified in the Bgn-10 Fmod-1- mandibular condylar cartilages in vivo. In order to identify how the absence of Bgn and Fmod contributed to early aberrant chondrocyte activity, chondrogenesis was investigated using younger mice before overt tissue destruction transpired. Given the unavailability of cell lines, a method to isolate primary mandibular condylar chondrocytes (MCCs) from the TMJ was first developed, and characterization of MCCs confirmed that they retained fibrocartilage-like phenotype in vitro. Using MCCs isolated from Bgn-10Fmod-1- mice this study showed that the absence of Bgn and Fmod caused increased chondrogenesis. Furthermore, it was discovered that the early basis for TMJ OA pathology arises from overall increased ECM turnover (biosynthesis/degradation). Given TGF-βl is a potent regulator of ECM turnover and binds to both Bgn and Fmod, it was proposed that Bgn and Fmod may regulate ECM turnover by inhibiting TGF-βl activity. In the absence of Bgn and Fmod, TGF-βl sequestration within the ECM was decreased, leading to increased TGF-βl bioavailability and overactive TGF-βl signal transduction. Using organ cultures, evidence demonstrated that increased TGF-βl signals induced ECM turnover in the Bgn -10Fmod-1- condylar cartilages. Taken together, this study revealed that Bgn and Fmod are critical for postnatal chondrogenesis and maintaining adult mandibular condylar cartilage ECM integrity. More specifically, this study identified Bgn and Fmod as novel key players in inhibiting ECM turnover, thereby preventing TMJ OA pathology.

Rights

Copyright is held by the author. All rights reserved.

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