Biglycan (Bgn) and fibromodulin (Fmod) are members of the small leucine-rich repeat proteoglycan family (SLRPs) and are highly expressed in bone, tendon and cartilage. Mice deficient in Bgn and Fmod (Bgn /Fmod deplete), develop osteoarthritis in multiple joints, including the temporomandibular joint (TMJ). Functionally, SLRPs can control ECM structure by interacting with the network of cartilage proteins and can mediate cell metabolism by binding to members of the transforming growth factor beta superfamily (TGF-β). Bgn and Fmod both bind to TGF-β1, a potent growth factor that regulates the formation and degradation of the ECM and maintains cartilage integrity in murine and human articular cartilage. The goal of the present study was to understand how the bgn and fmod regulate the differentiation and function of mandibular cartilage cells (MCCs). First, we isolated and characterized MCCs derived from mandibular condylar cartilage and hyaline articular chondrocytes (HACs) derived from knee hyaline articular cartilage. We showed that MCCs were phenotypically distinct from HACs, which underscores the importance for using MCCs specifically to study TMJ OA. Using genetically modified mice, we identified Bgn and Fmod as critical components of the ECM, which control the differentiation and function of MCCs by modulating TGF beta-1 activity. In the absence of Bgn and Fmod, TGF beta-1 sequestration within the ECM was decreased, leading to hyper-sensitive TGF beta-1 signaling. Increased TGF beta-1 signals accelerated both type II collagen and aggrecan production and degradation. Taken together, the absence of Bgn and Fmod ultimately led to an overall imbalance in ECM turnover and favored cartilage degradation and the onset of TMJ OA. In summary we demonstrated for the first time a comprehensive study revealing the importance of the ECM in maintaining the mandibular condylar cartilage integrity and identified biglycan and fibromodulin as novel key players in regulating chondrogenesis and ECM turnover during temoporomandibular joint osteoarthritis pathology. Other studies have examined how biglycan controls cell and tissue functions in cooperation with other SLRPS in craniofacial and skeletal tissues besides the TMJ. This work revealed functional compensation of SRLPs in dentin mineralization, collagen fibrillogenesis in the cornea, as well as in the development of osteoarthritis in the spine and the knee. Future studies are aimed to identify additional factors that interact with the SLRPs to control skeletal formation and function.
Showing the most recent 10 out of 48 publications
