Catabolism of Fibromodulin in Developmental Rudiment and Pathologic Articular Cartilage Demonstrates Novel Roles for MMP-13 and ADAMTS-4 in C-terminal Processing of SLRPs

Significance 

Osteoarthritis is a disease of the joint that is caused by the progressive deterioration and loss of the articular cartilage that cushions the end of the bones. The high incidence of osteoarthritis has been partially attributed to the global epidemic increase in body mass index (BMI). Osteoarthritis has caused major individual and socioeconomic impacts in various countries across the globe. Thus, there is a need to understand and develop effective ways to treat this refractory disease. Previous studies have indicated that the enzymatic pathways responsible for the breakdown of the key structural components of articular cartilage (i.e. aggrecan and type-2 collagen) are suitable therapeutic targets for the treatment of osteoarthritis.

The articular cartilage comprises small leucine-rich proteoglycans (SLRPs) (e.g. fibromodulin and lumican) that play a critical role in the maintenance of normal cartilage and joint function. Although recent studies have indicated that degradative proteins like MMP-2, -3, -8, -9, -12, -13, ADAMTS-4 and ADAMTS-5 can be used for the extensive degradation of fibromodulin and lumican in osteoarthritis and the development of articular cartilage, the enzymes responsible for the proteolysis of SLRPs in osteoarthritis and the development of articular cartilage are not well-defined. Thus, this study aimed to use sequence-specific antibodies to elucidate the degradation of fibromodulin and lumican in osteoarthritis and the development of articular cartilage.

To this effect, University of Sydney scientists: Dr. Cindy Shu, Professor Christopher Little, and Professor James Melrose together with Dr. Carl Flannery at Bioventus LLC reported the susceptibility of fibromodulin to degradation by the proteinases (i.e. MMP-13, ADAMTS-4, and ADAMTS-5) that are active during the development of articular cartilage and osteoarthritis. The research team used sequence-specific antibodies to identify the proteolytic enzymes that are responsible for the degradation of fibromodulin and lumican in osteoarthritis. The research work was published in International Journal of Molecular Sciences.

The authors observed that the distribution of MMP-13-cleaved fibromodulin was more prominent in the terminal hypertrophic chondrocytes of the metatarsal growth plates while the distribution of full-length fibromodulin was more prominent in the superficial cartilage of both normal and fibrillated zones in osteoarthritis cartilage. This distribution of MMP-13-cleaved fibromodulin in the hypertrophic chondrocytes of the metatarsal growth plates was easily identified by TsYG11 antibody.

The researchers also observed that ADAMTS-4 and ADAMTS-5 generated FMOD fragments that were easily detected by TsYG11 antibody in fibrillated and normal cartilage extracts from total knee replacements. However, PR-184 antibody failed to identify fibromodulin fragments in fibrillated and normal cartilage extracts from total knee replacements. Although the PR-353 antibody identified three lumican fragments in osteoarthritis cartilages, the in vitro digestion of cartilage samples with MMP-13, ADAMTS-4 or ADAMTS-5 did not generate similar fragments of lumican.

The novel findings documented in their study provide compelling evidence that fibromodulin is susceptible to degradation by the three proteinases that are active during osteoarthritis and the development of articular cartilage. These findings will advance further studies on the specific roles of fibromodulin in cartilage homeostasis and the development of therapeutic targets for the treatment of osteoarthritis.

Catabolism of Fibromodulin Developmental Rudiment and Pathologic Articular Cartilage-Medicine Innovates

Reference

Shu, C.C., Flannery, C.R., Little, C.B., and Melrose, J. Catabolism of Fibromodulin in Developmental Rudiment and Pathologic Articular Cartilage Demonstrates Novel Roles for MMP-13 and ADAMTS-4 in C-terminal Processing of SLRPs, International Journal of Molecular Sciences 20, 579 (2019).

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