Abstract

IntroductionThe small leucine-rich proteoglycans (SLRPs) modulate tissue organization, cellular proliferation, matrix adhesion, growth factor and cytokine responses, and sterically protect the surface of collagen type I and II fibrils from proteolysis. Catabolism of SLRPs has important consequences for the integrity of articular cartilage and meniscus by interfering with their tissue homeostatic functions.MethodsSLRPs were dissociatively extracted from articular cartilage from total knee and hip replacements, menisci from total knee replacements, macroscopically normal and fibrillated knee articular cartilage from mature age-matched donors, and normal young articular cartilage. The tissue extracts were digested with chondroitinase ABC and keratanase-I before identification of SLRP core protein species by Western blotting using antibodies to the carboxyl-termini of the SLRPs.ResultsMultiple core-protein species were detected for all of the SLRPs (except fibromodulin) in the degenerate osteoarthritic articular cartilage and menisci. Fibromodulin had markedly less fragments detected with the carboxyl-terminal antibody compared with other SLRPs. There were fewer SLRP catabolites in osteoarthritic hip than in knee articular cartilage. Fragmentation of all SLRPs in normal age-matched, nonfibrillated knee articular cartilage was less than in fibrillated articular cartilage from the same knee joint or total knee replacement articular cartilage specimens of similar age. There was little fragmentation of SLRPs in normal control knee articular cartilage. Only decorin exhibited a consistent increase in fragmentation in menisci in association with osteoarthritis. There were no fragments of decorin, biglycan, lumican, or keratocan that were unique to any tissue. A single fibromodulin fragment was detected in osteoarthritic articular cartilage but not meniscus. All SLRPs showed a modest age-related increase in fragmentation in knee articular and meniscal cartilage but not in other tissues.ConclusionEnhanced fragmentation of SLRPs is evident in degenerate articular cartilage and meniscus. Specific decorin and fibromodulin core protein fragments in degenerate meniscus and/or human articular cartilage may be of value as biomarkers of disease. Once the enzymes responsible for their generation have been identified, further research may identify them as therapeutic targets.

Highlights

  • The small leucine-rich proteoglycans (SLRPs) modulate tissue organization, cellular proliferation, matrix adhesion, growth factor and cytokine responses, and sterically protect the surface of collagen type I and II fibrils from proteolysis

  • There were no fragments of decorin, biglycan, lumican, or keratocan that were unique to any tissue

  • (page number not for citation purposes) occurring SLRP catabolites identified in human tissues in the present study do not correlate in size with fragments generated by in vitro digests with specific proteinases. This may indicate that enzymes other than those far studied in vitro are responsible for SLRP catabolism in vivo or that the cleavage sites and susceptibility may be different in situ as opposed to solution-phase digests

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Summary

Introduction

The small leucine-rich proteoglycans (SLRPs) modulate tissue organization, cellular proliferation, matrix adhesion, growth factor and cytokine responses, and sterically protect the surface of collagen type I and II fibrils from proteolysis. The small leucine-rich proteoglycans (SLRPs) – including biglycan, decorin, fibromodulin, lumican and keratocan – play important linking, shape determining and matrix organizing roles [14,15,16] These roles are essential for the correct functioning of musculoskeletal tissues such as the articular cartilages, which cover the ends of the long bones in the hip and knee, and fibrocartilages of the meniscus [17,18] and intervertebral disc. These tissues provide weight-bearing and tensile properties that are important for both joint articulation and the flexibility and mechanical stability of the appendicular skeleton. With the onset of osteoarthritis (OA), the extracellular matrix of the menisci and articular cartilages undergo structural changes that are detrimental to their normal weight-bearing functional properties [18,19,20,21,22]

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