Disease relevance of Fmod

• A syndrome of joint laxity and impaired tendon integrity in lumican- and fibromodulin-deficient mice [1].
• This study demonstrates that the collagen fibril-modifying proteoglycans, lumican and fibromodulin, are candidate genes and key players in the pathogenesis of certain types of Ehlers-Danlos syndrome and other connective tissue disorders [1].
• Fibromodulin-null murine knee joints display increased incidences of osteoarthritis and alterations in tissue biochemistry [2].
• However, qualitative ultrastructural investigation did not indicate either any aberrant tissue ultrastructure or any abnormal collagen fibril forms in FM-null articular cartilage compared with WT [2].
• In this study, we examined effects of exopolysaccharide from A. halophytica Fremy (EPAH) on influenza virus A FM (H1N1) (FM1)-induced pneumonia and reduction in immunocompetence in mice [3].

High impact information on Fmod

• Similar repeats have been found in two other proteoglycans, biglycan and fibromodulin, and in several other proteins including Drosophila morphogenetic proteins [4].
• The observed increased ratio of fibromodulin to lumican and a competition for the same binding site could mediate these transitions [5].
• Fibromodulin-deficient tendons were comparable with the lumican-null in early developmental periods and acquired a severe phenotype by maturation [5].
• These studies indicate that lumican and fibromodulin have different developmental stage and leucine-rich repeat protein specific functions in the regulation of fibrillogenesis [5].
• The double-deficient mice had a phenotype that was additive early and comparable with the fibromodulin-deficient mice at maturation [5].

Biological context of Fmod

• At the protein level, we show marked increase of lumican in Fmod(-/-) tendons, which may partially rescue the tendon phenotype in this genotype [1].
• The murine fibromodulin gene, Fmod, was similar with that in other species, with three exons and 86% of the translated sequence in exon 2 [6].
• Lumican maps within the chromosome 12q21-q23 autosomal dominant high grade myopia-3 (MYP3) interval, and fibromodulin maps to chromosome 1q32 [7].

Anatomical context of Fmod

• Lumican and fibromodulin regulate the assembly of collagens into higher order fibrils in connective tissues [1].
• Interestingly, no underlying ultrastructural or fibril abnormalities within the articular cartilage could be identified to explain why FM-null cartilage is more prone to pathological changes than wild-type tissue [2].
• CONCLUSION: This report indicates for the first time that FM-null mice have a higher propensity towards degenerative changes in their knee joints than comparable WT animals [2].
• These results indicate that DCN, in addition to its effects on fibrillogenesis, plays a regulatory role in angiogenesis and that FMOD in endothelial cells may be able to partially substitute for DCN [8].
• Moreover, blood vessels of DCN-deficient mice exhibited a similar expression level of BGN as control mice, while FMOD was increased on day 3 after injury [8].

Associations of Fmod with chemical compounds

• Lumican and fibromodulin are collagen-binding leucine-rich proteoglycans widely distributed in interstitial connective tissues [9].
• Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed several low molecular mass proteins which reacted with 5-D-4, specific for keratan sulfate, one of which showed characteristics of fibromodulin [10].
• A comparative profile of action reveals that the neuropharmacological action of FM are qualitatively similar to those induced by nialamide, and likely to be due to inhibition of MAO [11].

Physical interactions of Fmod

• In tissues like the tendon, where both proteoglycans are present, fibromodulin may be required early in collagen fibrillogenesis to stabilize small-diameter fibril-intermediates and lumican may be needed at a later stage, primarily to limit lateral growth of fibrils[9]

Other interactions of Fmod

• Also, glomerular components such as versican, decorin and fibromodulin were found to be downregulated after 40 weeks of diabetes [12].
• In the old mice, calcified cartilage became enriched with regard to fibromodulin, while, in contrast, decorin deposition diminished, particularly near the tidemark [6].
• Fibromodulin may function in the early genesis of articular cartilage and COMP may be associated with elaboration of a weight-bearing chondrocyte matrix [13].
• No significant differences between skin and mucosal wounds were observed for the expression of the anti-inflammatory cytokine IL-10 and the TGF-beta1 modulators, fibromodulin and LTBP-1 [14].

Analytical, diagnostic and therapeutic context of Fmod

• Immunohistochemistry provides evidence for compensatory mechanisms in Fmod-deficient mice [15].
• CONCLUSION: The biglycan/fibromodulin double knock-out mouse constitutes a useful animal model to decipher the pathobiology of osteoarthritis in the TMJ [16].
• FM showed per se antinociceptive activity and potentiated morphine analgesia [11].

References