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Differential expression of lumican and fibromodulin regulate collagen fibrillogenesis in developing mouse tendons.

Ezura Y, Chakravarti S, Oldberg A, Chervoneva I, Birk DE - J. Cell Biol. (2000)

Bottom Line: With development, the amount of lumican decreases to barely detectable levels while fibromodulin increases significantly, and these changing patterns may regulate this process.The observed increased ratio of fibromodulin to lumican and a competition for the same binding site could mediate these transitions.These studies indicate that lumican and fibromodulin have different developmental stage and leucine-rich repeat protein specific functions in the regulation of fibrillogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

ABSTRACT
Collagen fibrillogenesis is finely regulated during development of tissue-specific extracellular matrices. The role(s) of a leucine-rich repeat protein subfamily in the regulation of fibrillogenesis during tendon development were defined. Lumican-, fibromodulin-, and double-deficient mice demonstrated disruptions in fibrillogenesis. With development, the amount of lumican decreases to barely detectable levels while fibromodulin increases significantly, and these changing patterns may regulate this process. Electron microscopic analysis demonstrated structural abnormalities in the fibrils and alterations in the progression through different assembly steps. In lumican-deficient tendons, alterations were observed early and the mature tendon was nearly normal. Fibromodulin-deficient tendons were comparable with the lumican- in early developmental periods and acquired a severe phenotype by maturation. The double-deficient mice had a phenotype that was additive early and comparable with the fibromodulin-deficient mice at maturation. Therefore, lumican and fibromodulin both influence initial assembly of intermediates and the entry into fibril growth, while fibromodulin facilitates the progression through growth steps leading to mature fibrils. The observed increased ratio of fibromodulin to lumican and a competition for the same binding site could mediate these transitions. These studies indicate that lumican and fibromodulin have different developmental stage and leucine-rich repeat protein specific functions in the regulation of fibrillogenesis.

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Model for regulation of fibril growth by lumican and fibromodulin. The steps in collagen fibrillogenesis during tendon development are presented (a–c). (a) In the early steps of fibril formation, the molecular assembly of collagen monomers into fibril intermediates occurs in the pericellular space. Collagen molecules (bars) assemble into quarter-staggered arrays forming fibril intermediates, seen here as striated structures with tapered ends in longitudinal section and in cross section as circular profiles. Growth in length and diameter is by accretion of collagen at this stage. (b) Fibril intermediates ∼65 nm in mouse tendons are stabilized, presumably through their interactions with fibril-associated macromolecules. (c) The fibril intermediates are the basic units used in the growth of fibrils. Fusion of the fibril intermediates generates the mature fibril in a multistep manner. Progression through this growth process could be both by additive fusion (i.e., the 64-nm diameter intermediate adds to its product, indicated by horizontal arrows) and by like-fusion (i.e., products from different steps can only fuse with like products, indicated by arrows in the oblique direction). (d, top) The proportion of the assembly and growth steps occurring during development is illustrated. At early stages, assembly is the main event and its proportion gradually decreases to the minimum degree necessary for maintenance at maturation. The proportion of progressional growth increases gradually to ∼1 mo and decreases to maturation. (bottom) The expression data for lumican and fibromodluin is illustrated. The phenotypes observed in mutant mice indicate stage-specific regulatory mechanisms. At 4 d, both lumican and fibromodulin limit the assembly of the collagen monomers (bars). Characteristic of 10 d, progressional growth begins, and changes in both lumican and fibromodulin promote the transition from assembly to fibril growth by fusion (thin arrows). At later stages, only fibromodulin promotes the progressional growth steps (thick arrows).
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Figure 7: Model for regulation of fibril growth by lumican and fibromodulin. The steps in collagen fibrillogenesis during tendon development are presented (a–c). (a) In the early steps of fibril formation, the molecular assembly of collagen monomers into fibril intermediates occurs in the pericellular space. Collagen molecules (bars) assemble into quarter-staggered arrays forming fibril intermediates, seen here as striated structures with tapered ends in longitudinal section and in cross section as circular profiles. Growth in length and diameter is by accretion of collagen at this stage. (b) Fibril intermediates ∼65 nm in mouse tendons are stabilized, presumably through their interactions with fibril-associated macromolecules. (c) The fibril intermediates are the basic units used in the growth of fibrils. Fusion of the fibril intermediates generates the mature fibril in a multistep manner. Progression through this growth process could be both by additive fusion (i.e., the 64-nm diameter intermediate adds to its product, indicated by horizontal arrows) and by like-fusion (i.e., products from different steps can only fuse with like products, indicated by arrows in the oblique direction). (d, top) The proportion of the assembly and growth steps occurring during development is illustrated. At early stages, assembly is the main event and its proportion gradually decreases to the minimum degree necessary for maintenance at maturation. The proportion of progressional growth increases gradually to ∼1 mo and decreases to maturation. (bottom) The expression data for lumican and fibromodluin is illustrated. The phenotypes observed in mutant mice indicate stage-specific regulatory mechanisms. At 4 d, both lumican and fibromodulin limit the assembly of the collagen monomers (bars). Characteristic of 10 d, progressional growth begins, and changes in both lumican and fibromodulin promote the transition from assembly to fibril growth by fusion (thin arrows). At later stages, only fibromodulin promotes the progressional growth steps (thick arrows).

Mentions: Our model of fibril growth in the tendon and its regulation by lumican and fibromodulin is presented in Fig. 7. The first step in fibrillogenesis is the molecular assembly of collagen monomers into fibril intermediates. Previous studies have shown that growth at this stage is by accretion of collagen and occurs within extracellular compartments, where the microenvironment is under cellular control (Birk and Trelstad 1986). This initial assembly step is regulated, at least in part, by interactions between two fibrillar collagens. In the tendon, these are types I and III (Fleischmajer et al. 1990; Birk and Mayne 1997). In addition, our data indicate that both lumican and fibromodulin influence this step, as evidenced by the larger diameter fibrils seen at 4 d. Recent work indicates that decorin, a related leucine-rich repeat protein, may influence molecular interactions at these early stages or perhaps within secretory vesicles (Weber et al. 1996; Keene et al. 2000). These fibrils have regular profiles that are inconsistent with premature entry into growth, although a rapid molecular rearrangement of the immature fibril intermediates cannot be ruled out. Fibril intermediates ∼64 nm in mouse tendons are stabilized presumably through their interactions with leucine-rich repeat proteoglycans. Our data indicate that both lumican and fibromodulin are involved in this stabilization and mediating the entry into fibril growth. The fibril intermediates are the basic units used in the growth of fibrils (Birk et al. 1989, Birk et al. 1995, Birk et al. 1997; Graham et al. 2000). Fusion of the fibril intermediates generates the mature fibril in a multi-step manner. Progression through this growth process could be both by additive-fusion (i.e., the 64-nm diameter intermediate adds to its product) and by like-fusion (i.e., products from different steps can only fuse with like products of existing fibrils). We suggest that changing patterns of lumican and fibromodulin expression during tendon development are responsible for the regulation of this process. As fibrillogenesis progresses, lumican decreases to barely detectable levels while fibromodulin increases significantly. In addition, lumican and fibromodulin compete for the same binding sites on the fibril and fibromodulin has the higher affinity (Svensson et al. 2000). This suggests that the transitions in growth could be mediated by the fibromodulin-displacing lumican from the fibril surface during a period critical for intermediate fusion. Our data also indicate that fibromodulin facilitates the formation of the mature, large-diameter fibrils seen at 3-mo postnatal.


Differential expression of lumican and fibromodulin regulate collagen fibrillogenesis in developing mouse tendons.

Ezura Y, Chakravarti S, Oldberg A, Chervoneva I, Birk DE - J. Cell Biol. (2000)

Model for regulation of fibril growth by lumican and fibromodulin. The steps in collagen fibrillogenesis during tendon development are presented (a–c). (a) In the early steps of fibril formation, the molecular assembly of collagen monomers into fibril intermediates occurs in the pericellular space. Collagen molecules (bars) assemble into quarter-staggered arrays forming fibril intermediates, seen here as striated structures with tapered ends in longitudinal section and in cross section as circular profiles. Growth in length and diameter is by accretion of collagen at this stage. (b) Fibril intermediates ∼65 nm in mouse tendons are stabilized, presumably through their interactions with fibril-associated macromolecules. (c) The fibril intermediates are the basic units used in the growth of fibrils. Fusion of the fibril intermediates generates the mature fibril in a multistep manner. Progression through this growth process could be both by additive fusion (i.e., the 64-nm diameter intermediate adds to its product, indicated by horizontal arrows) and by like-fusion (i.e., products from different steps can only fuse with like products, indicated by arrows in the oblique direction). (d, top) The proportion of the assembly and growth steps occurring during development is illustrated. At early stages, assembly is the main event and its proportion gradually decreases to the minimum degree necessary for maintenance at maturation. The proportion of progressional growth increases gradually to ∼1 mo and decreases to maturation. (bottom) The expression data for lumican and fibromodluin is illustrated. The phenotypes observed in mutant mice indicate stage-specific regulatory mechanisms. At 4 d, both lumican and fibromodulin limit the assembly of the collagen monomers (bars). Characteristic of 10 d, progressional growth begins, and changes in both lumican and fibromodulin promote the transition from assembly to fibril growth by fusion (thin arrows). At later stages, only fibromodulin promotes the progressional growth steps (thick arrows).
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Related In: Results  -  Collection

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Figure 7: Model for regulation of fibril growth by lumican and fibromodulin. The steps in collagen fibrillogenesis during tendon development are presented (a–c). (a) In the early steps of fibril formation, the molecular assembly of collagen monomers into fibril intermediates occurs in the pericellular space. Collagen molecules (bars) assemble into quarter-staggered arrays forming fibril intermediates, seen here as striated structures with tapered ends in longitudinal section and in cross section as circular profiles. Growth in length and diameter is by accretion of collagen at this stage. (b) Fibril intermediates ∼65 nm in mouse tendons are stabilized, presumably through their interactions with fibril-associated macromolecules. (c) The fibril intermediates are the basic units used in the growth of fibrils. Fusion of the fibril intermediates generates the mature fibril in a multistep manner. Progression through this growth process could be both by additive fusion (i.e., the 64-nm diameter intermediate adds to its product, indicated by horizontal arrows) and by like-fusion (i.e., products from different steps can only fuse with like products, indicated by arrows in the oblique direction). (d, top) The proportion of the assembly and growth steps occurring during development is illustrated. At early stages, assembly is the main event and its proportion gradually decreases to the minimum degree necessary for maintenance at maturation. The proportion of progressional growth increases gradually to ∼1 mo and decreases to maturation. (bottom) The expression data for lumican and fibromodluin is illustrated. The phenotypes observed in mutant mice indicate stage-specific regulatory mechanisms. At 4 d, both lumican and fibromodulin limit the assembly of the collagen monomers (bars). Characteristic of 10 d, progressional growth begins, and changes in both lumican and fibromodulin promote the transition from assembly to fibril growth by fusion (thin arrows). At later stages, only fibromodulin promotes the progressional growth steps (thick arrows).
Mentions: Our model of fibril growth in the tendon and its regulation by lumican and fibromodulin is presented in Fig. 7. The first step in fibrillogenesis is the molecular assembly of collagen monomers into fibril intermediates. Previous studies have shown that growth at this stage is by accretion of collagen and occurs within extracellular compartments, where the microenvironment is under cellular control (Birk and Trelstad 1986). This initial assembly step is regulated, at least in part, by interactions between two fibrillar collagens. In the tendon, these are types I and III (Fleischmajer et al. 1990; Birk and Mayne 1997). In addition, our data indicate that both lumican and fibromodulin influence this step, as evidenced by the larger diameter fibrils seen at 4 d. Recent work indicates that decorin, a related leucine-rich repeat protein, may influence molecular interactions at these early stages or perhaps within secretory vesicles (Weber et al. 1996; Keene et al. 2000). These fibrils have regular profiles that are inconsistent with premature entry into growth, although a rapid molecular rearrangement of the immature fibril intermediates cannot be ruled out. Fibril intermediates ∼64 nm in mouse tendons are stabilized presumably through their interactions with leucine-rich repeat proteoglycans. Our data indicate that both lumican and fibromodulin are involved in this stabilization and mediating the entry into fibril growth. The fibril intermediates are the basic units used in the growth of fibrils (Birk et al. 1989, Birk et al. 1995, Birk et al. 1997; Graham et al. 2000). Fusion of the fibril intermediates generates the mature fibril in a multi-step manner. Progression through this growth process could be both by additive-fusion (i.e., the 64-nm diameter intermediate adds to its product) and by like-fusion (i.e., products from different steps can only fuse with like products of existing fibrils). We suggest that changing patterns of lumican and fibromodulin expression during tendon development are responsible for the regulation of this process. As fibrillogenesis progresses, lumican decreases to barely detectable levels while fibromodulin increases significantly. In addition, lumican and fibromodulin compete for the same binding sites on the fibril and fibromodulin has the higher affinity (Svensson et al. 2000). This suggests that the transitions in growth could be mediated by the fibromodulin-displacing lumican from the fibril surface during a period critical for intermediate fusion. Our data also indicate that fibromodulin facilitates the formation of the mature, large-diameter fibrils seen at 3-mo postnatal.

Bottom Line: With development, the amount of lumican decreases to barely detectable levels while fibromodulin increases significantly, and these changing patterns may regulate this process.The observed increased ratio of fibromodulin to lumican and a competition for the same binding site could mediate these transitions.These studies indicate that lumican and fibromodulin have different developmental stage and leucine-rich repeat protein specific functions in the regulation of fibrillogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

ABSTRACT
Collagen fibrillogenesis is finely regulated during development of tissue-specific extracellular matrices. The role(s) of a leucine-rich repeat protein subfamily in the regulation of fibrillogenesis during tendon development were defined. Lumican-, fibromodulin-, and double-deficient mice demonstrated disruptions in fibrillogenesis. With development, the amount of lumican decreases to barely detectable levels while fibromodulin increases significantly, and these changing patterns may regulate this process. Electron microscopic analysis demonstrated structural abnormalities in the fibrils and alterations in the progression through different assembly steps. In lumican-deficient tendons, alterations were observed early and the mature tendon was nearly normal. Fibromodulin-deficient tendons were comparable with the lumican- in early developmental periods and acquired a severe phenotype by maturation. The double-deficient mice had a phenotype that was additive early and comparable with the fibromodulin-deficient mice at maturation. Therefore, lumican and fibromodulin both influence initial assembly of intermediates and the entry into fibril growth, while fibromodulin facilitates the progression through growth steps leading to mature fibrils. The observed increased ratio of fibromodulin to lumican and a competition for the same binding site could mediate these transitions. These studies indicate that lumican and fibromodulin have different developmental stage and leucine-rich repeat protein specific functions in the regulation of fibrillogenesis.

Show MeSH
Related in: MedlinePlus