Development of Collagen Fibres and Lysyl Oxidase Expression in the Presumptive Dermis of Chick Limb Bud

Yamazaki, Yosuke; Mikami, Yohei; Yuguchi, Maki; Namba, Yuichi; Isokawa, Keitaro

doi:10.1111/j.1439-0264.2011.01103.x

Cited by 10 publications

(7 citation statements)

References 27 publications

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“…Cell to fiber ratio at ED6 would be ∼2:1, when estimated by the present data (18.7 fibers in 50‐μm 2 area; Fig. 3A) and our previous data (23.3 cells in 40‐μm 2 area; Yamazaki et al, 2012). The possibility that a thicker fiber is formed by combining more than two thinner fibers together cannot be excluded completely and we indeed observed such cases in oxytalan fiber formation in the ED10‐chick gizzard (unpublished data).…”

Section: Discussionsupporting

confidence: 84%

Progressive Bundling of Fibrillin Microfibrils into Oxytalan Fibers in the Chick Presumptive Dermis

Shinozuka

Yamazaki

Yuguchi

et al. 2012

The Anatomical Record

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Dorsoventral fibers in the presumptive dermis of the chick limb bud reported first by Hurle's group in 1989 are now revealed as bundles of fibrillin microfibrils (Isokawa et al., 2004). The bundles, which could be called oxytalan fibers at the light microscopic level, are aligned perpendicularly to the overlying ectoderm and form a unique fiber array, originating directly from the basal lamina. This well-oriented organization is beneficial in examining the process of in vivo bundling of microfibrils into oxytalan fibers. In this study, sections through the presumptive limb dermis were preferentially prepared from chick embryos at Days 4-6 (ED4-6). Immunohistochemically, fibrillin-positive dots representing cross-sectioned surfaces of individual fibers, increased in size from ED4 to 6, but their number per unit area remained constant. Ultrastructurally, a single oxytalan fiber at ED4 consisted of $15 microfibrils; the latter number increased fourfold from ED4 to 5 and threefold from ED5 to 6. Oxytalan fibers were all closely associated with mesenchymal cell; notably, the fibers at ED5 and 6 were held in a shallow ditch on the cell body or by lamellipodial cytoplasmic protrusion. In the sites of cell-fiber adhesion, microfibrils in the periphery of an oxytalan fiber appeared to adhere directly or by means of short flocculent strands to a nearby cell membrane; the latter showed a thickening of plasmalemma and its undercoat, indicating the presence of adhesive membrane specification. These findings suggest that the bundling of microfibrils is a progressive and closely cell-associated process. Anat Rec, 296:71-78,

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Section: Discussionsupporting

confidence: 84%

Progressive Bundling of Fibrillin Microfibrils into Oxytalan Fibers in the Chick Presumptive Dermis

Shinozuka

Yamazaki

Yuguchi

et al. 2012

The Anatomical Record

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“…We found large and rapid increases in total collagen content during tendon development (Fig. 3), while others have reported that LOX protein density is relatively constant during development in embryonic chick skin [34] and aorta [35]. Given this, perhaps the rate of collagen synthesis was outcompeting that of crosslink formation during HH 35 to 40, resulting in a decrease in the crosslink-to-collagen ratio.…”

Section: Discussionmentioning

confidence: 55%

Lysyl oxidase-mediated collagen crosslinks may be assessed as markers of functional properties of tendon tissue formation

et al. 2014

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Mechanical property elaboration of engineered tissues is often assumed on the basis of gene and protein characterizations, rather than mechanical testing. However, we recently demonstrated mechanical properties are not consistently correlated with matrix content and organization during embryonic tissue development. Based on this, mechanical properties should be assessed independently during natural or engineered tissue formation. Unfortunately, mechanical testing is destructive, and thus alternative means of assessing these properties are desirable. In this study, we examined lysyl oxidase (LOX)-mediated crosslinks as markers for mechanical properties during embryonic tendon formation and the potential to detect them non-destructively. We used tandem mass spectrometry (LC-MS/MS) to quantify changes in hydroxylysyl pyridinoline (HP) and lysyl pyridinoline (LP) crosslink density in embryonic chick tendon as a function of developmental stage. In addition, we assessed a multiphoton imaging approach that exploits the natural fluorescence of HP and LP. With both techniques, we quantified crosslink density in normal and LOX-inhibited tendons, and correlated measurements with mechanical properties. HP and LP crosslink density varied as a function of developmental stage, with HP-to-dry mass ratio correlating highly to elastic modulus, even when enzymatic crosslink formation was inhibited. Multiphoton optical imaging corroborated LC-MS/MS data, identifying significant reductions in crosslink density from LOX inhibition. Taken together, crosslink density may be useful as a marker of tissue mechanical properties that could be assessed with imaging non-destructively and perhaps non-invasively. These outcomes could have significant scientific and clinical implications, enabling continuous and long-term monitoring of mechanical properties of collagen-crosslinked tissues or engineered constructs.

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“…LOX expression has also been shown to be closely correlated with elevated collagen I expression during development (36). However, no one has yet investigated the effects of collagen I crosslinking on metastatic tumor growth.…”

Section: Introductionmentioning

confidence: 99%

LOX-Mediated Collagen Crosslinking Is Responsible for Fibrosis-Enhanced Metastasis

et al. 2013

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Tumor metastasis is a highly complex, dynamic, and inefficient process involving multiple steps, yet it accounts for more than 90% of cancer-related deaths. Although it has long been known that fibrotic signals enhance tumor progression and metastasis, the underlying molecular mechanisms are still unclear. Identifying events involved in creating environments that promote metastatic colonization and growth are critical for the development of effective cancer therapies. Here, we show a critical role for lysyl oxidase (LOX) in establishing a milieu within fibrosing tissues that is favorable to growth of metastastic tumor cells. We show that LOX-dependent collagen crosslinking is involved in creating a growth-permissive fibrotic microenvironment capable of supporting metastatic growth by enhancing tumor cell persistence and survival. We show that therapeutic targeting of LOX abrogates not only the extent to which fibrosis manifests, but also prevents fibrosis-enhanced metastatic colonization. Finally, we show that the LOXmediated collagen crosslinking directly increases tumor cell proliferation, enhancing metastatic colonization and growth manifesting in vivo as increased metastasis. This is the first time that crosslinking of collagen I has been shown to enhance metastatic growth. These findings provide an important link between ECM homeostasis, fibrosis, and cancer with important clinical implications for both the treatment of fibrotic disease and cancer. Cancer Res; 73(6);

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Development of Collagen Fibres and Lysyl Oxidase Expression in the Presumptive Dermis of Chick Limb Bud

Cited by 10 publications

References 27 publications

Progressive Bundling of Fibrillin Microfibrils into Oxytalan Fibers in the Chick Presumptive Dermis

Progressive Bundling of Fibrillin Microfibrils into Oxytalan Fibers in the Chick Presumptive Dermis

Lysyl oxidase-mediated collagen crosslinks may be assessed as markers of functional properties of tendon tissue formation

LOX-Mediated Collagen Crosslinking Is Responsible for Fibrosis-Enhanced Metastasis

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