Biosynthesis of skin collagens in normal and diabetic mice

Kern, Patrick; Moczar, M; Robert, L.

doi:10.1042/bj1820337

Cited by 54 publications

(22 citation statements)

References 47 publications

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“…It has previously been reported in the literature that diabetic skin has a higher type III to I collagen ratio than nondiabetic skin. 33 This relative increase in type III collagen might account for the decreased strength and stiffness of diabetic skin.…”

Section: Figure 8 Amentioning

confidence: 99%

Impaired Biomechanical Properties of Diabetic Skin

Bermudez

Herdrich

et al. 2011

The American Journal of Pathology

106

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Diabetic skin is known to have deficient wound healing properties, but little is known of its intrinsic biomechanical properties. We hypothesize that diabetic skin possesses inferior biomechanical properties at baseline, rendering it more prone to injury. Skin from diabetic and nondiabetic mice and humans underwent biomechanical testing. Real-time PCR was performed for genes integral to collagen synthesis and degradation. MMP-2 and MMP-9, and TIMP-1 protein levels were assessed by ELISA and zymography. Collagen I and III content was assessed using Western blot analysis. At baseline, both murine and human diabetic skin was biomechanically inferior compared to nondiabetic skin, with decreased maximum stress and decreased modulus (P < 0.001 and < 0.05, respectively). Surprisingly, the expression of genes involved in collagen synthesis were significantly up-regulated, and genes involved in collagen degradation were significantly down-regulated in murine diabetic skin (P < 0.01). In addition, MMP-2 and MMP-9/TIMP-1 protein ratios were significantly lower in murine diabetic skin (P < 0.05). Collagen I levels and I:III ratios were lower in diabetic skin (P < 0.05). These findings suggest that the predisposition of diabetics to wounds may be the result of impaired tissue integrity at baseline, and are due, in part, to a defect in the regulation of collagen protein synthesis at the post-transcriptional level. Diabetes is associated with increased morbidity and mortality, 1 as well as impaired wound healing. 2 Diabetesrelated admissions accounted for 22% of all hospital inpatient days in 2007, and diabetic foot ulcers account for 20% of all hospital admissions in diabetic patients, which are the leading cause of lower extremity amputations. 2 Improvements made in diabetic wound management and prevention clearly have the potential to affect a large number of patients and decrease diabetic-related health care expenditures.More than 100 factors have been identified that contribute to the impairment in diabetic wound healing. 3 Decreased angiogenesis, 4 impaired growth factor production, 5 an altered inflammatory and immune response, 5 a decreased rate of wound contraction, 6 and an imbalance between the accumulation of extracellular components and their remodeling by matrix metalloproteinases (MMPs) 7,8 have all been demonstrated in diabetic wounds. MMP-2 and MMP-9 have been shown to be present in greater concentration in wounded diabetic animals than their nondiabetic littermates, which is similar to findings from patients with nonhealing ulcers. 9 Diabetes is characterized by significantly increased cross linking and nonenzymatic glycation of collagen, as well as elevated levels of advanced glycation end products (AGEs). 10,11 Blockade of the receptor for advanced glycation end products (RAGEs) can restore the wound healing properties of diabetic (Db/Db) mice. 12 Hyperglycemic animals have been shown to have significantly higher concentrations of glycated collagen and higher levels of collagenase activity. 9,13 Furthermore...

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Section: Figure 8 Amentioning

confidence: 99%

Impaired Biomechanical Properties of Diabetic Skin

Bermudez

Herdrich

et al. 2011

The American Journal of Pathology

106

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“…This increase in the rate of biosynthesis and processing offibronectin and the increase of collagen type III (5) appears to be accompanied by a decreased rate of synthesis and/or increased rate of removal of heparan sulfate proteoglycans in diabetic basal lamina (ref. These perturbations of the biosynthesis of extracellular matrix macromolecules result in the increased thickness and permeability of diabetic basement membranes (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The increased capillary permeability may also enable plasma fibronectin to diffuse in increased amounts to the extracellular matrix (19).…”

Section: Discussionmentioning

confidence: 99%

“…Fibronectin was immunoprecipitated from the dialyzed culture medium and its radioactivity was determined. After 1 hr of incubation (i.e., 30-min pulse plus 30-min chase) 5.3% of total radioactivity was recovered in the fibronectin immunoprecipitate of the KK mouse fibroblast culture medium, whereas only 2.7% was recovered in the immunoprecipitate of the control C57BL fibroblast culture medium (data not shown). It appears, therefore, that the secretion of fibronectin during the first hour of incubation of the diabetic fibroblasts is about twice that for the nondiabetic fibroblasts.…”

mentioning

confidence: 97%

“…The diabetic state is accompanied by deranged regulation of the biosynthesis of extracellular matrix macromolecules (1)(2)(3)(4)(5). The increased thickness of capillary basement membranes is one of the histologically and electron-microscopically detectable manifestations of this perturbed matrix biosynthesis (6)(7)(8).…”

mentioning

confidence: 99%

“…The increased thickness of capillary basement membranes is one of the histologically and electron-microscopically detectable manifestations of this perturbed matrix biosynthesis (6)(7)(8). It has been proposed that the deranged regulation of extracellular matrix biosynthesis concerns most if not all mesenchymal cells, not only those involved in basement membrane deposition (1)(2)(3)(4)(5)(6)(7)(8)(9). Biosynthetic experiments performed with biopsy specimens of diabetic human conjunctiva and skin, with biopsy specimens from diabetic (KK strain) mouse conjunctiva, and with diabetic (streptozotocin-induced) rat conjunctiva showed an increased rate of incorporation of [14C]proline into polymeric (insoluble) collagen (ref.…”

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confidence: 99%

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Increased biosynthesis and processing of fibronectin in fibroblasts from diabetic mice.

Phan‐Thanh¹,

Robert²,

Derouette³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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Diabetic connective tissues exhibit a deranged regulation of extracellular matrix biosynthesis. Fibronectin is shown to be increased in human dermal connective tissue by immunofluorescence, mainly at the dermoepidermal and capillary basement membranes. The rate of fibronectin biosynthesis, excretion, and incorporation in a pericellular polymeric form was investigated using genetically diabetic KK mouse skin and fibroblasts as compared to Swiss and C57BL mouse skin and fibroblasts. The rate of incorporation of [mS]methionine into proteins recovered in the culture medium or in deoxycholate and NaDodSO4 or urea extracts was investigated. The rate of incorporation in the medium and deoxycholate extracts was comparable. However, the relative rate of incorporation of the tracer in the NaDodSO4-extractable, pericellular polymeric form was increased in the diabetic KK fibroblasts both for total proteins and for fibronectin. In pulse-chase experiments, the deoxycholate-soluble and NaDodSO4-soluble fractions exhibited a precursor-product relationship. The rate of passage of fibronectin from the deoxycholate-soluble (cellular compartment) form to the NaDodSO4-soluble (pericellular polymeric) form was strongly accelerated in the diabetic fibroblast cultures. These results confirm the increased rate of synthesis of fibronectin in diabetic fibroblasts as well as its processing from the cellular compartment to the polymeric pericellular form. The increase of fibronectin in diabetic connective tissues, in the matrix as well as in the basement membranes, may play a role in the mechanism of micro-and macroangiopathies and in the perturbed permeability characteristics of the diabetic capillaries, and as a glycoprotein it may contribute to the increased periodic acid/Schiff reagent staining of diabetic capillary basement membranes.The diabetic state is accompanied by deranged regulation of the biosynthesis of extracellular matrix macromolecules (1-5). The increased thickness of capillary basement membranes is one of the histologically and electron-microscopically detectable manifestations of this perturbed matrix biosynthesis (6)(7)(8). It has been proposed that the deranged regulation of extracellular matrix biosynthesis concerns most if not all mesenchymal cells, not only those involved in basement membrane deposition (1-9). Biosynthetic experiments performed with biopsy specimens of diabetic human conjunctiva and skin, with biopsy specimens from diabetic (KK strain) mouse conjunctiva, and with diabetic (streptozotocin-induced) rat conjunctiva showed an increased rate of incorporation of [14C]proline into polymeric (insoluble) collagen (ref. 1, pp. 314-323; refs. 4-9). In these same experiments, an increased rate of incorporation of glucosamine into connective tissue glycoproteins was also seen (ref. 1, pp. 314-323; refs. 3-9). Experiments performed on genetically diabetic (KK strain) mouse skin explants showed an increased rate of incorporation of ["4C]proline into type III collagen, with no increase of total collagen...

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Collagen synthesis by vascular smooth muscle cells in the presence of antiproliferative polysaccharides

Logeart

Letourneur

Jozefonvicz

et al. 1996

J. Biomed. Mater. Res.

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Production of various components of the extracellular matrix (ECM) modulates biological functions of the vascular tissue. This process is generally amplified in pathologic states as atherosclerosis. Atheroma originates from smooth muscle cells (SMC) which have migrated and proliferated in the vascular intima. In this study we investigated protein synthesis, collagen synthesis, and types I, III, and V collagen distribution by SMC in the presence of three families of watersoluble polysaccharides, heparin, fucans, and derivatized dextrans. We observed that fucan and derivatized dextran were able, as was heparin, to inhibit rat aortic SMC growth in culture. We then analyzed collagen modulation by measuring the incorporation of the radiolabeled precursor (3H)-proline into vascular SMC. Our results showed uncoupling of the antiproliferative capacity with collagen biosynthesis. However, fucan, the most antiproliferative polysaccharide, was also the most active in inhibiting protein and collagen synthesis. In addition, compounds that decreased total collagen synthesis preferentially increased the proportion of cell-associated collagen. Interestingly, only the antiproliferative polysaccharides inhibited significantly type V collagen biosynthesis. These new biomaterials appear to be valuable tools to study and control extracellular-matrix interactions with cells from the vascular walls.

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Biosynthesis of skin collagens in normal and diabetic mice

Cited by 54 publications

References 47 publications

Impaired Biomechanical Properties of Diabetic Skin

Impaired Biomechanical Properties of Diabetic Skin

Increased biosynthesis and processing of fibronectin in fibroblasts from diabetic mice.

Collagen synthesis by vascular smooth muscle cells in the presence of antiproliferative polysaccharides

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