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Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice.

Michalik L, Desvergne B, Tan NS, Basu-Modak S, Escher P, Rieusset J, Peters JM, Kaya G, Gonzalez FJ, Zakany J, Metzger D, Chambon P, Duboule D, Wahli W - J. Cell Biol. (2001)

Bottom Line: Interestingly, PPARalpha and beta expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing.PPARalpha is mainly involved in the early inflammation phase of the healing, whereas PPARbeta is implicated in the control of keratinocyte proliferation.In addition and very interestingly, PPARbeta mutant primary keratinocytes show impaired adhesion and migration properties.

View Article: PubMed Central - PubMed

Affiliation: Institut de Biologie Animale, Université de Lausanne, Bâtiment de Biologie, CH-1015 Lausanne, Switzerland.

ABSTRACT
We show here that the alpha, beta, and gamma isotypes of peroxisome proliferator-activated receptor (PPAR) are expressed in the mouse epidermis during fetal development and that they disappear progressively from the interfollicular epithelium after birth. Interestingly, PPARalpha and beta expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing. Using PPARalpha, beta, and gamma mutant mice, we demonstrate that PPARalpha and beta are important for the rapid epithelialization of a skin wound and that each of them plays a specific role in this process. PPARalpha is mainly involved in the early inflammation phase of the healing, whereas PPARbeta is implicated in the control of keratinocyte proliferation. In addition and very interestingly, PPARbeta mutant primary keratinocytes show impaired adhesion and migration properties. Thus, the findings presented here reveal unpredicted roles for PPARalpha and beta in adult mouse epidermal repair.

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Related in: MedlinePlus

PPAR α and β expression and respective mice phenotypes compared with the major phases of skin wound healing. (A) Summary of time sequence of the major overlapping phases of skin wound healing. (B) Plain lines indicate the expression of PPARα and β in the healing epidermis; dotted lines indicate the duration of the observed phenotype on PPAR mutant mice.
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fig7: PPAR α and β expression and respective mice phenotypes compared with the major phases of skin wound healing. (A) Summary of time sequence of the major overlapping phases of skin wound healing. (B) Plain lines indicate the expression of PPARα and β in the healing epidermis; dotted lines indicate the duration of the observed phenotype on PPAR mutant mice.

Mentions: The healing kinetics obtained with the PPARβ+/− heterozygous mice were different from the one described above for PPARα−/− mice. The healing of the PPARβ+/− mice was delayed during the whole repair process compared with their wild-type littermates (Fig. 6 C), and final closure was postponed by 2–3 d. With respect to the cascade of events implicated in the closure of a skin wound (Fig. 7) , a delay observed during the whole process suggests either a default in skin elasticity and contraction of the wound, or an impaired keratinocyte migration/proliferation. To test the first possibility, elastin- and collagen-specific stainings and dorsal incisional wounds were made on PPARβ+/− and wild-type mice. In unchallenged adult skin, the elastin and collagen deposits were similar in the PPARβ wild-type and mutant dermis (Fig. 8) . Moreover, the time course of collagen accumulation in the granulation tissue during the healing of a wound is identical in the PPARβ+/− mice compared with the wild-type controls (Fig. 8). Finally, the incisional wounds remained perfectly linear in both genotypes, indicating that skin elasticity is not impaired in the heterozygous mice (data not shown) and that the healing delay is not due to a loss of skin elasticity in the mutated animals.


Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice.

Michalik L, Desvergne B, Tan NS, Basu-Modak S, Escher P, Rieusset J, Peters JM, Kaya G, Gonzalez FJ, Zakany J, Metzger D, Chambon P, Duboule D, Wahli W - J. Cell Biol. (2001)

PPAR α and β expression and respective mice phenotypes compared with the major phases of skin wound healing. (A) Summary of time sequence of the major overlapping phases of skin wound healing. (B) Plain lines indicate the expression of PPARα and β in the healing epidermis; dotted lines indicate the duration of the observed phenotype on PPAR mutant mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196455&req=5

fig7: PPAR α and β expression and respective mice phenotypes compared with the major phases of skin wound healing. (A) Summary of time sequence of the major overlapping phases of skin wound healing. (B) Plain lines indicate the expression of PPARα and β in the healing epidermis; dotted lines indicate the duration of the observed phenotype on PPAR mutant mice.
Mentions: The healing kinetics obtained with the PPARβ+/− heterozygous mice were different from the one described above for PPARα−/− mice. The healing of the PPARβ+/− mice was delayed during the whole repair process compared with their wild-type littermates (Fig. 6 C), and final closure was postponed by 2–3 d. With respect to the cascade of events implicated in the closure of a skin wound (Fig. 7) , a delay observed during the whole process suggests either a default in skin elasticity and contraction of the wound, or an impaired keratinocyte migration/proliferation. To test the first possibility, elastin- and collagen-specific stainings and dorsal incisional wounds were made on PPARβ+/− and wild-type mice. In unchallenged adult skin, the elastin and collagen deposits were similar in the PPARβ wild-type and mutant dermis (Fig. 8) . Moreover, the time course of collagen accumulation in the granulation tissue during the healing of a wound is identical in the PPARβ+/− mice compared with the wild-type controls (Fig. 8). Finally, the incisional wounds remained perfectly linear in both genotypes, indicating that skin elasticity is not impaired in the heterozygous mice (data not shown) and that the healing delay is not due to a loss of skin elasticity in the mutated animals.

Bottom Line: Interestingly, PPARalpha and beta expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing.PPARalpha is mainly involved in the early inflammation phase of the healing, whereas PPARbeta is implicated in the control of keratinocyte proliferation.In addition and very interestingly, PPARbeta mutant primary keratinocytes show impaired adhesion and migration properties.

View Article: PubMed Central - PubMed

Affiliation: Institut de Biologie Animale, Université de Lausanne, Bâtiment de Biologie, CH-1015 Lausanne, Switzerland.

ABSTRACT
We show here that the alpha, beta, and gamma isotypes of peroxisome proliferator-activated receptor (PPAR) are expressed in the mouse epidermis during fetal development and that they disappear progressively from the interfollicular epithelium after birth. Interestingly, PPARalpha and beta expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing. Using PPARalpha, beta, and gamma mutant mice, we demonstrate that PPARalpha and beta are important for the rapid epithelialization of a skin wound and that each of them plays a specific role in this process. PPARalpha is mainly involved in the early inflammation phase of the healing, whereas PPARbeta is implicated in the control of keratinocyte proliferation. In addition and very interestingly, PPARbeta mutant primary keratinocytes show impaired adhesion and migration properties. Thus, the findings presented here reveal unpredicted roles for PPARalpha and beta in adult mouse epidermal repair.

Show MeSH
Related in: MedlinePlus