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JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models.

ABSTRACT: Pathologic skin scarring presents a vast economic and medical burden. Unfortunately, the molecular mechanisms underlying scar formation remain to be elucidated. We used a hypertrophic scarring (HTS) mouse model in which Jun is overexpressed globally or specifically in α-smooth muscle or collagen type I–expressing cells to cause excessive extracellular matrix deposition by skin fibroblasts in the skin after wounding. Jun overexpression triggered dermal fibrosis by modulating distinct fibroblast subpopulations within the wound, enhancing reticular fibroblast numbers, and decreasing lipofibroblasts. Analysis of human scars further revealed that JUN is highly expressed across the wide spectrum of scars, including HTS and keloids. CRISPR-Cas9–mediated JUN deletion in human HTS fibroblasts combined with epigenomic and transcriptomic analysis of both human and mouse HTS fibroblasts revealed that JUN initiates fibrosis by regulating CD36. Blocking CD36 with salvianolic acid B or CD36 knockout model counteracted JUN-mediated fibrosis efficacy in both human fibroblasts and mouse wounds. In summary, JUN is a critical regulator of pathological skin scarring, and targeting its downstream effector CD36 may represent a therapeutic strategy against scarring.

SUBMITTER: Griffin MF

PROVIDER: S-EPMC8988368 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models.

Griffin Michelle F MF Borrelli Mimi R MR Garcia Julia T JT Januszyk Michael M King Megan M Lerbs Tristan T Cui Lu L Moore Alessandra L AL Shen Abra H AH Mascharak Shamik S Diaz Deleon Nestor M NM Adem Sandeep S Taylor Walter L WL desJardins-Park Heather E HE Gastou Marc M Patel Ronak A RA Duoto Bryan A BA Sokol Jan J Wei Yuning Y Foster Deshka D Chen Kellen K Wan Derrick C DC Gurtner Geoffrey C GC Lorenz Hermann P HP Chang Howard Y HY Wernig Gerlinde G Longaker Michael T MT

Science translational medicine 20210901 609

Pathologic skin scarring presents a vast economic and medical burden. Unfortunately, the molecular mechanisms underlying scar formation remain to be elucidated. We used a hypertrophic scarring (HTS) mouse model in which <i>Jun</i> is overexpressed globally or specifically in α-smooth muscle or collagen type I–expressing cells to cause excessive extracellular matrix deposition by skin fibroblasts in the skin after wounding. <i>Jun</i> overexpression triggered dermal fibrosis by modulating distinc ...[more]

PMID: 34516825

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Project description:Background:Connective tissue growth factor (CTGF) is a matricellular protein that plays a key role in wound healing and scar formation. Inhibition of CTGF by a specific antisense oligonucleotide significantly reduced scarring and fibrosis in animal models. This study examined whether an antisense oligonucleotide that inhibits human CTGF expression could reduce the severity of hypertrophic scar formation in patients following surgical revision of preexisting breast scars. Methods:This study was a 24-week multicenter, randomized, double-blind, within-subject, placebo-controlled phase 2b study evaluating the efficacy and safety of PF-06473871 in 2 regimens of either 3 or 4 intradermal injections (postsurgery weeks 2, 5, 8, and 11) of 5?mg/cm adjacent to the new surgical incision. One hundred subjects with bilateral hypertrophic scars resulting from prior breast surgery were randomized. Efficacy was determined by the Patient and Observer Scar Assessment Scale (POSAS). Results:The Physician/Observer POSAS overall opinion score at (week 24) for the 4-injection regimen demonstrated a statistically significant (P = 0.022) treatment difference from placebo of 0.68, and the treatment difference for the 3-injection regimen was nonsignificant (P = 0.4). Physician evaluation of scar severity at (week 24) with the photo-guide in the 4-injection regimen had a significant reduction (point estimate of treatment difference of 0.43 favoring PF-06473871). The surgical effect was approximately 2.0 at week 24 and was nearly 3 times greater than the treatment effect. Patient evaluations using the POSAS and photo-guide were not significantly improved with either dose regimen. PF-06473871 was generally well tolerated systemically and locally. Conclusion:The 4-dose regimen of PF-06473871 provided statistically significant improvement, inhibiting severity of hypertrophic scar formation based on physician assessment. However, the effect of revision surgery alone is significant and may dominate the treatment effect of PF-06473871.

Dataset Information

JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models.

Publications

JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models.

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