Aberrant connective tissue differentiation towards cartilage and bone underlies human keloids in African Americans

Abstract

Keloids are benign fibroproliferative tumors more frequently found among African Americans. Until now, keloid etiopathogenesis is not fully understood. To characterize keloids in African Americans, we performed transcriptional profiling of biopsies from large chronic keloids, adjacent nonlesional (NL) skin (n=3) and a newly formed keloid lesion using Affymetrix HGU133 2.0 plus arrays. Quantitative RT-PCR (qRT-PCR) and immunohistochemistry staining were done to confirm increased expression of relevant genes. We identified 1,202 up-regulated and 961 down-regulated differentially expressed genes (DEGs) between keloid and NL skin; 1,819 up- and 1,867 down-regulated DEGs between newly formed keloid and NL skin; and 492 up- and 775 down-regulated DEGs between chronic and newly formed keloid (Fold change >2, False discovery rate <0.05). Many of the top up-regulated DEGs between chronic keloid and NL skin, and between newly formed keloid and NL skin are involved in bone/cartilage formation including Fibrillin 2(FBN2), Collagen type X alpha1(COL10A1), Asporin(ASPN), Cadherin 11(CDH11), Bone morphogenic protein 1(BMP1), Secreted phosphoprotein 1(SPP1), and Runt-related transcription factor2(RUNX2). qRT-PCR confirmed significant (p<0.05) up-regulation of BMP1, RUNX2, CDH11 and FBN2 in chronic keloid compared to NL skin. Immunohistochemistry staining showed increased protein expression of ASPN, CDH11, BMP1 and RUNX2 on chronic and newly formed keloid compared to NL skin. Our study shows that large keloids in African Americans represent a dysplasia of cutaneous connective tissue towards immature cartilage or bone differentiation. The phenotype is potentially regulated by overexpression of RUNX2. This knowledge may give insights to guide the development of better treatment for the disease in the future.

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“…1f). We next validated genes involved in cartilage/bone development, previously reported as highly expressed in keloids, 6 including cadherin-11 and fibrillin-2, among others; all significantly increased in keloid lesions versus controls and versus non-lesional skin (P < 0.05; Fig. 2).…”

“…Genetic studies have identified chromosome variants associated with keloid formation in AAs and Asians. 1,5 A genomic profiling study on lesional and non-lesional keloid skin from three AA patients identified bone/cartilage abnormalities, 6 but did not assess inflammatory pathways. Recently, atopic dermatitis (AD) has been indicated as an independent risk factor for developing keloids.…”

“…As a result of successful keloid response to dupilumab, we used real-time PCR to evaluate Th2 gene expression (IL-4R, IL-13 and CCL18) in lesional and non-lesional keloid skin from three previously reported AA patients (3 females, mean age, 47.3 years) with severe chronic keloids and no concurrent AD. 6 Five healthy AA controls (2 females, 3 males, mean age, 39.8 years) were included for comparisons. Six-millimeter whole-skin biopsy specimens were obtained from the extremities under IRB-approved protocols.…”

“…[2][3][4][5] Its photocoagulating effect allows therefore the specific targeting of the venous tissue, decreasing the possibility of relapse, and presents sufficient penetration for the treatment of deep-seated lesions. Several types of lasers have been used for the treatment of venous lakes of the lips and vascular malformations of the oral mucosa, including diode laser, 6 pulse-dye laser 7 and argon laser. 8 Although these seem effective for superficial and small lesions, the longer wavelength of the Nd:YAG laser allows better and quicker results in the treatment of deeper and thicker lesions 1 : a single session is often sufficient for the treatment of venous lakes of the lips and oral…”

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“…Although our understanding of scar biology is improving, the wound healing process is complex and the mechanisms that lead to abnormal scar development remain unclear [52]. It is likely that the most effective treatment for abnormal scars is one that simultaneously focuses on one or several of multiple targets, particularly molecules and processes that are involved in inflammation, vasculogenesis, and fibrosis.…”