Tissue Engineering for In Vitro Analysis of Matrix Metalloproteinases in the Pathogenesis of Keloid Lesions

Abstract

eloids represent an extreme form of abnormal cutaneous wound healing that can result in both functionally restrictive and disfiguring scars. In normal wound healing, a series of physiologic responses results in the formation of a scar that is randomly disorganized and predominantly composed of collagen deposition. 1,2 Remodeling of the newly formed tissue affects the type of scar that forms. Keloid lesions are a form of abnormal wound healing whose molecular mechanism and pathogenesis are not well understood, thus making it a therapeutic challenge. In keloids, aberrant remodeling is thought to result in large quantities of collagen deposition after skin trauma in predisposed individuals. However, what distinguishes keloids is not only the abnormal quantity of collagen formation but also the physical extent of it. Clinically, keloids differ from hypertrophic scars in that they extend beyond the boundaries of the initial injury by invading surrounding healthy skin at the level of the dermis and fail to regress over time. 3 An increase in inflammatory markers, such as transforming growth factor β1, and elevated levels of extracellular matrix (ECM) components, such as fibronectin and certain proteoglycans, are also associated with the formation of keloid lesions. 4-9 Currently available treatments for keloid lesions include combinations of steroid injections, surgical removal, silicone IMPORTANCE Keloid lesions form because of alterations in the mechanisms that govern cutaneous wound healing. Although matrix metalloproteinases (MMPs) have been implicated in keloid pathophysiology, many questions still remain about their involvement. Our incomplete understanding of keloid pathophysiology has led to high recurrence rates in current treatments. No reliable animal model is available for studying keloids. OBJECTIVE To gain a better understanding of the disease mechanisms involved in keloid lesions in the hopes of identifying therapeutic options. DESIGN Fibroblasts derived from keloid tissue were incorporated in either Matrigel or polyethylene glycol diacrylate mixed with type I collagen to create 3-dimensional models to investigate the role MMPs play in keloid formation. The MMP gene expressions were also compared between fibroblasts isolated from different sites within the same keloid lesion.

Extracellular Matrix and Dermal Fibroblast Function in the Healing Wound

“…Interestingly, exogenous decorin added to cultured keloid fibroblasts resulted in a reduction of collagen I, MMP1, MMP9, and MMP13. 121 …”

Keloids: The paradigm of skin fibrosis — Pathomechanisms and treatment

“…MMPs, which comprise a family of 25 proteinases that are zinc- and calcium-dependent, act specifically to degrade collagens I and III while also cleaving chemokines thereby limiting inflammation [55,56]. In keloid lesions, the activity of these proteolytic enzymes is elevated in the peripheral, leading edge of the original wound, thereby enhancing the degree of wound remodeling that occurs [57]. Specifically, MMP-1, MMP2, MMP3, and MMP9 have been demonstrated to be elevated in keloid-derived fibroblasts, when isolated from the superficial periphery and deep center of lesions [57].…”

“…In keloid lesions, the activity of these proteolytic enzymes is elevated in the peripheral, leading edge of the original wound, thereby enhancing the degree of wound remodeling that occurs [57]. Specifically, MMP-1, MMP2, MMP3, and MMP9 have been demonstrated to be elevated in keloid-derived fibroblasts, when isolated from the superficial periphery and deep center of lesions [57]. The synthesis and activity of proteases and MMPs is a complex process largely regulated by TGF-β1 and SMADs 3 and 4 [58–60].…”

Tracking Healing Process of Experimental Liver Injuries Treated with Different Sealants and Adhesives Biomaterials. Matrix Metalloproteinase Evaluation

“…In fact, when an injury becomes chronic, as is the case with dermal ulcers caused by burns, MMP1 concentration remains high after the first week of healing. [25] Prolonged MMP1 activity in chronic skin ulcers can have a critical effect on tissue re-epithelialization. [26] Gelatinases (MMP2 and MMP9) play an important role in the formation and maturation of granulation tissue during wound healing.…”