Scleroderma is a chronic disease characterized by excessive tissue fibrosis. Recent studies indicate that cultured dermal fibroblasts isolated from patients produce excessive amounts of collagen and other extracellular matrix components. In this study, we investigated the mechanism(s) of abnormal extracellular matrix accumulation in the scleroderma biopsies and the healing wounds of Tsk1/+ mice. Full-thickness excisional wounds were made in Tsk1/+ and wild-type mice and were subsequently harvested at days 7, 10, and 14 postinjury. The levels of profibrotic cytokine, transforming growth factor were elevated in the wounds of Tsk1/+ mice. Interestingly, the levels of matrix metalloproteinase were significantly reduced in the granulation tissue of Tsk1/+ mice in comparison with wild-type. Furthermore, immunohistochemical analysis of the wounds indicated that the levels of γ-glutamyl-ε-lysine cross-links were elevated in the granulation tissue of Tsk1/+ mice as well as the fibrotic lesions of scleroderma specimens. Collectively, these findings indicate that elevated collagen synthesis and decreased matrix metalloproteinase levels, in combination with increased isopeptide bond cross-links, contribute to abnormal collagen synthesis and assembly in granulation tissue of Tsk1/+ mice and the fibrotic lesions of scleroderma patients.Scleroderma is an intricate disorder of connective tissue that initially affects the skin but later also involves internal organs such as the kidneys, lungs, gastrointestinal tract, and cardiovascular system. 1 The key morphological features are (a) structural and functional vascular abnormalities, (b) mononuclear cellular infiltrates that very likely reflect an autoimmune disturbance, and (c) increased deposition of newly synthesized matrix, mainly type I collagen. 1 The morbidity of scleroderma largely depends upon a third facet of the disease -fibrosis. Recent studies have focused on identifying the ways in which different cellular components interact to culminate in the major vascular and fibrotic pathology of scleroderma. 2,3 Experimental evidence from in vitro and in vivo analyses of cells and tissues from scleroderma patients, as well as from animal models, point to a complex cascade of primary and secondary mediators. 4,5Perhaps the most striking feature of the pathology in scleroderma is the excessive deposition of extracellular matrix (ECM) components, which is the basis for the destruction of normal tissue architecture that leads to tissue and organ dysfunction. 6,7 Collagen is the predominant component of the ECM and is synthesized and secreted by fibroblasts. It has been demonstrated that cultured dermal fibroblasts from scleroderma patients produce more collagen type I and