1 Although the pathogenesis of scleroderma is not fully understood, activation of connective-tissue-type mast cells (CTMCs) has been implicated in various fibrotic diseases. 2 Our previous study showed that the number of CTMCs was markedly increased during fibrous proliferation in the skin of a scleroderma model, namely tight-skin (Tsk) mice. Because mast cells express numerous bioactive factors, such as
cytokines,
growth factors,
proteases, and others, it is crucial to identify the primary factors that may be involved in the pathogenesis of scleroderma. Our previous study also showed that a CTMC-specific
protease, chymase-4, was selectively upregulated in accordance with the development of skin
fibrosis in Tsk mice. 3 To further elucidate the role of
chymase secreted from CTMCs, we evaluated the
therapeutic effects of a synthetic
chymase-specific inhibitor,
SUN-C8257, on the development of skin
fibrosis in Tsk mice.
SUN-C8257 (50 mg kg-1 day-1) was administered via
intraperitoneal injection in 13-week-old Tsk mice for a period of 2 weeks. 4 Treatment with
SUN-C8257 significantly reduced
chymase activity by 43% and the chymase-4
mRNA level by 47%, and also decreased the thickness of the subcutaneous fibrous layer of Tsk mice by 42% compared with that of Tsk mice injected with vehicle. 5 Furthermore, immunohistochemical analysis revealed that
transforming growth factor (TGF)-beta1 staining in the fibrous layer of Tsk skin was markedly reduced by the treatment with
SUN-C8257. This
chymase inhibitor may prevent the
chymase-dependent pathway that activates the latent
TGF-beta1 in fibrous tissue, and may exhibit beneficial effects that inhibit the development of
fibrosis. 6 In conclusion, our results strongly support the assumption that CTMC-derived
chymase may play a key role in the pathogenesis of scleroderma.