Local injection of latency‐associated peptide, a linker propeptide specific for active form of transforming growth factor‐beta1, inhibits dermal sclerosis in bleomycin‐induced murine scleroderma

Abstract

Transforming growth factor-β1 (TGF-β1) has been thought to play a key role in the pathogenesis of scleroderma; however, therapeutic approaches targeting TGF-β1 and/or related molecules have provided inconsistent results. In this study, we demonstrate the antifibrotic effects of local administration of latency-associated peptide (LAP), a linker propeptide that specifically converts the active form of TGF-β1 to the inactive from, in the bleomycin (BLM)-induced scleroderma mouse model. Histologically, co-injection of BLM and LAP into the dorsal skin prevented proinflammatory and later sclerotic responses, features seen in mice injected with BLM alone or together with PBS as control. In addition, the skin sites co-injected with BLM and LAP showed a marked decrease in mast cell infiltration. Isoform-specific ELISA and real-time RT-PCR revealed transient decreases in connective tissue growth factor and collagen α1(I) mRNA expression 2 weeks after the co-injection, preceded by a decrease in active TGF-β1 protein production. In contrast, the baseline expression of TGF-β1 mRNA remained unchanged. By contrast, after induction of scleroderma by BLM, the inhibitory effects of LAP did not occur, suggesting time course-dependent TGF-β1 regulation. Our data may have novel therapeutic implications regarding in vivo TGF-β1 inactivation in human scleroderma, and the post-transcriptional interrelationship between major fibrogenic cytokines in the autoimmune aspects of the disease.