한빛사 논문
Jong-Sung Park1,2, Yumin Oh1,2, Yong Joo Park1,2, Ogyi Park1,2,3, Hoseong Yang4, Stephanie Slania5, Laura K. Hummers6, Ami A. Shah6, Hyoung-Tae An1,2, Jiyeon Jang1,2, Maureen R. Horton7, Joseph Shin8, Harry C. Dietz8, Eric Song9, Dong Hee Na10, Eun Ji Park10, Kwangmeyung Kim11, Kang Choon Lee12, Viktor V. Roschke3, Justin Hanes2,5, Martin G. Pomper1,13 & Seulki Lee1,2,13,*
1 Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore 21205 MD, USA. 2 Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore 21205 MD, USA. 3 Theraly Fibrosis Inc., Germantown 20876 MD, USA. 4 Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore 21205 MD, USA. 5 Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore 21205 MD, USA. 6 Scleroderma Center, Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore 21224 MD, USA. 7 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore 21205 MD, USA. 8 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore 21205 MD, USA. 9 Department of Immunobiology, Yale University School of Medicine, New Haven 06520 CT, USA. 10 College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea. 11 Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea. 12 School of Pharmacy, SungKyunKwan University, Jangangu 16419 Suwon, Republic of Korea. 13 Department of Materials and Science, Johns Hopkins University, Baltimore 21218 MD, USA. These authors contributed equally: Jong-Sung Park, Yumin Oh.
*Correspondence and requests for materials should be addressed to S.L.
Abstract
Scleroderma is an autoimmune rheumatic disorder accompanied by severe fibrosis in skin and other internal organs. During scleroderma progression, resident fibroblasts undergo activation and convert to α-smooth muscle actin (α-SMA) expressing myofibroblasts (MFBs) with increased capacity to synthesize collagens and fibrogenic components. Accordingly, MFBs are a major therapeutic target for fibrosis in scleroderma and treatment with blocking MFBs could produce anti-fibrotic effects. TLY012 is an engineered human TNF-related apoptosis-inducing ligand (TRAIL) which induces selective apoptosis in transformed cells expressing its cognate death receptors (DRs). Here we report that TLY012 selectively blocks activation of dermal fibroblasts and induces DR-mediated apoptosis in α-SMA+ MFBs through upregulated DR5 during its activation. In vivo, TLY012 reverses established skin fibrosis to near-normal skin architecture in mouse models of scleroderma. Thus, the TRAIL pathway plays a critical role in tissue remodeling and targeting upregulated DR5 in α-SMA+ MFBs is a viable therapy for fibrosis in scleroderma.
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