Your browser doesn't support javascript.
loading
Targeting CD13/aminopeptidase N as a novel therapeutic approach for scleroderma fibrosis.
Muraoka, Sei; Brodie, William D; Mattichak, Megan N; Gurrea-Rubio, Mikel; Ikari, Yuzo; Foster, Caroline; Amin, M Asif; Khanna, Neha; Amin, Hafsa; Campbell, Phillip L; Vichaikul, Sirapa; Model, Ellen N; Omara, Morgan M; Petrovski, Steven; Kozicki, Karly; Amarista, Camilia; Webber, Anna; Ali, Mustafa; Palisoc, Pamela J; Hervoso, Jonatan; Ruth, Jeffrey H; Tsoi, Lam C; Varga, John; Gudjonsson, Johann E; Khanna, Dinesh; Fox, David A; Tsou, Pei-Suen.
Affiliation
  • Muraoka S; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Brodie WD; Division of Rheumatology, Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan.
  • Mattichak MN; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Gurrea-Rubio M; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Ikari Y; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Foster C; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Amin MA; Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
  • Khanna N; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Amin H; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Campbell PL; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Vichaikul S; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Model EN; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Omara MM; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Petrovski S; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Kozicki K; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Amarista C; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Webber A; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Ali M; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Palisoc PJ; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Hervoso J; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Ruth JH; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Tsoi LC; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Varga J; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Gudjonsson JE; Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
  • Khanna D; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Fox DA; Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
  • Tsou PS; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Arthritis Rheumatol ; 2024 Aug 22.
Article in En | MEDLINE | ID: mdl-39175116
ABSTRACT

OBJECTIVE:

Systemic sclerosis (SSc) is an autoimmune multisystem disease with poorly understood pathogenesis and ineffective treatment options. Soluble CD13 (sCD13), generated by cleavage of cell surface CD13 via matrix metalloproteinase 14 (MMP14), signals through the bradykinin receptor B1 (B1R) to elicit pro-inflammatory, pro-arthritic, and pro-angiogenic responses. In this study we explored the anti-fibrotic potential of targeting the sCD13-B1R axis in SSc.

METHODS:

The expression of CD13, B1R and MMP14 was examined in SSc skin and explanted dermal fibroblasts. The efficacy of B1R antagonists in the inhibition on fibrosis was determined in vitro and in vivo.

RESULTS:

Expression of the genes for CD13, B1R and MMP14 was elevated in skin biopsies from patients with diffuse cutaneous (dc)SSc. Notably, single cell analysis of SSc skin biopsies revealed the highest BDKRB1 expression in COL8A1-positive myofibroblasts, a population exclusively seen in SSc. TGF-ß induced the expression of BDKRB1 and production of sCD13 by dcSSc skin fibroblasts. Treatment of dcSSc fibroblasts with sCD13 promoted fibrotic gene expression, signaling, cell proliferation, migration, and gel contraction. The profibrotic sCD13 or TGFß responses were prevented by a B1R antagonist. Mice lacking Cd13 or Bdkrb1 were resistant to bleomycin-induced skin fibrosis and inflammation. Pharmacological B1R inhibition had a comparable antifibrotic effect.

CONCLUSION:

These results are the first to demonstrate a key role for sCD13 in SSc skin fibrosis, and suggest that targeting the sCD13-B1R signaling axis is a promising novel therapeutic approach for SSc.
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Arthritis Rheumatol Year: 2024 Document type: Article
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Arthritis Rheumatol Year: 2024 Document type: Article