Background/Purpose:  Dipeptidyl-peptidase-4 (DPP4) has been recently shown to identify a distinct dermal lineage with intrinsic fibrogenic potential and its targeted inhibition leads to reduced scar formation (1). Fibrotic disease may be considered as a consequence of persistent, exaggerated and uncontrolled tissue repair processes. Systemic sclerosis is the prototype of fibrotic diseases and effective antifibrotic therapies are still lacking. DPP4 inhibitors are already used in treatment of diabetes. The aim of the study was to characterize the DPP4 positive cells, investigate the expression of DPP4 in SSc skin and to evaluate the antifibrotic effect of DPP4 inhibitors in preclinical models of systemic sclerosis.

Methods:  Mouse fibroblasts were isolated and DPP4 positive cells properties were assessed after cell sorting. Expression of DPP4 in human and murine skin was analyzed by immunofluorescence. DPP4 inhibitors were tested in two different concentrations administered orally (Sitagliptin 3mg/kg/d and 10mg/kg/d, Vildagliptin 1,5mg/kg/d and 15mg/kg/d) in bleomycin induced skin fibrosis and in sclerodermatous chronic graft-versus-host disease mouse model (cGvHD). The antifibrotic effect on skin was assessed by hydroxyproline assay, alpha smooth muscle cells quantification and measuring the dermal thickness. Inflammatory infiltrate was asses by CD45 immunofluorescence staining.

Results: We have demonstrated that DPP4 positive cells are a unique population of cells implicated in fibrosis. DPP4 positive fibroblasts count is increased not only in experimental fibrosis, but also in skin biopsies from SSc patients as compared to healthy volunteers. Treatment with DPP4 inhibitor reduced dermal thickness in both mouse models (p<0.05). The differentiation of resting myofibroblast into fibroblast was also significantly decreased (p<0.05) in all treatment groups. Collagen content of the skin diminished by 40% in comparison with NaCl injected mice or syngeneic transplanted mice. Moreover, DDP4 inhibitors reduced the inflammatory infiltrates in two different pathophysiological settings of fibrosis.

Conclusion:  DPP4 identifies a subpopulation of fibrosis-promoting fibroblasts that plays a key role in the pathogenesis of fibrosis in SSc. Moreover, inhibitors of DPP4 show a significant antifibrotic effect in several mouse models of established fibrosis in well tolerated doses. These results may have direct clinical implications as DPP4 inhibitors are already in clinical use for diabetes.

Reference: 1. Rinkevich Y, Walmsley GG, Hu MS, Maan ZN, Newman AM, Drukker M, et al. Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science. 2015;348(6232):aaa2151.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dipeptidyl-peptidase-4-dpp4-positive-fibroblast-subpopulation-promotes-fibrosis-and-are-a-molecular-target-for-treatment-of-fibrosis/