Session Type: Abstract Submissions (ACR)
Background/Purpose: Skin fibrosis in systemic sclerosis (SSc) is associated with loss of subcutaneous adipose tissue (SCAT) and reduction in adiponectin. The mechanism underlying SCAT atrophy and its significance in pathogenesis are not known. In light of emerging insights into adipogenesis and the plasticity of adipogenic progenitor cells, we investigated the mechanistic basis of adipose atrophy and its relation to fibrosis in the skin.
Methods: The kinetics of SCAT loss was investigated in mouse models of dermal fibrosis. Transgenic mice were used for adipocyte lineage tracing. Modulation of adipogenic differentiation was evaluated in mouse and human stem cells and skin fibroblasts by real-time qPCR, immunoblotting, cytochemistry, and DNA microarrays.
Results: Skin biopsies from a cohort of well characterized patients with diffuse cutaneous SSc showed variable but consistent SCAT atrophy. Moreover, striking loss of SCAT was observed in mouse models of scleroderma induced by bleomycin. Careful time-course studies demonstrated that loss of SCAT preceded the onset of dermal fibrosis. Furthermore, loss of adipogenic markers preceded the increase in fibrogenic markers in the lesional skin. These observations suggest that adipogenic progenitor cell differentiation was redirected towards fibrogenic fates. Indeed, TGF-beta was able to preferentially promote fibrogenic differentiation of mouse 3T3L1 preadipocytes in vitro. Remarkably, the tyrosine kinase abl prevented adipogenesis, which was rescued by the putative antifibrotic drug imatinib. Moreover, in normal skin fibroblasts imatinib caused dramatic induction of adipogenic genes. The potential significance of preadipocyte-fibroblast transitions in fibrogenesis is directly addressed by fate-mapping studies using adipocyte-labeled transgenic reporter mice.
Conclusion: Our studies indicate that SCAT atrophy is consistently associated with human and mouse scleroderma, and appears to precede the onset of dermal fibrosis. Cellular adipocyte/fibroblast plasticity, readily induced in vitro and manipulated by imatinib, may directly contribute to fibrogenesis. We conclude that loss of SCAT might be a primary event in the pathogenesis of SSc, and adipogenic progenitor cell differentiation may be a potential target of therapeutic manipulation.
R. Goncalves Marangoni,
M. E. Hinchcliff,
« Back to 2012 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/aberrant-adipogenesis-in-the-pathogenesis-of-scleroderma/