Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Adipocyte-Targeted Wnt Activation Results in Spontaneous Dermal Fibrosis and Subcutaneous Lipoatrophy.
Wei3, Jun, Melichian2, Denisa S., Kumora2, Kazuhiro, Macdougald4, Ormond, Varga1, John
Fibrosis and subcutaneous lipoatrophy are hallmarks of scleroderma, and are thought to reflect mesenchymal cell differentiation into activated fibroblasts. The Wnts are a family of extracellular ligands and are involved in development and cell fate determinations. Canonical Wnt signaling drives preadipocyte differentiation into osteoblasts in part through negative modulation of PPAR-g expression and function. Recent studies implicate abnormalities in the canonical Wnt pathway in scleroderma and pulmonary fibrosis. Because Wnt signaling has profound effects on regulating mesenchymal cell lineage, we examined the effect of adipocyte-specific ectopic Wnt10b expression on skin homeostasis and differentiation in transgenic mice.
Female transgenic mice harboring Wnt10b under the control of the FABP4 promoter were studied. Adiponectin levels were determined by ELISA. Dermal thickness was measured. Collagen accumulation in the skin was determined histochemical stains, and by colorimetric assays. Mast cells were identified by Astra Blue staining. Fibroblasts were explanted from the skin and evaluated in vitro at early passage. Gene expression was assessed by real-time qPCR and Western blot analysis.
At six months of age, female FABP4-Wnt10b transgenic mice showed a marked loss of subcutaneous and visceral adipose tissue. Serum levels of adiponectin were >80% lower than in wildtype littermates. In the skin from Wnt10b transgenic mice, a dramatic increase in Wnt10b mRNA expression was noted, and mRNA level for axin 2 was significantly elevated. The dermis showed a >60% increase in thickness, with a striking reorganization of the collagenous matrix, and a >80% increase in soluble collagen content. Degranulating mast cells were seen in the reticular dermis and among muscle bundles in Wnt10b transgenic mice but not in wildtype littermates. mRNA levels for Type I collagen and a-smooth muscle actin were elevated. Explanted dermal fibroblasts showed elevated Wnt10b expression. Expression of the adipogenic markers PPAR-g and FABP4 were reduced, whereas mRNA levels for Type I collagen a-SMA were elevated, compared to wildtype fibroblasts examined in parallel.
Ectopic Wnt10b expression targeted to adipocytes results in progressive loss of cutaneous and visceral adipose tissue accompanied by the spontaneous development of dermal fibrosis with increased expression of fibrotic markers. Dermal fibroblasts explanted from Wnt10b transgenic mice show sustained activation of Wnt10b-driven canonical signaling and upregulation of collagen gene expression in vitro, suggesting that ectopic Wnt10b drives a shifts in mesenchymal cell fate toward myofibroblasts by induction of fibrotic genes while simultaneously suppressing adipogenic gene expression. This shift appears to be driven, at least in part, by suppression of the adipogenic master regulator transcription factor PPAR-g. The results implicate that Wnt signaling plays an important role in the pathogenesis of scleroderma. Modulating Wnt activity may therefore represent a novel therapeutic approach for the treatment of scleroderma.
To cite this abstract, please use the following information:
Wei, Jun, Melichian, Denisa S., Kumora, Kazuhiro, Macdougald, Ormond, Varga, John; Adipocyte-Targeted Wnt Activation Results in Spontaneous Dermal Fibrosis and Subcutaneous Lipoatrophy. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :601