Restoring the activity of the protein adiponectin ameliorates skin fibrosis in mouse models of scleroderma, a new study shows.
The study, “Adiponectin is an endogenous anti-fibrotic mediator and therapeutic target,” appeared in the journal Scientific Reports.
The research team was led by John Varga, MD, from the Northwestern Scleroderma Program at the Feinberg School of Medicine in Chicago.
The biology of fibrosis in scleroderma remains poorly understood, despite relevant findings related to mechanisms that activate fibroblasts — key cells in the maintenance of the extracellular matrix (ECM) that provide support to cells and whose disruption is implicated in fibrosis.
Skin fibrosis in scleroderma is associated with the weakening of dermal white adipose tissue (dWAT), a layer within the skin that is a crucial contributor to skin physiology. This process is accompanied by the loss of adipocytes, which are cells that act as energy reservoirs.
The generation of new adipocytes is controlled by the protein receptor PPAR-gamma, located in the cell nucleus. Activation of PPAR-gamma with agonists (molecules that bind to this receptor) ameliorated fibroblast activation in vitro, and improved fibrosis and dWAT weakening in vivo.
The fibrosis-ameliorating role of PPAR-gamma is mediated by adiponectin — a protein released almost exclusively by adipocytes — which attenuates fibroblast activation in scleroderma.
Research has shown that blood levels of adiponectin are reduced in patients with diffuse cutaneous scleroderma. In addition, low levels of adiponectin are associated with increased disease activity, severity, and duration.
Now, scientists evaluated adiponectin activity in skin biopsies from scleroderma patients, and studied its mechanisms in two mouse models of fibrosis. These mice either lacked or had elevated levels of adiponectin.
The team also assessed the effects and mechanism of action of a synthetic agonist of the adiponectin receptors in vitro and in vivo.
Results showed that adiponectin activity was decreased in a subgroup of scleroderma skin biopsies.
Moreover, mice lacking adiponectin exhibited exaggerated skin fibrosis. Conversely, transgenic mice with augmented adiponectin demonstrated dWAT expansion and protection from fibrosis.
In addition, the agonists of adiponectin receptors showed potent anti-fibrotic activity in fibroblasts and in 3D human skin models, while presenting good tolerability. This was partially achieved by diminishing the assembly of complexes connecting the cells with the ECM, a relevant process also seen in lung fibrosis. Prevention and reversal of organ fibrosis in mice also was observed.
These findings suggest that adiponectin “exerts powerful negative regulatory effects on fibrosis, and suggest that impaired adiponectin signaling may contribute to persistence of skin fibrosis,” the team wrote.
Furthermore, the study indicates that “peptides activating adiponectin pathways might represent viable tools for further development as anti-fibrotic therapies” in scleroderma.
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