Systemic and local ACTH produced during inflammatory states promotes osteochondrogenic mesenchymal cell differentiation contributing to the pathologic progression of calcified atherosclerosis.

Jodi F Evans, Louis Ragolia

Medical hypotheses 2012 Dec

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There are many well-known roles for the proopiomelanocortin (POMC) derived peptides and their receptors, the melanocortin receptors (MC-R). The focus here is on the evolving role of the melanocortin system in inflammation. Chronic inflammatory states such as those occurring in diabetes and obesity are associated with both a hyperactive hypothalamic-pituitary-adrenal (HPA) axis as well as increased incidence of atherosclerosis. An inflammation-induced hyperactive HPA axis along with increased leukocyte infiltration can lead to significant exposure to melanocortin peptides, particularly ACTH, in an inflamed vasculature. Mesenchymal progenitor cells are present throughout the vasculature, express receptors for the melanocortin peptides, and respond to ACTH with increased osteochondrogenic differentiation. Coupled to the increased exposure to ACTH during HPA hyperactivity is increased glucocorticoid (GC) exposure. GCs also promote chondrogenic differentiation of mesenchymal progenitors and increase their expression of MC-R as well as their expression of POMC and its cleavage products. It is hypothesized that during inflammatory states systemically produced ACTH and glucocorticoid as well as ACTH produced locally by macrophage and other immune cells, can influence and potentiate mesenchymal progenitor cell differentiation along the osteochondrogenic lineages. In turn the increase in osteochondrogenic matrix contributes to the pathophysiological progression of the calcified atherosclerotic plaque. The roles of the melanocortin system in inflammation and its resolution have just begun to be explored. Investigations into the ACTH-induced matrix changes among mesenchymal cell populations are warranted. ACTH signaling through the MC-R represents a new therapeutic target for the prevention and treatment of calcified atherosclerosis. Copyright © 2012 Elsevier Ltd. All rights reserved.

Citation

Jodi F Evans, Louis Ragolia. Systemic and local ACTH produced during inflammatory states promotes osteochondrogenic mesenchymal cell differentiation contributing to the pathologic progression of calcified atherosclerosis. Medical hypotheses. 2012 Dec;79(6):823-6