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

Abstract

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.

Evaluation of Midnight Salivary Cortisol as a Predictor Factor for Common Carotid Arteries Intima Media Thickness in Patients with Clinically Inapparent Adrenal Adenomas

“…In animal experiments, ACTH and cortisone were shown to produce vascular injury and to enhance experimentally induced atherosclerosis [ 21 , 22 ]. In humans, the use of glucocorticoids caused significant changes in vascular connective tissue [ 23 – 25 ]. In addition, a cause and effect relationship between corticosteroid treatment and premature atherosclerosis was hypothesized in patients with rheumatoid arthritis or systemic lupus erythematosus chronically treated with glucocorticoids [ 26 , 27 ].…”

Effects of Mindfulness-Based Interventions on Biomarkers and Low-Grade Inflammation in Patients with Psychiatric Disorders: A Meta-Analytic Review

“…Measurements were collected from the outcomes of such indices as adrenocorticotropic hormone (ACTH), cortisol (area under the curve or AUC, awakening response or CAR, and diurnal slope), cytokines (IL-6, IL-8 and TNF-α), nuclear factor enhancer of the kappa light chains of activated B cells (NF-kB), high-sensitive CRP (hsCRP) and epidermal growth factor (EGF). ACTH is a melanocortin peptide produced in response to inflammatory mediators, with higher levels indicating a worse health status [43]. AUC is one of the methods for analysing the overall secretion of cortisol over a specific time-period (e.g., a whole day) in endocrinologic studies, with a higher AUC output considered to be an indicator of worse health status [8,44,45].…”

The Importance of Melanocortin Receptors and Their Agonists in Pulmonary Disease

“…It has been proposed that ACTH increases intracellular calcium in mesenchymal cells and initiate differentiations. (10) Other roles of ACTH that are beginning to be explored are thymic cell growth and differentiation, androgen production via direct action on Leydig cells, a reno-protective effect in chronic kidney disease, and influences on mood (6).…”