Cystic fibrosis being a polyendocrine disease (Review)

Abstract

The cystic fibrosis transmembrane regulator (CFTR) gene encodes the synthesis of a protein of the same name, which functions as a direct activator of anionic transport. Chloride is the most abundant anion; as an antagonist of Na+ and K+, it provides electroneutrality of cell membranes at rest; together with cations, it serves as an important osmolyte and forms water flow across cell membranes for transepithelial secretion.Glandular cells in CF trap Cl– and Na+, and the prodused secretion is excessively viscous. Subnormal CFTR activity leads to stagnation of mucociliary clearance, inhibition of intestinal transport.In addition to exocrine disorders, CFTR mutations are associated with a decrease in volume, mass, increased apoptosis of β-cells of the pancreas, a significant suppression of insulin exocytosis in response to stimulation with glucose and glucagon-like peptide-1, hyperglucagonemia against the background of a defect in the suppression of α-cell function by insulin, but a decrease in maximum capacity α-cells.Deficiency and progressive decline in bone mineral density is an expected secondary manifestation of CF due to pancreatic exocrine insufficiency with malabsorption of nutrients and fat-soluble vitamins. However, in patients with the F508del mutation, a significant decrease in the synthesis of OPG, COX-2, PGE2 in the osteoblastic formation, and an increase in the activity of the antianabolic NF-kB were found. We are talking about a defect in the canonical signaling pathway (Wnt/β-catenin), which regulates the expression of genes-activators of osteoblastogenesis, dissociation of the stages of physiological bone remodeling.In addition to congenital bilateral or unilateral aplasia of the vas deferens, an increase in the frequency of CFTR mutations is also found in non-obstructive azoospermia, oligo-, astheno- and teratospermia. CFTR is involved in the entry of HCO3– into Sertoli cells to trigger cAMP-dependent transcription and its defects lead to suppression of FSH-dependent gene expression of spermatogenesis, loss of sequence in the Wnt cascade, destruction of the PGE2-dependent transepithelial interaction and, as a consequence, the blood-testicular barrier.CF is characterized, along with classical signs, by endocrine dysfunction of the pancreas, osteoporosis with suppression of osteoblastogenesis, and a defect in spermatogenesis.

Family case of cystic fibrosis

“…Кистозный фиброз (МКБ-10 Е84.0-84.9; МКБ 11 CA25.0-CA25.2) представляет собой моногенное заболевание, наследуемое аутосомно-рецессивно и обусловленное мутацией гена трансмембранного регулятора кистозного фиброза (Cystic Fibrosis Transmembrane conductance Regulator, CFTR), расположенного в длинном плече 7-й хромосомы (7q31.2), вследствие чего нарушается транспорт ионов натрия и хлора между межклеточной жидкостью и эпителиальными клетками выводных протоков экзокринных желёз. В результате разнообразных мутаций гена CFTR, являющегося прямым активатором анионного транспорта в билипидной мембране железистых клеток, выделяемый гландулоцитами, секрет становится вязким, дегидрированным из-за задержки и обратной реабсорбции ионов-антагонистов Clи Na + [2]. Субнормально функционирующий CFTR приводит к снижению работы мукоцилиарного клиренса и фагоцитарной активности в альвеолах, развитию оксидативного стресса вследствие недостаточной функции антиоксидантного глутатиона, мукостазу в дыхательном тракте, обструкции выводных протоков в поджелудочной железе и последующему аутолизу ткани и др.…”

Progress of Wnt Signaling Pathway in Osteoporosis

“…Until now, three Wnt signaling pathways have been found, including the Wnt/ β -catenin pathway, the non-Wnt/Ca 2+ pathway, and the Wnt planar cell polarity (PCP) pathway [ 107 ]. An increasing number of studies show that the Wnt signaling pathway is related to bone formation and bone remodeling [ 108 , 109 ]. It is highly conserved and widely present in invertebrates and vertebrates.…”