Paracrine Kynurenic Pathway Activation in the Bone of Young Uremic Rats Can Antagonize Anabolic Effects of PTH on Bone Turnover and Strength through the Disruption of PTH-Dependent Molecular Signaling

被引:5
|
作者
Pawlak, Krystyna [1 ]
Sieklucka, Beata [2 ]
Pawlak, Dariusz [2 ]
机构
[1] Med Univ Bialystok, Dept Monitored Pharmacotherapy, Mickiewicza 2C, PL-15222 Bialystok, Poland
[2] Med Univ Bialystok, Dept Pharmacodynam, Mickiewicza 2C, PL-15222 Bialystok, Poland
关键词
kynurenine pathway; parathyroid hormone (PTH); activating transcription factor 4; parathyroid hormone 1 receptor; cyclic adenosine monophosphate (PTH1R; ATF4; cAMP) axis; osteoblasts; osteoclasts; bone turnover; bone biomechanical properties; ARYL-HYDROCARBON RECEPTOR; HORMONE-RELATED PEPTIDE; TRANSCRIPTION FACTOR 4; OSTEOBLAST-LIKE CELLS; PARATHYROID-HORMONE; GROWING RATS; DISEASE; PROLIFERATION; ALENDRONATE; METABOLISM;
D O I
10.3390/ijms22126563
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Secondary hyperparathyroidism and abnormalities in tryptophan (TRP) metabolism are commonly observed in chronic kidney disease (CKD). The present study aimed to establish potential interactions between endogenous parathyroid hormone (PTH) and activation of the bone kynurenine (KYN) pathway in relation to bone turnover and strength in young rats after one month (CKD-1) and three months (CKD-3) of experimental CKD. TRP, KYN, KYN/TRP ratio and bone turnover markers (BTMs) were measured in trabecular and cortical bone tissue. Expression of aryl hydrocarbon receptor (AhR) and the genes involved in osteogenesis was determined in femoral bone. Biomechanical testing of femoral diaphysis and femoral neck was also performed. Activation of the KYN pathway in trabecular bone during CKD development intensified the expression of genes related to osteogenesis, which led to a decrease in cyclic adenosine monophosphate (cAMP) and BTMs levels, resulting in a stiffer and mechanically weaker femoral neck. In contrast, reduction of the KYN pathway in cortical bone allowed to unblock the PTH-dependent anabolic activating transcription factor 4/parathyroid hormone 1 receptor (PTH1R/ATF4) axis, led to cAMP accumulation, better bone turnover and strength in the course of CKD development. In summary, the paracrine KYN pathway in bone can interfere with the anabolic effects of PTH on bone through disrupting PTH-dependent molecular signaling.
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页数:18
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