Abstract
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.
Highlights
Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), leading to osteoporosis, bone fragility and increased risk of fracture [1,2].Among chronic kidney disease (CKD) patients, low bone turnover is considered to be one of the most common types of renal osteodystrophy; it has been recognized both among CKD patients undergoing conservative treatment [3] and in patients on hemodialysis [4,5].Bone turnover defines the rate of skeletal remodeling, reflected as the ratio between bone formation and bone resorption
Since bone turnover in CKD is a function in large part of the degree of secondary hyperparathyroidism (SHPT), circulating parathyroid hormone (PTH) levels together with serum calcium, phosphorus and total alkaline phosphatase (ALP) activity are used to diagnose bone turnover and to guide the pharmacologic treatment of CKD-MBD [4]
During three months of CKD development (CKD-3), the concentrations of TRP, KYN as well as the KYN/TRP ratio were higher in uremic rats compared with appropriate controls (CON-3), and the activation of the KYN system was observed in these animals in comparison with the CKD-1 group (Figure 1A–C)
Summary
Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), leading to osteoporosis, bone fragility and increased risk of fracture [1,2].Among CKD patients, low bone turnover is considered to be one of the most common types of renal osteodystrophy; it has been recognized both among CKD patients undergoing conservative treatment [3] and in patients on hemodialysis [4,5].Bone turnover defines the rate of skeletal remodeling, reflected as the ratio between bone formation and bone resorption. Bone resorption is achieved by osteoclasts (OCs), after which the osteoblasts (OBs) form new bone matrix, leading to the restoration of the removed bone [6]. In physiological conditions, these two processes, which are referred to as coupling bone remodeling, are tightly balanced [7]. Since bone turnover in CKD is a function in large part of the degree of secondary hyperparathyroidism (SHPT), circulating parathyroid hormone (PTH) levels together with serum calcium, phosphorus and total alkaline phosphatase (ALP) activity are used to diagnose bone turnover and to guide the pharmacologic treatment of CKD-MBD [4]. During the early stages of the disease, patients with CKD often exhibit low bone turnover before transitioning to high bone turnover when SHPT is exacerbated. The variations in bone turnover are considered in part a function of abnormalities in PTH signaling [9], but the complex relationship between them during
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