RANKL/OPG system regulation by endogenous PTH and PTH1R/ATF4 axis in bone: Implications for bone accrual and strength in growing rats with mild uremia

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

“…Interestingly, the activation of bone resorptive activity was positively related to the majority of the analyzed biomechanical parameters. Previously, we showed that serum PTH and the bone PTH1R/ATF4 axis beneficially impacted cortical bone strength in young rats with CKD [ 16 ], and the present results further support this observation by demonstrating a link between PTH-dependent ATF4 expression and TRAP—5b activity at the cortical bone level. ATF4 gene expression has been reported both in OBs and OCs [ 41 , 42 , 43 ], and the fact that herein we observed a clear relation only between ATF4 expression and osteoclastic activity (although a positive, weak association existed between ATF4 expression and ALP activity as well) may be explained by varying temporal regulation of PTH—dependent maturation of pre-osteoblasts and pre-osteoclasts, which has been previously described by Locklin et al [ 45 ].…”

“…It has been shown that ATF4 was crucial for the induction of RANK expression on bone marrow monocyte cultures and bones of mice with ATF4 deletion; and lack of ATF4 caused a shift in OCs precursors to macrophages [ 43 ]. Since ATF4 gene expression was strongly related to both osteoblasto- and osteoclastogenesis genes in this study ( Table 2 ), and previously we showed that the PTH-mediated PTH1R/ATF4 axis was associated with anabolic effects in the bone of these rats [ 16 ], we suppose that ATF4 may be a PTH-dependent link, coupling bone resorption with bone formation in young, uremic organisms. Moreover, the intensification of resorptive activity was accompanied by a slight increase in bone formation, reflected by ALP activity ( Figure 2 D).…”

“…In the next step of our study, we tried to identify the potential molecular mechanism by which KYN may affect osteogenesis in young animals with CKD. Previously [ 16 , 25 ], we showed that the expression of genes involved in osteoblastogenesis, as well as PTH1R mRNA levels, significantly increased during CKD progression, as schematically presented in Figure 5 A. In the present study, we measured the expression of key genes associated with osteoclastogenesis—RANK, NFATc1 and TRAP.…”

“…OC differentiation is supported by OBs expressing membrane-bound receptor activator of the NF-kB ligand (RANKL), and its secreted decoy receptor-osteoprotegerin (OPG) [ 15 ]. Previously, we found that serum PTH and the bone activating transcription factor 4/parathyroid hormone 1 receptor (PTH1R/ATF4) axis, the major pathway responsible for anabolic PTH effect in bone, can inversely affect the bone RANKL/OPG ratio and thus it may regulate bone accrual and strength in young rats with CKD [ 16 ].…”

Modulation of the Paracrine Kynurenic System in Bone as a New Regulator of Osteoblastogenesis and Bone Mineral Status in an Animal Model of Chronic Kidney Disease Treated with LP533401

“…Total RNA was isolated from femoral tissue using a Thermo Scientific GeneJET RNA Purification Kit (Thermo Scientific, Vilnius, Lithuania), and a quantitative real-time polymerase chain reaction assay was performed, as described in detail previously [50]. Primers were designed using Primer-BLAST software.…”