P0870THE ACTIVATION OF KYNURENIC SYSTEM IN BONE TISSUE AS A NEW REGULATOR OF OSTEOBLASTOGENESIS IN RATS WITH EXPERIMENTAL CHRONIC KIDNEY DISEASE DURING LP533401 THERAPY

Abstract Background and Aims Abnormalities in bone metabolism represent the most complex disorder accompanying a chronic kidney disease (CKD) development. Serotonin – one of the tryptophan metabolites, has received intensive attention due to its potential role in bone metabolism. The synthesis of peripheral serotonin is initiated by the tryptophan hydroxylase-1 (TPH-1) in the gut. LP533401 is a small-molecule inhibitor of TPH-1. Previously, we found that inhibition of TPH-1 by LP533401 may improve bone mineralization in rats with experimentally induced CKD (Pawlak et al, Bone, 2018). The aim of this study was to establish whether the inhibition of serotonin synthesis by LP533401 may affect kynurenine pathway activity in bone tissue of nephrectomized rats, and to determine the potential consequence of this process in relation to osteoblastogenesis. Method Nephrectomized rats were randomized into: untreated (CKD), treated with vehicle (VEH), treated with LP533401 at a dose of 30 (LP 30) and 100 mg/kg (LP 100) daily for 8 weeks. The shame-operated animals served as controls (CON). Tryptophan (TRP) and kynurenine (KYN) concentrations in trabecular and cortical homogenates of femoral bone were determined using high-performance liquid chromatography (HPLC). The expression of tryptophan 2,3-dioxygenase (TDO) as well as genes associated with osteoblastogenesis: activating transcription factor 4 (ATF4), forkhead box protein O1 (FOXO1), Cyclin D1, osteocalcin (Bglap) and sclerostin (Sost) were assessed using the QRT-PCR method. Results We demonstrated a presence of TDO-dependent, paracrine kynurenic system in bone homogenates of rats with CKD. The significant decrease in TDO mRNA level was observed in the bone of all nephrectomized groups in comparison with CON (all p