{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T19:21:29Z","timestamp":1781032889674,"version":"3.54.1"},"reference-count":50,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,8,19]],"date-time":"2020-08-19T00:00:00Z","timestamp":1597795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2015\/19\/N\/NZ4\/01347"],"award-info":[{"award-number":["2015\/19\/N\/NZ4\/01347"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014269","name":"Uniwersytet Medyczny w Bia\u0142ymstoku","doi-asserted-by":"publisher","award":["N\/ST\/ZB\/18\/002\/2228"],"award-info":[{"award-number":["N\/ST\/ZB\/18\/002\/2228"]}],"id":[{"id":"10.13039\/501100014269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014269","name":"Uniwersytet Medyczny w Bia\u0142ymstoku","doi-asserted-by":"publisher","award":["N\/ST\/ZB\/18\/003\/2228"],"award-info":[{"award-number":["N\/ST\/ZB\/18\/003\/2228"]}],"id":[{"id":"10.13039\/501100014269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>An increase in the peripheral synthesis of serotonin and kynurenine, observed during the chronic kidney disease (CKD) course, is negatively associated with bone health. Serotonin and kynurenine are connected by the common precursor, tryptophan. LP533401 is an inhibitor of peripheral serotonin synthesis. This study aimed to establish if the inhibition of serotonin synthesis by LP533401 may affect the kynurenine pathway activity in bone tissue and its potential consequence with regard to osteogenesis and bone mineral status. Nephrectomized rats were treated with LP533401 at a dose of 30 and 100 mg\/kg daily for eight weeks. Tryptophan and kynurenine concentrations were determined, and tryptophan 2,3-dioxygenase (TDO) expression was assessed. We discovered the presence of a TDO-dependent, paracrine kynurenic system in the bone of rats with CKD. Its modulation during LP533401 treatment was associated with impaired bone mineral status. Changes in TDO expression affecting the kynurenine pathway activity were related to the imbalance between peripheral serotonin and 25-hydroxyvitamin D. There were also close associations between the expression of genes participating in osteoblastogenesis and activation of the kynurenine pathway in the bones of LP53301-treated rats. Our results represent the next step in studying the role of tryptophan metabolites in renal osteodystrophy.<\/jats:p>","DOI":"10.3390\/ijms21175979","type":"journal-article","created":{"date-parts":[[2020,8,19]],"date-time":"2020-08-19T21:37:40Z","timestamp":1597873060000},"page":"5979","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["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"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1308-7323","authenticated-orcid":false,"given":"Adrian","family":"Mor","sequence":"first","affiliation":[{"name":"Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2254-7982","authenticated-orcid":false,"given":"Krystyna","family":"Pawlak","sequence":"additional","affiliation":[{"name":"Department of Monitored Pharmacotherapy, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4968-4429","authenticated-orcid":false,"given":"Bartlomiej","family":"Kalaska","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2126-8423","authenticated-orcid":false,"given":"Tomasz","family":"Domaniewski","sequence":"additional","affiliation":[{"name":"Department of Monitored Pharmacotherapy, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8384-7116","authenticated-orcid":false,"given":"Beata","family":"Sieklucka","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Zieminska","sequence":"additional","affiliation":[{"name":"Department of Monitored Pharmacotherapy, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan","family":"Cylwik","sequence":"additional","affiliation":[{"name":"Department of Paediatric Laboratory Diagnostics, Medical University of Bialystok, Waszyngtona 17, 15-269 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3751-0608","authenticated-orcid":false,"given":"Dariusz","family":"Pawlak","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1038\/sj.ki.5000414","article-title":"Definition, evaluation and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO)","volume":"69","author":"Moe","year":"2006","journal-title":"Kidney Int."},{"key":"ref_2","first-page":"S1","article-title":"KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease mineral and bone disorder (CKD-MBD)","volume":"76","author":"Moe","year":"2009","journal-title":"Kidney Int. Suppl."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Wang, Q., Chen, D., Nicholson, P., Cheng, S., Alen, M., Mao, L., and Cheng, S. (2014). The associations of serum serotonin with bone traits are age- and gender-specific. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109028"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1083\/jcb.201006123","article-title":"The two faces of serotonin in bone biology","volume":"191","author":"Ducy","year":"2010","journal-title":"J. Cell. Biol."},{"key":"ref_5","first-page":"421","article-title":"New insights into the physiology of bone regulation: The role of neurohormones","volume":"63","author":"Matucha","year":"2014","journal-title":"Physiol. Res."},{"key":"ref_6","first-page":"49","article-title":"Serotonin and the bone assessment","volume":"7","author":"Carsote","year":"2014","journal-title":"J. Med. Life"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1177\/0004867414565475","article-title":"The association between use of antidepressant and bone quality using quantitative heel ultrasound","volume":"49","author":"Rauma","year":"2015","journal-title":"Aust. N. Z. J. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Pawlak, D., Oksztulska-Kolanek, E., Znorko, B., Domaniewski, T., Rogalska, J., Roszczenko, A., Brz\u00f3ska, M.M., Pryczynicz, A., Kemona, A., and Pawlak, K. (2016). The association between elevated levels of peripheral serotonin and its metabolite\u20145-hydroxyindoleacetic acid and bone strength and metabolism in growing rats with mild experimental chronic kidney disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0163526"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bone.2017.08.004","article-title":"The impact of peripheral serotonin on leptin-brain serotonin axis, bone metabolism and strength in growing rats with experimental chronic kidney disease","volume":"105","author":"Pawlak","year":"2017","journal-title":"Bone"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1038\/nm.2098","article-title":"Pharmacological inhibition of gutderived serotonin synthesis is a potential bone anabolic treatment for osteoporosis","volume":"16","author":"Yadav","year":"2010","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.bone.2018.05.022","article-title":"LP533401 restores bone health in 5\/6 nephrectomized rats by a decrease of gut-derived serotonin and regulation of serum phosphate through the inhibition of phosphate co-transporters expression in the kidneys","volume":"113","author":"Pawlak","year":"2018","journal-title":"Bone"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.coph.2003.10.006","article-title":"The kynurenine pathway of tryptophan degradation as a drug target","volume":"4","author":"Schwarcz","year":"2004","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1042\/BST0361120","article-title":"Exploring the mechanism of tryptophan 2,3-dioxygenase","volume":"36","author":"Thackray","year":"2008","journal-title":"Biochem. Soc. Trans."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1178646917691938","DOI":"10.1177\/1178646917691938","article-title":"Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects","volume":"10","author":"Badawy","year":"2017","journal-title":"Int. J. Tryptophan Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1093\/brain\/115.5.1249","article-title":"Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease","volume":"115","author":"Heyes","year":"1992","journal-title":"Brain"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/sj.cdd.4401073","article-title":"T cell apoptosis by tryptophan catabolism","volume":"9","author":"Fallarino","year":"2002","journal-title":"Cell Death Differ."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/S0361-9230(02)00813-4","article-title":"Increased levels of 3-hydroxykynurenine in different brain regions of rats with chronic renal insufficiency","volume":"58","author":"Pawlak","year":"2002","journal-title":"Brain Res. Bull."},{"key":"ref_18","first-page":"263","article-title":"Behavioral changes in the course of chronic renal insufficiency in rats","volume":"53","author":"Tankiewicz","year":"2001","journal-title":"Pol. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1111\/j.1440-1681.2006.04490.x","article-title":"Kynurenine pathway metabolism in patients with osteoporosis after 2 years of drug treatment","volume":"33","author":"Forrest","year":"2006","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.3923\/pjbs.2009.1025.1030","article-title":"New evidence on hypoglycemic effect of quinolinic acid in diabetic rats","volume":"12","author":"Dayer","year":"2009","journal-title":"Pak. J. Biol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"254","DOI":"10.3109\/13813455.2011.623705","article-title":"Evaluation of indoleamine 2,3-dioxygenase expression and kynurenine pathway metabolites levels in serum samples of diabetic retinopathy patients","volume":"117","author":"Munipally","year":"2011","journal-title":"Arch. Physiol. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/478192a","article-title":"Cancer: Why tumours eat tryptophan","volume":"478","author":"Prendergast","year":"2011","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1111\/cei.12288","article-title":"Interferon (IFN)-gamma-mediated inflammation and the kynurenine pathway in relation to bone mineral density: The Hordaland Health Study","volume":"176","author":"Apalset","year":"2014","journal-title":"Clin. Exp. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.neuropharm.2016.03.013","article-title":"Kynurenine pathway metabolites and enzymes involved in redox reactions","volume":"112","author":"Pineda","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/stem.1836","article-title":"The kynurenine pathway of tryptophan degradation is activated during osteoblastogenesis","volume":"33","author":"Vidal","year":"2015","journal-title":"Stem Cells"},{"key":"ref_26","first-page":"110778","article-title":"The multiple faces of tryptophan in bone biology","volume":"129","author":"Sharma","year":"2019","journal-title":"Exp. Gerontol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"836","DOI":"10.3389\/fphys.2017.00836","article-title":"Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease","volume":"8","author":"Kalaska","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e3199","DOI":"10.7717\/peerj.3199","article-title":"A link between central kynurenine metabolism and bone strength in rats with chronic kidney disease","volume":"5","author":"Kalaska","year":"2017","journal-title":"Peer J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/0006-2952(75)90248-8","article-title":"Effects of hydrocortisone and immobilization on tryptophan metabolism in brain and liver of rats of different ages","volume":"24","author":"Green","year":"1975","journal-title":"Biochem. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.cccn.2005.04.013","article-title":"The effect of age on the enzyme activities of tryptophan metabolism along the kynurenine pathway in rats","volume":"360","author":"Comai","year":"2005","journal-title":"Clin. Chim. Acta"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1080\/14728222.2019.1586883","article-title":"The use of LP533401 as a therapeutic option for renal osteodystrophy affects, renal calcium handling, vitamin D metabolism, and bone health in uremic rats","volume":"23","author":"Pawlak","year":"2019","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"165528","DOI":"10.1016\/j.bbadis.2019.08.004","article-title":"Inhibition of peripheral serotonin synthesis by LP533401 and disturbances in calciotropic hormones attenuated excessive osteoblastogenesis with simultaneous improvement of bone mineral status in 5\/6 nephrectomized rats","volume":"1865","author":"Pawlak","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.mce.2015.01.034","article-title":"Oxidation of the aromatic amino acids tryptophan and tyrosine disrupts their anabolic effects on bone marrow mesenchymal stem cells","volume":"410","author":"Watkins","year":"2015","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s00223-010-9372-1","article-title":"Sclerostin: Current knowledge and future perspectives","volume":"87","author":"Moester","year":"2010","journal-title":"Calcif. Tissue Int."},{"key":"ref_35","first-page":"755","article-title":"Kynurenine and its metabolites in the rat with experimental renal insufficiency","volume":"52","author":"Pawlak","year":"2001","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1159\/000049069","article-title":"Tryptophan metabolism via the kynurenine pathway in experimental chronic renal failure","volume":"90","author":"Pawlak","year":"2002","journal-title":"Nephron"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.atherosclerosis.2008.08.014","article-title":"The kynurenines are associated with oxidative stress, inflammation and the prevalence of cardiovascular disease in patients with end-stage renal disease","volume":"204","author":"Pawlak","year":"2009","journal-title":"Atherosclerosis"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"196","DOI":"10.2478\/v10039-010-0015-6","article-title":"Kynurenine pathway\u2014A new link between endothelial dysfunction and carotid atherosclerosis in chronic kidney disease patients","volume":"55","author":"Pawlak","year":"2010","journal-title":"Adv. Med. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1093\/ndt\/gfn739","article-title":"Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: A possible link between chronic inflammation and uraemic symptoms","volume":"24","author":"Schefold","year":"2009","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1002\/j.1460-2075.1987.tb04800.x","article-title":"Glucocorticoid induction of the rat tryptophan oxygenase gene is mediated by two widely separated glucocorticoid-responsive elements","volume":"6","author":"Danesch","year":"1987","journal-title":"EMBO J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1756-6606-2-8","article-title":"Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice","volume":"2","author":"Kanai","year":"2009","journal-title":"Mol. Brain"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.1002\/jbmr.3224","article-title":"Kynurenine, a Tryptophan Metabolite That Accumulates With Age, Induces Bone Loss","volume":"32","author":"Fulzele","year":"2017","journal-title":"J. Bone Miner. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature10491","article-title":"An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor","volume":"478","author":"Opitz","year":"2011","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3490","DOI":"10.1172\/JCI64906","article-title":"FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin","volume":"122","author":"Kode","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1359\/jbmr.070328","article-title":"Cyclin D1 as a target for the proliferative effects of PTH and PTHrP in early osteoblastic cells","volume":"22","author":"Datta","year":"2007","journal-title":"J. Bone Miner. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/ki.2014.347","article-title":"Primary osteoblast-like cells from patients with end-stage kidney disease reflect gene expression, proliferation, and mineralization characteristics ex vivo","volume":"87","author":"Pereira","year":"2015","journal-title":"Kidney Int."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1002\/jbmr.439","article-title":"Efficacy of serotonin inhibition in mouse models of bone loss","volume":"26","author":"Inose","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1111\/jre.12346","article-title":"The effect of an inhibitor of gut serotonin (LP533401) during the induction of peridontal disease","volume":"51","author":"Lima","year":"2016","journal-title":"J. Periodontal Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/0003-2697(88)90478-2","article-title":"Determination of serum kynurenine and hepatic tryptophan dioxygenase activity by high-performance liquid chromatography","volume":"172","author":"Holmes","year":"1988","journal-title":"Anal. Biochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cyto.2018.03.002","article-title":"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","volume":"106","author":"Znorko","year":"2018","journal-title":"Cytokine"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/17\/5979\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:03:34Z","timestamp":1760177014000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/17\/5979"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,19]]},"references-count":50,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["ijms21175979"],"URL":"https:\/\/doi.org\/10.3390\/ijms21175979","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,19]]}}}