Skip to main content

Advertisement

SpringerLink
Log in

Kynurenic acid promotes osteogenesis via the Wnt/β-catenin signaling

  • Published:
In Vitro Cellular & Developmental Biology - Animal Aims and scope Submit manuscript

Abstract

The role of kynurenic acid (KynA) in neurological and mental diseases has been widely studied. Emerging studies disclosed that KynA has a protective effect on tissues including heart, kidney, and retina. However, the role of KynA in osteoporosis has not been reported so far. To elucidate the role of KynA in age-related osteoporosis, both control and osteoporosis mice were administrated KynA for three consecutive months, and micro-computed tomography (μCT) analysis was then performed. In addition, primary bone marrow mesenchymal stem cells (BMSCs) were isolated for osteogenic differentiation induction and treated with KynA in vitro. Our data suggested that KynA administration rescued age-related bone loss in vivo, and KynA treatment promotes BMSC osteogenic differentiation in vitro. Moreover, KynA activated the Wnt/β-catenin signaling during BMSC osteogenic differentiation. Wnt inhibitor MSAB inhibited KynA-induced osteogenic differentiation. Further data demonstrated that KynA exerted its effect on BMSC osteogenic differentiation and Wnt/β-catenin signaling activation via G protein-coupled receptor 35 (GPR35). In conclusion, the protective effect of KynA on age-related osteoporosis was disclosed. Additionally, the promoting effect of KynA on osteoblastic differentiation via Wnt/β-catenin signaling was verified and the effect dependent on GPR35. These data suggest that KynA administration potentially contributes to the treatment of age-related osteoporosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.

Similar content being viewed by others

Data availability

Data will be made available upon reasonable request.

References

  • Almeida M, Ambrogini E, Han L, Manolagas SC, Jilka RL (2009) Increased lipid oxidation causes oxidative stress, increased peroxisome proliferator-activated receptor-gamma expression, and diminished pro-osteogenic Wnt signaling in the skeleton. J Biol Chem 284:27438–27448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anaya JM, Bollag WB, Hamrick MW, Isales CM (2020) The role of tryptophan metabolites in musculoskeletal stem cell aging. Int J Mol Sci 21:6670

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen Q, Shou P, Zheng C, Jiang M, Cao G, Yang Q, Cao J, Xie N, Velletri T, Zhang X, Xu C, Zhang L, Yang H, Hou J, Wang Y, Shi Y (2016) Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? Cell Death Differ 23:1128–1139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim WJ, Shin HL, Kim BS, Kim HJ, Ryoo HM (2020) RUNX2-modifying enzymes: therapeutic targets for bone diseases. Exp Mol Med 52:1178–1184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leklem JE (1971) Quantitative aspects of tryptophan metabolism in humans and other species: a review. Am J Clin Nutr 24:659–672

    Article  CAS  PubMed  Google Scholar 

  • Ma J, Chen P, Wang R (2022) G-protein-coupled receptor 124 promotes osteogenic differentiation of BMSCs through the Wnt/β-catenin pathway. In Vitro Cell Dev Biol Anim 58:529–538

    Article  CAS  PubMed  Google Scholar 

  • Majláth Z, Török N, Toldi J, Vécsei L (2016) Memantine and kynurenic acid: current neuropharmacological aspects. Curr Neuropharmacol 14:200–209

    Article  PubMed  PubMed Central  Google Scholar 

  • Michalowska M, Znorko B, Kaminski T, Oksztulska-Kolanek E, Pawlak D (2015) New insights into tryptophan and its metabolites in the regulation of bone metabolism. J Physiol Pharmacol 66:779–791

    CAS  PubMed  Google Scholar 

  • Nahomi RB, Nam MH, Rankenberg J, Rakete S, Houck JA, Johnson GC, Stankowska DL, Pantcheva MB, MacLean PS, Nagaraj RH (2020) Kynurenic acid protects against ischemia/reperfusion-induced retinal ganglion cell death in mice. Int J Mol Sci 21:1795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ostapiuk A, Urbanska EM (2022) Kynurenic acid in neurodegenerative disorders-unique neuroprotection or double-edged sword? CNS Neurosci Ther 28:19–35

  • Parada-Turska J, Zgrajka W, Majdan M (2013) Kynurenic acid in synovial fluid and serum of patients with rheumatoid arthritis, spondyloarthropathy, and osteoarthritis. J Rheumatol 40:903–909

    Article  CAS  PubMed  Google Scholar 

  • Perkins MN, Stone TW (1982) An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res 247:184–187

    Article  CAS  PubMed  Google Scholar 

  • Pierce JL, Begun DL, Westendorf JJ, McGee-Lawrence ME (2019) Defining osteoblast and adipocyte lineages in the bone marrow. Bone 118:2–7

    Article  CAS  PubMed  Google Scholar 

  • Ramos-Chávez LA, Lugo Huitrón R, González Esquivel D, Pineda B, Ríos C, Silva-Adaya D, Sánchez-Chapul L, Roldán-Roldán G, Pérez de la Cruz V (2018) Relevance of alternative routes of kynurenic acid production in the brain. Oxid Med Cell Longev 2018:5272741

    Article  PubMed  PubMed Central  Google Scholar 

  • Rejdak R, Junemann A, Grieb P, Thaler S, Schuettauf F, Chorągiewicz T, Zarnowski T, Turski WA, Zrenner E (2011) Kynurenic acid and kynurenine aminotransferases in retinal aging and neurodegeneration. Pharmacol Rep 63:1324–1334

    Article  CAS  PubMed  Google Scholar 

  • Roth W, Zadeh K, Vekariya R, Ge Y, Mohamadzadeh M (2021) Tryptophan metabolism and gut-brain homeostasis. Int J Mol Sci 22:2973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwarcz R, Du F, Schmidt W, Turski WA, Gramsbergen JB, Okuno E, Roberts RC (1992) Kynurenic acid: a potential pathogen in brain disorders. Ann N Y Acad Sci 648:140–153

    Article  CAS  PubMed  Google Scholar 

  • Solvang SH, Nordrehaug JE, Aarsland D, Lange J, Ueland PM, McCann A, Midttun Ø, Tell GS, Giil LM (2019) Kynurenines, neuropsychiatric symptoms, and cognitive prognosis in patients with mild dementia. Int J Trp Res 12:1178646919877883

  • Stone TW, Stoy N, Darlington LG (2013) An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci 34:136–143

    Article  CAS  PubMed  Google Scholar 

  • Tomaszewska E, Muszyński S (2019) Chronic dietary supplementation with kynurenic acid, a neuroactive metabolite of tryptophan, decreased body weight without negative influence on densitometry and mandibular bone biomechanical endurance in young rats. PLoS One 14:e0226205

  • Tu KN, Lie JD, Wan CKV, Cameron M, Austel AG, Nguyen JK, Van K, Hyun D (2018) Osteoporosis: a review of treatment options. Phar Ther Peer Rev J F Mgt 43:92–104

  • Tuboly G, Tar L, Bohar Z, Safrany-Fark A, Petrovszki Z, Kekesi G, Vecsei L, Pardutz A, Horvath G (2015) The inimitable kynurenic acid: the roles of different ionotropic receptors in the action of kynurenic acid at a spinal level. Brain Res Bull 112:52–60

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Simonavicius N, Wu X, Swaminath G, Reagan J, Tian H, Ling L (2006) Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J Biol Chem 281:22021–22028

    Article  CAS  PubMed  Google Scholar 

  • Wei W, Wan Y (2011) Thiazolidinediones on PPARγ: the roles in bone remodeling. PPAR Res 2011:867180

    Article  PubMed  PubMed Central  Google Scholar 

  • Wirthgen E, Hoeflich A, Rebl A, Günther J (2017) Kynurenic acid: the Janus-faced role of an immunomodulatory tryptophan metabolite and its link to pathological conditions. Front Immunol 8:1957

    Article  PubMed  Google Scholar 

  • Wyant GA, Yu W, Doulamis IP, Nomoto RS, Saeed MY, Duignan T, McCully JD, Kaelin WG Jr (2022) Mitochondrial remodeling and ischemic protection by G protein-coupled receptor 35 agonists. Science (New York, NY) 377:621–629

    Article  CAS  Google Scholar 

  • Yuan Z, Li Q, Luo S, Liu Z, Luo D, Zhang B, Zhang D, Rao P, Xiao J (2016) PPARγ and Wnt signaling in adipogenic and osteogenic differentiation of mesenchymal stem cells. Curr Stem Cell Res Ther 11:216–225

    Article  CAS  PubMed  Google Scholar 

  • Zakrocka I, Załuska W (2022) Kynurenine pathway in kidney diseases. Pharmacol Rep 74:27–39

    Article  PubMed  Google Scholar 

  • Zarnowski T, Tulidowicz-Bielak M, Zarnowska I, Mitosek-Szewczyk K, Wnorowski A, Jozwiak K, Gasior M, Turski WA (2017) Kynurenic acid and neuroprotective activity of the ketogenic diet in the eye. Curr Med Chem 24:3547–3558

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Shi T, He Y (2021) GPR35 regulates osteogenesis via the Wnt/GSK3β/β-catenin signaling pathway. Biochem Biophys Res Commun 556:171–178

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Jiangwei Ma and Pu Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopedics, The First Hospital of Yulin, No. 93, Yu Xi Street, Yulin, 719000, Shaanxi, People’s Republic of China

    Jiangwei Ma

  2. Department of General Practice, The First Hospital of Yulin, No. 93, Yu Xi Street, Yulin, 719000, Shaanxi, People’s Republic of China

    Baojuan Deng & Rong Wang

  3. Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China

    Pu Chen

Authors
  1. Jiangwei Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Baojuan Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WR designed the study and supervised the data collection. MJW and CP performed the experiments and DBJ prepared the manuscript. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Rong Wang.

Ethics declarations

Ethics approval

All the experimental procedures were approved by the Ethics Committee of The First Hospital of Yulin.

Conflict of interest

The authors declare no competing interests.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 107 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, J., Chen, P., Deng, B. et al. Kynurenic acid promotes osteogenesis via the Wnt/β-catenin signaling. In Vitro Cell.Dev.Biol.-Animal 59, 356–365 (2023). https://doi.org/10.1007/s11626-023-00774-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11626-023-00774-2

Keywords

Search

Navigation