Local Wnt3a treatment restores bone regeneration in large osseous defects after surgical debridement of osteomyelitis.
Animals
Bone Regeneration
/ drug effects
Debridement
Disease Management
Disease Models, Animal
Disease Susceptibility
Female
Fluorescent Antibody Technique
Glycogen Synthase Kinase 3 beta
/ metabolism
Image Processing, Computer-Assisted
Male
Mice
Osteoclasts
/ metabolism
Osteogenesis
/ genetics
Osteomyelitis
/ diagnosis
Recombinant Proteins
/ administration & dosage
Wnt Signaling Pathway
/ drug effects
Wnt3A Protein
/ administration & dosage
X-Ray Microtomography
beta Catenin
/ metabolism
Bone
Bone regeneration
Canonical Wnt-pathway
Osteomyelitis
Wnt3a
Journal
Journal of molecular medicine (Berlin, Germany)
ISSN: 1432-1440
Titre abrégé: J Mol Med (Berl)
Pays: Germany
ID NLM: 9504370
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
22
12
2019
accepted:
11
05
2020
revised:
13
04
2020
pubmed:
20
5
2020
medline:
8
6
2021
entrez:
20
5
2020
Statut:
ppublish
Résumé
Impaired bone homeostasis caused by osteomyelitis provokes serious variations in the bone remodeling process, thereby involving multiple inflammatory cytokines to activate bone healing. We have previously established a mouse model for post-traumatic osteomyelitis and studied bone regeneration after sufficient debridement. Moreover, we could further characterize the postinfectious inflammatory state of bony defects after debridement with elevated osteoclasts and decreased bone formation despite the absence of bacteria. In this study, we investigated the positive effects of Wnt-pathway modulation on bone regeneration in our previous established mouse model. This was achieved by local application of Wnt3a, a recombinant activator of the canonical Wnt-pathway. Application of Wnt3a could enhance new bone formation, which was verified by histological and μ-CT analysis. Moreover, histology and western blots revealed enhanced osteoblastogenesis and downregulated osteoclasts in a RANKL-dependent manner. Further analysis of Wnt-pathway showed downregulation after bone infections were reconstituted by application of Wnt3a. Interestingly, Wnt-inhibitory proteins Dickkopf 1 (DKK1), sclerostin, and secreted frizzled protein 1 (sFRP1) were upregulated simultaneously to Wnt-pathway activation, indicating a negative feedback for active form of Beta-catenin. In this study, we could demonstrate enhanced bone formation in defects caused by post-traumatic osteomyelitis after Wnt3a application. KEY MESSAGES: Osteomyelitis decreases bone regeneration Wnt3a restores bone healing after infection Canonical Wnt-pathway activation with negative feedback.
Identifiants
pubmed: 32424558
doi: 10.1007/s00109-020-01924-9
pii: 10.1007/s00109-020-01924-9
pmc: PMC8526481
doi:
Substances chimiques
Recombinant Proteins
0
Wnt3A Protein
0
Wnt3a protein, mouse
0
beta Catenin
0
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
897-906Commentaires et corrections
Type : ErratumIn
Références
Lew DP, Waldvogel FA (2004) Osteomyelitis. Lancet 364:369–379
pubmed: 15276398
doi: 10.1016/S0140-6736(04)16727-5
Costerton JW (2006) Biofilm theory can guide the treatment of device-related orthopaedic infections. Clin Orthop Relat Res 437:7–11
Wagner JM, Zollner H, Wallner C, Ismer B, Schira J, Abraham S, Harati K, Lehnhardt M, Behr B (2016) Surgical debridement is superior to sole antibiotic therapy in a novel murine posttraumatic osteomyelitis model. PLoS One 11:e0149389
pubmed: 26872128
pmcid: 4752466
doi: 10.1371/journal.pone.0149389
Wagner JM, Jaurich H, Wallner C, Abraham S, Becerikli M, Dadras M, Harati K, Duhan V, Khairnar V, Lehnhardt M, Behr B (2017) Diminished bone regeneration after debridement of posttraumatic osteomyelitis is accompanied by altered cytokine levels, elevated B cell activity and increased osteoclast activity. J Orthop Res 35:2425–2434
pubmed: 28263017
doi: 10.1002/jor.23555
Pinzur MS, Gold J, Schwartz D, Gross N (1992) Energy demands for walking in dysvascular amputees as related to the level of amputation. Orthopedics 15:1033–1037
pubmed: 1437862
doi: 10.3928/0147-7447-19920901-07
Jones D, Glimcher LH, Aliprantis AO (2011) Osteoimmunology at the nexus of arthritis, osteoporosis, cancer, and infection. J Clin Invest 121:2534–2542
pubmed: 21737885
pmcid: 3223839
doi: 10.1172/JCI46262
Takayanagi H (2012) New developments in osteoimmunology. Nat Rev Rheumatol 8:684–689
pubmed: 23070645
doi: 10.1038/nrrheum.2012.167
Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL (2005) IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest 115:282–290
pubmed: 15668736
pmcid: 544608
doi: 10.1172/JCI200523394
Samee N, Geoffroy V, Marty C, Schiltz C, Vieux-Rochas M, Levi G, de Vernejoul M-C (2008) Dlx5, a positive regulator of osteoblastogenesis, is essential for osteoblast-osteoclast coupling. Am J Pathol 173:773–780
pubmed: 18669617
pmcid: 2527089
doi: 10.2353/ajpath.2008.080243
Xue B, Dunker AK, Uversky VN (2012) The roles of intrinsic disorder in orchestrating the Wnt-pathway. J Biomol Struct Dyn 29:843–861
doi: 10.1080/073911012010525024
pubmed: 22292947
Seo E, E-h J (2007) Axin-independent phosphorylation of APC controls beta-catenin signaling via cytoplasmic retention of beta-catenin. Biochem Biophys Res Commun 357:81–86
doi: 10.1016/j.bbrc.2007.03.117
pubmed: 17418091
Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127:469–480
pubmed: 17081971
doi: 10.1016/j.cell.2006.10.018
Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W (1996) Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382:638–642
doi: 10.1038/382638a0
pubmed: 8757136
Quarto N, Behr B, Longaker MT (2010) Opposite spectrum of activity of canonical Wnt signaling in the osteogenic context of undifferentiated and differentiated mesenchymal cells: implications for tissue engineering. Tissue Eng Part A 16:3185–3197
pubmed: 20590472
pmcid: 2947420
doi: 10.1089/ten.tea.2010.0133
Minear S, Leucht P, Jiang J, Liu B, Zeng A, Fuerer C, Nusse R, Helms JA (2010) Wnt proteins promote bone regeneration. Sci Transl Med 2:29ra30
doi: 10.1126/scitranslmed.3000231
pubmed: 20427820
Arioka M, Takahashi-Yanaga F, Sasaki M, Yoshihara T, Morimoto S, Takashima A, Mori Y, Sasaguri T (2013) Acceleration of bone development and regeneration through the Wnt/beta-catenin signaling pathway in mice heterozygously deficient for GSK-3beta. Biochem Biophys Res Commun 440:677–682
doi: 10.1016/j.bbrc.2013.09.126
pubmed: 24099767
Dixit M, Raghuvanshi A, Gupta CP, Kureel J, Mansoori MN, Shukla P, John AA, Singh K, Purohit D, Awasthi P, Singh D, Goel A (2015) Medicarpin, a natural pterocarpan, heals cortical bone defect by activation of notch and Wnt canonical signaling pathways. PLoS One 10:e0144541
pubmed: 26657206
pmcid: 4676632
doi: 10.1371/journal.pone.0144541
Wei Q, Zhang J, Hong G, Chen Z, Deng W, He W, Chen MH (2016) Icariin promotes osteogenic differentiation of rat bone marrow stromal cells by activating the ERalpha-Wnt/beta-catenin signaling pathway. Biomed Pharmacother 84:931–939
doi: 10.1016/j.biopha.2016.09.107
pubmed: 27764755
Zhang X, Chen Q, Liu J, Fan C, Wei Q, Chen Z, Mao X (2017) Parthenolide promotes differentiation of osteoblasts through the Wnt/beta-catenin signaling pathway in inflammatory environments. J Interferon Cytokine Res 37:406–414
doi: 10.1089/jir.2017.0023
pubmed: 28829282
Leucht P, Lee S, Yim N (2018) Wnt signaling and bone regeneration: Can't have one without the other. Biomaterials. 196:46–50
doi: 10.1016/j.biomaterials.2018.03.029
pubmed: 29573821
Olsen JJ, Pohl SÖ-G, Deshmukh A, Visweswaran M, Ward NC, Arfuso F, Agostino M, Dharmarajan A (2017) The role of Wnt signalling in angiogenesis. Clin Biochem Rev 38:131–142
pubmed: 29332977
pmcid: 5759160
Colnot C, Romero DM, Huang S, Helms JA (2005) Mechanisms of action of demineralized bone matrix in the repair of cortical bone defects. Clin Orthop Relat Res:69–78
Taylor SC, Berkelman T, Yadav G, Hammond M (2013) A defined methodology for reliable quantification of Western blot data. Mol Biotechnol 55:217–226
pubmed: 23709336
pmcid: 3840294
doi: 10.1007/s12033-013-9672-6
Behr B, Leucht P, Longaker MT, Quarto N (2010) Fgf-9 is required for angiogenesis and osteogenesis in long bone repair. PNAS 107:11853–11858
pubmed: 20547837
pmcid: 2900703
doi: 10.1073/pnas.1003317107
Sawyer A, Lott P, Titrud J, McDonald J (2003) Quantification of tartrate resistant acid phosphatase distribution in mouse tibiae using image analysis. Biotechnic Histochem 78:271–278
doi: 10.1080/10520290310001646668
Schmidt-Rohlfing B, Lemmen SW, Pfeifer R, Pape HC (2012) Osteomyelitis in adults. Diagnostic principles and therapeutic strategies. Unfallchirurg 115:55–66
doi: 10.1007/s00113-011-2081-z
pubmed: 22274604
Ling Z, Wu L, Shi G, Chen L, Dong Q (2017) Increased Runx2 expression associated with enhanced Wnt signaling in PDLLA internal fixation for fracture treatment. Exp Ther Med 13:2085–2093
pubmed: 28565812
pmcid: 5443172
doi: 10.3892/etm.2017.4216
Chen Y, Whetstone HC, Lin AC, Nadesan P, Wei Q, Poon R, Alman BA (2007) Beta-catenin signaling plays a disparate role in different phases of fracture repair: implications for therapy to improve bone healing. PLoS Med 4:e249
pubmed: 17676991
pmcid: 1950214
doi: 10.1371/journal.pmed.0040249
Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PVN, Komm BS, Javed A, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2005) Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem 280:33132–33140
doi: 10.1074/jbc.M500608200
pubmed: 16043491
Komori T (2006) Regulation of osteoblast differentiation by transcription factors. J Cell Biochem 99:1233–1239
pubmed: 16795049
doi: 10.1002/jcb.20958
Lee M-H, Kwon T-G, Park H-S, Wozney JM, Ryoo H-M (2003) BMP-2-induced Osterix expression is mediated by Dlx5 but is independent of Runx2. Biochem Biophys Res Commun 309:689–694
pubmed: 12963046
doi: 10.1016/j.bbrc.2003.08.058
Lee M-H, Kim Y-J, Yoon W-J, Kim J-I, Kim B-G, Hwang Y-S, Wozney JM, Chi X-Z, Bae S-C, Choi K-Y, Cho JY, Choi JY, Ryoo HM (2005) Dlx5 specifically regulates Runx2 type II expression by binding to homeodomain-response elements in the Runx2 distal promoter. J Biol Chem 280:35579–35587
pubmed: 16115867
doi: 10.1074/jbc.M502267200
Ryoo H-M, Lee M-H, Kim Y-J (2006) Critical molecular switches involved in BMP-2-induced osteogenic differentiation of mesenchymal cells. Gene 366:51–57
pubmed: 16314053
doi: 10.1016/j.gene.2005.10.011
Cho Y-D, Kim W-J, Yoon W-J, Woo K-M, Baek J-H, Lee G, Kim G-S, Ryoo H-M (2012) Wnt3a stimulates Mepe, matrix extracellular phosphoglycoprotein, expression directly by the activation of the canonical Wnt signaling pathway and indirectly through the stimulation of autocrine bmp-2 expression. J Cell Physiol 227:2287–2296
pubmed: 22213482
doi: 10.1002/jcp.24038
Tanaka S, Tanaka Y, Ishiguro N, Yamanaka H, Takeuchi T (2018) RANKL: a therapeutic target for bone destruction in rheumatoid arthritis. Mod Rheumatol 28:9–16
pubmed: 28880683
doi: 10.1080/14397595.2017.1369491
Chiu YG, Ritchlin CT (2017) Denosumab: targeting the RANKL pathway to treat rheumatoid arthritis. Expert Opin Biol Ther 17:119–128
pubmed: 27871200
doi: 10.1080/14712598.2017.1263614
Wang D, Weng Y, Guo S, Zhang Y, Zhou T, Zhang M, Wang L, Ma J (2018) Platelet-rich plasma inhibits RANKL-induced osteoclast differentiation through activation of Wnt pathway during bone remodeling. Int J Mol Med 41:729–738
pubmed: 29207140
Amirhosseini M, Madsen RV, Escott KJ, Bostrom MP, Ross FP, Fahlgren A (2018) GSK-3beta inhibition suppresses instability-induced osteolysis by a dual action on osteoblast and osteoclast differentiation. J Cell Physiol 233:2398–2408
doi: 10.1002/jcp.26111
pubmed: 28731198
Weivoda MM, Ruan M, Hachfeld CM, Pederson L, Howe A, Davey RA, Zajac JD, Kobayashi Y, Williams BO, Westendorf JJ, Khosla S, Oursler MJ (2016) Wnt signaling inhibits osteoclast differentiation by activating canonical and noncanonical cAMP/PKA pathways. J Bone Mineral Res 31:65–75
doi: 10.1002/jbmr.2599
Walsh NC, Reinwald S, Manning CA, Condon KW, Iwata K, Burr DB, Gravallese EM (2009) Osteoblast function is compromised at sites of focal bone erosion in inflammatory arthritis. J Bone Miner Res 24:1572–1585
doi: 10.1359/jbmr.090320
pubmed: 19338457
Jin H, Wang B, Li J, Xie W, Mao Q, Li S, Dong F, Sun Y, Ke H-Z, Babij P, Tong P, Chen D (2015) Anti-DKK1 antibody promotes bone fracture healing through activation of beta-catenin signaling. Bone 71:63–75
pubmed: 25263522
doi: 10.1016/j.bone.2014.07.039
Duan Y, Liao AP, Kuppireddi S, Ye Z, Ciancio MJ, Sun J (2007) Beta-catenin activity negatively regulates bacteria-induced inflammation. Lab Investigation 87:613–624
doi: 10.1038/labinvest.3700545
Sun J, Hobert ME, Duan Y, Rao AS, He T-C, Chang EB, Madara JL (2005) Crosstalk between NF-kappaB and beta-catenin pathways in bacterial-colonized intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 289:G129–G137
pubmed: 15790758
doi: 10.1152/ajpgi.00515.2004
Niida A, Hiroko T, Kasai M, Furukawa Y, Nakamura Y, Suzuki Y, Sugano S, Akiyama T (2004) DKK1, a negative regulator of Wnt signaling, is a target of the beta-catenin/TCF pathway. Oncogene 23:8520–8526
pubmed: 15378020
doi: 10.1038/sj.onc.1207892
Ahn Y, Sanderson BW, Klein OD, Krumlauf R (2010) Inhibition of Wnt signaling by wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning. Development (Cambridge, England) 137:3221–3231
doi: 10.1242/dev.054668
Aurrekoetxea M, Irastorza I, Garcia-Gallastegui P, Jimenez-Rojo L, Nakamura T, Yamada Y, Ibarretxe G, Unda FJ (2016) Wnt/beta-catenin regulates the activity of epiprofin/Sp6, SHH, FGF, and BMP to coordinate the stages of odontogenesis. Front Cell Development Biol 4:25
doi: 10.3389/fcell.2016.00025
Stolina M, Dwyer D, Niu Q-T, Villasenor KS, Kurimoto P, Grisanti M, Han C-Y, Liu M, Li X, Ominsky MS, Ke HZ, Kostenuik PJ (2014) Temporal changes in systemic and local expression of bone turnover markers during six months of sclerostin antibody administration to ovariectomized rats. Bone 67:305–313
pubmed: 25093263
doi: 10.1016/j.bone.2014.07.031
Florio M, Gunasekaran K, Stolina M, Li X, Liu L, Tipton B, Salimi-Moosavi H, Asuncion FJ, Li C, Sun B, Tan HL, Zhang L, Han CY, Case R, Duguay AN, Grisanti M, Stevens J, Pretorius JK, Pacheco E, Jones H, Chen Q, Soriano BD, Wen J, Heron B, Jacobsen FW, Brisan E, Richards WG, Ke HZ, Ominsky MS (2016) A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. Nat Commun 7:11505
pubmed: 27230681
pmcid: 4894982
doi: 10.1038/ncomms11505
Wang N, Xue P, Wu X, Ma J, Wang Y, Li Y (2018) Role of sclerostin and dkk1 in bone remodeling in type 2 diabetic patients. Endocr Res 43:29–38
pubmed: 28972408
doi: 10.1080/07435800.2017.1373662
Esteve P, Bovolenta P (2010) The advantages and disadvantages of Sfrp1 and Sfrp2 expression in pathological events. Tohoku J Exp Med 221:11–17
doi: 10.1620/tjem.221.11
pubmed: 20448436
Ding M, Wang X (2017) Antagonism between hedgehog and Wnt signaling pathways regulates tumorigenicity. Oncol Lett 14:6327–6333
pubmed: 29391876
pmcid: 5770609
McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP, Diez-Perez A, Langdahl BL, Reginster J-Y, Zanchetta JR, Wasserman SM et al (2014) Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 370:412–420
doi: 10.1056/NEJMoa1305224
pubmed: 24382002