nach oben

Erschienen in:

01.10.2014 | Original Research

Nrf2 Deficiency Impairs Fracture Healing in Mice

verfasst von: Sebastian Lippross, Rainer Beckmann, Nadine Streubesand, Ferda Ayub, Mersedeh Tohidnezhad, Graeme Campbell, Yuet Wai Kan, Fischer Horst, Tolga Taha Sönmez, Deike Varoga, Philipp Lichte, Holger Jahr, Thomas Pufe, Christoph Jan Wruck

Erschienen in: Calcified Tissue International | Ausgabe 4/2014

Einloggen, um Zugang zu erhalten

Abstract

Oxidative stress plays an important role in wound healing but data relating oxidative stress to fracture healing are scarce. Nuclear factor erythroid 2-related factor 2 (Nrf2) is the major transcription factor that controls the cellular defence essential to combat oxidative stress by regulating the expression of antioxidative enzymes. This study examined the impact of Nrf2 on fracture healing using a standard closed femoral shaft fracture model in wild-type (WT) and Nrf2-knockout (Nrf2-KO)-mice. Healing was evaluated by histology, real-time RT-PCR, µCT and biomechanical measurements. We showed that Nrf2 expression is activated during fracture healing. Bone healing and remodelling were retarded in the Nrf2-KO compared to the WT-mice. Nrf2-KO-mice developed significantly less callus tissue compared to WT-mice. In addition, biomechanical testing demonstrated lower strength against shear stress in the Nrf2-KO-group compared to WT. The expression of vascular endothelial growth factor (VEGF) and osteocalcin is reduced during fracture healing in Nrf2-KO-mice. Taken together, our results demonstrate that Nrf2 deficiency in mice results in impaired fracture healing suggesting that Nrf2 plays an essential role in bone regeneration. Pharmacological activation of Nrf2 may have therapeutic potential for the enhancement of fracture healing.

Einhorn TA (1998) The cell and molecular biology of fracture healing. Clin Orthop Relat Res:S7–21

Turgut A, Gokturk E, Kose N, Kacmaz M, Ozturk HS, Seber S, Acar S (1999) Oxidant status increased during fracture healing in rats. Acta Orthop Scand 70:487–490PubMedCrossRef

Yeler H, Tahtabas F, Candan F (2005) Investigation of oxidative stress during fracture healing in the rats. Cell Biochem Funct 23:137–139PubMedCrossRef

Kelpke SS, Reiff D, Prince CW, Thompson JA (2001) Acidic fibroblast growth factor signaling inhibits peroxynitrite-induced death of osteoblasts and osteoblast precursors. J Bone Miner Res 16:1917–1925PubMedCrossRef

Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, Jakel RJ, Johnson JA (2005) Nrf2, a multi-organ protector? Faseb J 19:1061–1066PubMedCrossRef

Wruck CJ, Gotz ME, Herdegen T, Varoga D, Brandenburg LO, Pufe T (2008) Kavalactones protect neural cells against amyloid beta peptide-induced neurotoxicity via extracellular signal-regulated kinase 1/2-dependent nuclear factor erythroid 2-related factor 2 activation. Mol Pharmacol 73:1785–1795PubMedCrossRef

Wruck CJ, Claussen M, Fuhrmann G, Romer L, Schulz A, Pufe T, Waetzig V, Peipp M, Herdegen T, Gotz ME (2007) Luteolin protects rat PC12 and C6 cells against MPP + induced toxicity via an ERK dependent Keap1-Nrf2-ARE pathway. J Neural Transm Suppl: 57–67

Takahata Y, Takarada T, Iemata M, Yamamoto T, Nakamura Y, Kodama A, Yoneda Y (2009) Functional expression of beta2 adrenergic receptors responsible for protection against oxidative stress through promotion of glutathione synthesis after Nrf2 upregulation in undifferentiated mesenchymal C3H10T1/2 stem cells. J Cell Physiol 218:268–275PubMedCrossRef

Park CK, Lee Y, Kim KH, Lee ZH, Joo M, Kim HH (2014) Nrf2 is a novel regulator of bone acquisition. Bone

10.

Chan K, Lu R, Chang JC, Kan YW (1996) NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci USA 93:13943–13948PubMedCrossRefPubMedCentral

11.

Bonnarens F, Einhorn TA (1984) Production of a standard closed fracture in laboratory animal bone. J Orthop Res 2:97–101PubMedCrossRef

12.

Brandenburg LO, Kipp M, Lucius R, Pufe T, Wruck CJ (2010) Sulforaphane suppresses LPS-induced inflammation in primary rat microglia. Inflamm Res 59:443–450PubMedCrossRef

13.

Ben Amor IM, Glorieux FH, Rauch F (2011) Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos 2011:540178PubMedPubMedCentral

14.

Wruck CJ, Fragoulis A, Gurzynski A, Brandenburg LO, Kan YW, Chan K, Hassenpflug J, Freitag-Wolf S, Varoga D, Lippross S, Pufe T (2011) Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice. Ann Rheum Dis 70:844–850PubMedCrossRef

15.

Arai M, Shibata Y, Pugdee K, Abiko Y, Ogata Y (2007) Effects of reactive oxygen species (ROS) on antioxidant system and osteoblastic differentiation in MC3T3-E1 cells. IUBMB Life 59:27–33PubMedCrossRef

16.

Kim KS, Choi HW, Yoon HE, Kim IY (2010) Reactive oxygen species generated by NADPH Oxidase 2 and 4 are required for chondrogenic differentiation. J Biol Chem 285:40294–40302PubMedCrossRefPubMedCentral

17.

Morita K, Miyamoto T, Fujita N, Kubota Y, Ito K, Takubo K, Miyamoto K, Ninomiya K, Suzuki T, Iwasaki R, Yagi M, Takaishi H, Toyama Y, Suda T (2007) Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification. J Exp Med 204:1613–1623PubMedPubMedCentral

18.

Hinoi E, Fujimori S, Wang L, Hojo H, Uno K, Yoneda Y (2006) Nrf2 negatively regulates osteoblast differentiation via interfering with Runx2-dependent transcriptional activation. J Biol Chem 281:18015–18024PubMedCrossRef

19.

Hinoi E, Takarada T, Fujimori S, Wang L, Iemata M, Uno K, Yoneda Y (2007) Nuclear factor E2 p45-related factor 2 negatively regulates chondrogenesis. Bone 40:337–344PubMedCrossRef

20.

Maicas N, Ferrandiz ML, Brines R, Ibanez L, Cuadrado A, Koenders MI, Van den Berg WB, Alcaraz MJ (2011) Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease. Antioxid Redox Signal 15:889–901PubMedCrossRef

21.

Boskey AL, Gadaleta S, Gundberg C, Doty SB, Ducy P, Karsenty G (1998) Fourier transform infrared microspectroscopic analysis of bones of osteocalcin-deficient mice provides insight into the function of osteocalcin. Bone 23:187–196PubMedCrossRef

22.

Beck GR, Moran E, Knecht N (2003) Inorganic phosphate regulates multiple genes during osteoblast differentiation, including Nrf2. Exp Cell Res 288:288–300PubMedCrossRef

23.

Kweider N, Fragoulis A, Rosen C, Pecks U, Rath W, Pufe T, Wruck CJ (2011) Interplay between vascular endothelial growth factor (VEGF) and nuclear factor erythroid 2-related factor-2 (Nrf2): implications for preeclampsia. J Biol Chem 286:42863–42872PubMedCrossRefPubMedCentral

24.

Mayr-Wohlfart U, Waltenberger J, Hausser H, Kessler S, Gunther KP, Dehio C, Puhl W, Brenner RE (2002) Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts. Bone 30:472–477PubMedCrossRef

25.

Street J, Bao M, deGuzman L, Bunting S, Peale FV, Ferrara N, Steinmetz H, Hoeffel J, Cleland JL, Daugherty A, van Bruggen N, Redmond HP, Carano RAD, Filvaroff EH (2002) Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. P Natl Acad Sci USA 99:9656–9661CrossRef

26.

Keramaris NC, Calori GM, Nikolaou VS, Schemitsch EH, Giannoudis PV (2008) Fracture vascularity and bone healing: a systematic review of the role of VEGF. Injury 39(Suppl 2):S45–S57PubMedCrossRef

27.

Pufe T, Wildemann B, Petersen W, Mentlein R, Raschke M, Schmidmaier G (2002) Quantitative measurement of the splice variants 120 and 164 of the angiogenic peptide vascular endothelial growth factor in the time flow of fracture healing: a study in the rat. Cell Tissue Res 309:387–392PubMedCrossRef

28.

Weiss S, Zimmermann G, Pufe T, Varoga D, Henle P (2009) The systemic angiogenic response during bone healing. Arch Orthop Trauma Surg 129:989–997PubMedCrossRef

29.

Nazarian A, Entezari V, Vartanians V, Muller R, Snyder BD (2009) An improved method to assess torsional properties of rodent long bones. J Biomech 42:1720–1725PubMedCrossRef

Titel: Nrf2 Deficiency Impairs Fracture Healing in Mice
verfasst von: Sebastian Lippross
Rainer Beckmann
Nadine Streubesand
Ferda Ayub
Mersedeh Tohidnezhad
Graeme Campbell
Yuet Wai Kan
Fischer Horst
Tolga Taha Sönmez
Deike Varoga
Philipp Lichte
Holger Jahr
Thomas Pufe
Christoph Jan Wruck
Publikationsdatum: 01.10.2014
Verlag: Springer US
Erschienen in: Calcified Tissue International / Ausgabe 4/2014
Print ISSN: 0171-967X
Elektronische ISSN: 1432-0827
DOI: https://doi.org/10.1007/s00223-014-9900-5

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Mehr Lebenszeit mit Abemaciclib bei fortgeschrittenem Brustkrebs?

24.05.2024 Mammakarzinom Nachrichten

In der MONARCHE-3-Studie lebten Frauen mit fortgeschrittenem Hormonrezeptor-positivem, HER2-negativem Brustkrebs länger, wenn sie zusätzlich zu einem nicht steroidalen Aromatasehemmer mit Abemaciclib behandelt wurden; allerdings verfehlte der numerische Zugewinn die statistische Signifikanz.

ADT zur Radiatio nach Prostatektomie: Wenn, dann wohl länger

24.05.2024 Prostatakarzinom Nachrichten

Welchen Nutzen es trägt, wenn die Strahlentherapie nach radikaler Prostatektomie um eine Androgendeprivation ergänzt wird, hat die RADICALS-HD-Studie untersucht. Nun liegen die Ergebnisse vor. Sie sprechen für länger dauernden Hormonentzug.

„Überwältigende“ Evidenz für Tripeltherapie beim metastasierten Prostata-Ca.

22.05.2024 Prostatakarzinom Nachrichten

Patienten mit metastasiertem hormonsensitivem Prostatakarzinom sollten nicht mehr mit einer alleinigen Androgendeprivationstherapie (ADT) behandelt werden, mahnt ein US-Team nach Sichtung der aktuellen Datenlage. Mit einer Tripeltherapie haben die Betroffenen offenbar die besten Überlebenschancen.

So sicher sind Tattoos: Neue Daten zur Risikobewertung

22.05.2024 Melanom Nachrichten

Das größte medizinische Problem bei Tattoos bleiben allergische Reaktionen. Melanome werden dadurch offensichtlich nicht gefördert, die Farbpigmente könnten aber andere Tumoren begünstigen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2014

Osteoporosis and the Risk of Symptomatic Nephrolithiasis: A Population-Based 5-Year Follow-Up Study in Taiwan

Relationship of Bone Mineralization Density Distribution (BMDD) in Cortical and Cancellous Bone Within the Iliac Crest of Healthy Premenopausal Women

Gender-Specific Associations of Appendicular Muscle Mass with BMD in Elderly Italian Subjects

Targeted Sequencing of a Pediatric Metabolic Bone Gene Panel Using a Desktop Semiconductor Next-Generation Sequencer

Effects on Calcium Homeostasis of Changing PTH Replacement Therapy of Postoperative Hypoparathyroidism from Intact PTH to Teriparatide: A Case Series