Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende
Erweiterte Suche
Anmelden
nach oben
Calcified Tissue International
Erschienen in: Calcified Tissue International 5/2015

01.05.2015 | Original Research

Ubiquitin E3 Ligase LNX2 is Critical for Osteoclastogenesis In Vitro by Regulating M-CSF/RANKL Signaling and Notch2

verfasst von: Jian Zhou, Toshifumi Fujiwara, Shiqiao Ye, Xiaolin Li, Haibo Zhao

Erschienen in: Calcified Tissue International | Ausgabe 5/2015

Einloggen, um Zugang zu erhalten

Abstract

The Notch signaling pathway plays a crucial role in skeletal development and homeostasis by regulating the proliferation and differentiation of osteoblasts and osteoclasts. However, the molecular mechanisms modulating the level and activity of Notch receptors in bone cells remain unknown. In this study, we uncovered that LNX2, an E3 ubiquitin ligase and Notch inhibitor Numb binding protein, was up-regulated during osteoclast differentiation. Knocking-down LNX2 expression in bone marrow macrophages by lentivirus-mediated short hairpin RNAs markedly inhibited osteoclast formation. Decreased LNX2 expression attenuated macrophage colony-stimulating factor (M-CSF)-induced ERK and AKT activation and RANKL-stimulated activation of NF-κB and JNK pathways; therefore, accelerated osteoclast apoptosis. Additionally, loss of LNX2 led to an increased accumulation of Numb, which promoted the degradation of Notch and caused a reduction of the expression of the Notch downstream target gene, Hes1. We conclude that LNX2 regulates M-CSF/RANKL and the Notch signaling pathways during osteoclastogenesis.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
2.
Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH (2013) Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol 9:522–536CrossRefPubMed
3.
Henriksen K, Karsdal MA, John Martin T (2013) Osteoclast-derived coupling factors in bone remodeling. Calcif Tissue Int 94:88–97CrossRefPubMed
4.
Henriksen K, Neutzsky-Wulff AV, Bonewald LF, Karsdal MA (2009) Local communication on and within bone controls bone remodeling. Bone 44:1026–1033CrossRefPubMed
5.
Sims NA, Gooi JH (2008) Bone remodeling: multiple cellular interactions required for coupling of bone formation and resorption. Semin Cell Dev Biol 19:444–451CrossRefPubMed
6.
Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342CrossRefPubMed
7.
Nakashima T, Hayashi M, Takayanagi H (2012) New insights into osteoclastogenic signaling mechanisms. Trends Endocrinol Metab 23:582–590CrossRefPubMed
8.
Teitelbaum SL, Ross FP (2003) Genetic regulation of osteoclast development and function. Nat Rev Genet 4:638–649CrossRefPubMed
9.
10.
11.
12.
13.
14.
Canalis E, Parker K, Feng JQ, Zanotti S (2013) Osteoblast lineage-specific effects of notch activation in the skeleton. Endocrinology 154:623–634CrossRefPubMedCentralPubMed
15.
Engin F, Yao Z, Yang T, Zhou G, Bertin T, Jiang MM, Chen Y, Wang L, Zheng H, Sutton RE, Boyce BF, Lee B (2008) Dimorphic effects of Notch signaling in bone homeostasis. Nat Med 14:299–305CrossRefPubMedCentralPubMed
16.
Hilton MJ, Tu X, Wu X, Bai S, Zhao H, Kobayashi T, Kronenberg HM, Teitelbaum SL, Ross FP, Kopan R, Long F (2008) Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med 14:306–314CrossRefPubMedCentralPubMed
17.
Tezuka K, Yasuda M, Watanabe N, Morimura N, Kuroda K, Miyatani S, Hozumi N (2002) Stimulation of osteoblastic cell differentiation by Notch. J Bone Miner Res 17:231–239CrossRefPubMed
18.
Nobta M, Tsukazaki T, Shibata Y, Xin C, Moriishi T, Sakano S, Shindo H, Yamaguchi A (2005) Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling. J Biol Chem 280:15842–15848CrossRefPubMed
19.
Bai S, Kopan R, Zou W, Hilton MJ, Ong CT, Long F, Ross FP, Teitelbaum SL (2008) NOTCH1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells. J Biol Chem 283:6509–6518CrossRefPubMed
20.
Fukushima H, Nakao A, Okamoto F, Shin M, Kajiya H, Sakano S, Bigas A, Jimi E, Okabe K (2008) The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis. Mol Cell Biol 28:6402–6412CrossRefPubMedCentralPubMed
21.
Simpson MA, Irving MD, Asilmaz E, Gray MJ, Dafou D, Elmslie FV, Mansour S, Holder SE, Brain CE, Burton BK, Kim KH, Pauli RM, Aftimos S, Stewart H, Kim CA, Holder-Espinasse M, Robertson SP, Drake WM, Trembath RC (2011) Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat Genet 43:303–305CrossRefPubMed
22.
Cotton M, Benhra N, Le Borgne R (2013) Numb inhibits the recycling of Sanpodo in Drosophila sensory organ precursor. Curr Biol 23:581–587CrossRefPubMed
23.
Couturier L, Mazouni K, Schweisguth F (2013) Numb localizes at endosomes and controls the endosomal sorting of notch after asymmetric division in Drosophila. Curr Biol 23:588–593CrossRefPubMed
24.
Giebel B, Wodarz A (2012) Notch signaling: numb makes the difference. Curr Biol 22:R133–R135CrossRefPubMed
25.
McGill MA, McGlade CJ (2003) Mammalian numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain. J Biol Chem 278:23196–23203CrossRefPubMed
26.
Berdnik D, Torok T, Gonzalez-Gaitan M, Knoblich JA (2002) The endocytic protein alpha-Adaptin is required for numb-mediated asymmetric cell division in Drosophila. Dev Cell 3:221–231CrossRefPubMed
27.
Guo M, Jan LY, Jan YN (1996) Control of daughter cell fates during asymmetric division: interaction of Numb and Notch. Neuron 17:27–41CrossRefPubMed
28.
Song Y, Lu B (2012) Interaction of Notch signaling modulator Numb with alpha-Adaptin regulates endocytosis of Notch pathway components and cell fate determination of neural stem cells. J Biol Chem 287:17716–17728CrossRefPubMedCentralPubMed
29.
Gulino A, Di Marcotullio L, Screpanti I (2010) The multiple functions of Numb. Exp Cell Res 316:900–906CrossRefPubMed
30.
Dho SE, Jacob S, Wolting CD, French MB, Rohrschneider LR, McGlade CJ (1998) The mammalian numb phosphotyrosine-binding domain. Characterization of binding specificity and identification of a novel PDZ domain-containing numb binding protein, LNX. J Biol Chem 273:9179–9187CrossRefPubMed
31.
Nie J, McGill MA, Dermer M, Dho SE, Wolting CD, McGlade CJ (2002) LNX functions as a RING type E3 ubiquitin ligase that targets the cell fate determinant Numb for ubiquitin-dependent degradation. EMBO J 21:93–102CrossRefPubMedCentralPubMed
32.
Rice DS, Northcutt GM, Kurschner C (2001) The Lnx family proteins function as molecular scaffolds for Numb family proteins. Mol Cell Neurosci 18:525–540CrossRefPubMed
33.
34.
Ye S, Fowler TW, Pavlos NJ, Ng PY, Liang K, Feng Y, Zheng M, Kurten R, Manolagas SC, Zhao H (2011) LIS1 regulates osteoclast formation and function through its interactions with dynein/dynactin and Plekhm1. PLoS One 6:e27285CrossRefPubMedCentralPubMed
35.
Takeshita S, Kaji K, Kudo A (2000) Identification and characterization of the new osteoclast progenitor with macrophage phenotypes being able to differentiate into mature osteoclasts. J Bone Miner Res 15:1477–1488CrossRefPubMed
36.
Feng X, Novack DV, Faccio R, Ory DS, Aya K, Boyer MI, McHugh KP, Ross FP, Teitelbaum SL (2001) A Glanzmann’s mutation in beta 3 integrin specifically impairs osteoclast function. J Clin Invest 107:1137–1144CrossRefPubMedCentralPubMed
37.
Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108CrossRefPubMed
38.
Jilka RL, Hangoc G, Girasole G, Passeri G, Williams DC, Abrams JS, Boyce B, Broxmeyer H, Manolagas SC (1992) Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 257:88–91CrossRefPubMed
39.
Zhao H, Laitala-Leinonen T, Parikka V, Vaananen HK (2001) Downregulation of small GTPase Rab7 impairs osteoclast polarization and bone resorption. J Biol Chem 276:39295–39302CrossRefPubMed
40.
David JP, Sabapathy K, Hoffmann O, Idarraga MH, Wagner EF (2002) JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms. J Cell Sci 115:4317–4325CrossRefPubMed
41.
Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, Leonardi A, Tran T, Boyce BF, Siebenlist U (1997) Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev 11:3482–3496CrossRefPubMedCentralPubMed
42.
Gingery A, Bradley E, Shaw A, Oursler MJ (2003) Phosphatidylinositol 3-kinase coordinately activates the MEK/ERK and AKT/NFkappaB pathways to maintain osteoclast survival. J Cell Biochem 89:165–179CrossRefPubMed
43.
Iotsova V, Caamano J, Loy J, Yang Y, Lewin A, Bravo R (1997) Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med 3:1285–1289CrossRefPubMed
44.
Miyazaki T, Katagiri H, Kanegae Y, Takayanagi H, Sawada Y, Yamamoto A, Pando MP, Asano T, Verma IM, Oda H, Nakamura K, Tanaka S (2000) Reciprocal role of ERK and NF-kappaB pathways in survival and activation of osteoclasts. J Cell Biol 148:333–342CrossRefPubMedCentralPubMed
45.
McGill MA, Dho SE, Weinmaster G, McGlade CJ (2009) Numb regulates post-endocytic trafficking and degradation of Notch1. J Biol Chem 284:26427–26438CrossRefPubMedCentralPubMed
46.
Zhou J, Fujiwara T, Ye S, Li X, Zhao H (2014) Downregulation of Notch modulators, tetraspanin 5 and 10, inhibits osteoclastogenesis in vitro. Calcif Tissue Int 95:209–217CrossRefPubMed
47.
Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, Daro E, Smith J, Tometsko ME, Maliszewski CR, Armstrong A, Shen V, Bain S, Cosman D, Anderson D, Morrissey PJ, Peschon JJ, Schuh J (1999) RANK is essential for osteoclast and lymph node development. Genes Dev 13:2412–2424CrossRefPubMedCentralPubMed
48.
Fuller K, Wong B, Fox S, Choi Y, Chambers TJ (1998) TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med 188:997–1001CrossRefPubMedCentralPubMed
49.
Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, Tan HL, Elliott G, Kelley MJ, Sarosi I, Wang L, Xia XZ, Elliott R, Chiu L, Black T, Scully S, Capparelli C, Morony S, Shimamoto G, Bass MB, Boyle WJ (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 96:3540–3545CrossRefPubMedCentralPubMed
50.
Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176CrossRefPubMed
51.
Wiktor-Jedrzejczak W, Bartocci A, Ferrante AW Jr, Ahmed-Ansari A, Sell KW, Pollard JW, Stanley ER (1990) Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci USA 87:4828–4832CrossRefPubMedCentralPubMed
52.
Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95:3597–3602CrossRefPubMedCentralPubMed
53.
Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD, Nishikawa S (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345:442–444CrossRefPubMed
54.
Manolagas SC (2000) Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 21:115–137PubMed
55.
56.
57.
58.
D’Agostino M, Tornillo G, Caporaso MG, Barone MV, Ghigo E, Bonatti S, Mottola G (2011) Ligand of Numb proteins LNX1p80 and LNX2 interact with the human glycoprotein CD8alpha and promote its ubiquitylation and endocytosis. J Cell Sci 124:3545–3556CrossRefPubMed
59.
Kansaku A, Hirabayashi S, Mori H, Fujiwara N, Kawata A, Ikeda M, Rokukawa C, Kurihara H, Hata Y (2006) Ligand-of-Numb protein X is an endocytic scaffold for junctional adhesion molecule 4. Oncogene 25:5071–5084PubMed
60.
Takahashi S, Iwamoto N, Sasaki H, Ohashi M, Oda Y, Tsukita S, Furuse M (2009) The E3 ubiquitin ligase LNX1p80 promotes the removal of claudins from tight junctions in MDCK cells. J Cell Sci 122:985–994CrossRefPubMed
61.
Guo Z, Song E, Ma S, Wang X, Gao S, Shao C, Hu S, Jia L, Tian R, Xu T, Gao Y (2012) Proteomics strategy to identify substrates of LNX, a PDZ domain-containing E3 ubiquitin ligase. J Proteome Res 11:4847–4862CrossRefPubMed
62.
Wolting CD, Griffiths EK, Sarao R, Prevost BC, Wybenga-Groot LE, McGlade CJ (2011) Biochemical and computational analysis of LNX1 interacting proteins. PLoS One 6:e26248CrossRefPubMedCentralPubMed
63.
Yamada T, Yamazaki H, Yamane T, Yoshino M, Okuyama H, Tsuneto M, Kurino T, Hayashi S, Sakano S (2003) Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells. Blood 101:2227–2234CrossRefPubMed
64.
Choi YH, Ann EJ, Yoon JH, Mo JS, Kim MY, Park HS (2013) Calcium/calmodulin-dependent protein kinase IV (CaMKIV) enhances osteoclast differentiation via the up-regulation of Notch1 protein stability. Biochim Biophys Acta 1833:69–79CrossRefPubMed
65.
Duan L, de Vos P, Fan M, Ren Y (2008) Notch is activated in RANKL-induced osteoclast differentiation and resorption. Front Biosci 13:7064–7071CrossRefPubMed
Metadaten
Titel
Ubiquitin E3 Ligase LNX2 is Critical for Osteoclastogenesis In Vitro by Regulating M-CSF/RANKL Signaling and Notch2
verfasst von
Jian Zhou
Toshifumi Fujiwara
Shiqiao Ye
Xiaolin Li
Haibo Zhao
Publikationsdatum
01.05.2015
Verlag
Springer US
Erschienen in
Calcified Tissue International / Ausgabe 5/2015
Print ISSN: 0171-967X
Elektronische ISSN: 1432-0827
DOI
https://doi.org/10.1007/s00223-015-9967-7

Weitere Artikel der Ausgabe 5/2015

Calcified Tissue International 5/2015 Zur Ausgabe

Original Research

The Generation of C-3α Epimer of 25-Hydroxyvitamin D and Its Biological Effects on Bone Mineral Density in Adult Rodents

Original Research

Development of a Cyclosporin-A-Induced Immune Tolerant Rat Model to Test Marrow Allograft Cell Type Effects on Bone Repair

Original Research

Parathyroid Hormone, Calcium, and Sodium Bridging Between Osteoporosis and Hypertension in Postmenopausal Korean Women

Original Research

A Mutation in CTSK Gene in an Autosomal Recessive Pycnodysostosis Family of Chinese Origin

Original Research

Effect of Vitamin B12 and Folic Acid Supplementation on Bone Mineral Density and Quantitative Ultrasound Parameters in Older People with an Elevated Plasma Homocysteine Level: B-PROOF, a Randomized Controlled Trial

Original Research

Deteriorating Effect on Bone Metabolism and Microstructure by Passive Cigarette Smoking Through Dual Actions on Osteoblast and Osteoclast

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

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

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

Newsletter bestellen
Bildnachweise