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Global deletion of Optineurin results in altered type I IFN signaling and abnormal bone remodeling in a model of Paget’s disease


Genome-wide association studies (GWAS) have identified Optineurin (OPTN) as genetically linked to Paget’s disease of the bone (PDB), a chronic debilitating bone remodeling disorder characterized by localized areas of increased bone resorption and abnormal bone remodeling. However, only ~10% of mouse models with a mutation in Optn develop PDB, thus hindering the mechanistic understanding of the OPTN-PDB axis. Here, we reveal that 100% of aged Optn global knockout (Optn/−) mice recapitulate the key clinical features observed in PDB patients, including polyostotic osteolytic lesions, mixed-phase lesions, and increased serum levels of alkaline phosphatase (ALP). Differentiation of primary osteoclasts ex vivo revealed that the absence of Optn resulted in an increased osteoclastogenesis. Mechanistically, Optn-deficient osteoclasts displayed a significantly decreased type I interferon (IFN) signature, resulting from both defective production of IFNβ and impaired signaling via the IFNα/βR, which acts as a negative feedback loop for osteoclastogenesis and survival. These data highlight the dual roles of OPTN in the type I IFN response to restrain osteoclast activation and bone resorption, offering a novel therapeutic target for PDB. Therefore, our study describes a novel and essential mouse model for PDB and define a key role for OPTN in osteoclast differentiation.

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  1. 1.

    Teramachi J, Nagata Y, Mohammad K, Inagaki Y, Ohata Y, Guise T, et al. Measles virus nucleocapsid protein increases osteoblast differentiation in Paget’s disease. J Clin Invest. 2016;126:1012–22.

  2. 2.

    Kukita A, Chenu C, McManus LM, Mundy GR, Roodman GD. Atypical multinucleated cells form in long-term marrow cultures from patients with Paget’s disease. J Clin Invest. 1990;85:1280–6.

  3. 3.

    Rebel A, Malkani K, Basle M, Bregeon C. Osteoclast ultrastructure in Paget’s disease. Calcif Tissue Res. 1976;2:187–99.

  4. 4.

    Menaa C, Reddy SV, Kurihara N, Maeda H, Anderson D, Cundy T, et al. Enhanced RANK ligand expression and responsivity of bone marrow cells in Paget’s disease of bone. J Clin Invest. 2000;105:1833–8.

  5. 5.

    Ralston SH, Albagha OM. Genetics of Paget’s disease of bone. Curr Osteoporos Rep. 2014;12:263–71.

  6. 6.

    Albagha OM. Genetics of Paget’s disease of bone. Bone Rep. 2015;4:756.

  7. 7.

    Morissette J, Laurin N, Brown JP. Sequestosome 1: mutation frequencies, haplotypes, and phenotypes in familial Paget’s disease of bone. J Bone Min Res. 2006;21(Suppl 2):P38–44.

  8. 8.

    Sundaram K, Shanmugarajan S, Rao DS, Reddy SV. Mutant p62P392L stimulation of osteoclast differentiation in Paget’s disease of bone. Endocrinology. 2011;152:4180–9.

  9. 9.

    Albagha OM, Visconti MR, Alonso N, Langston AL, Cundy T, Dargie R, et al. Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget’s disease of bone. Nat Genet. 2010;42:520–4.

  10. 10.

    Obaid R, Wani SE, Azfer A, Hurd T, Jones R, Cohen P, et al. Optineurin negatively regulates osteoclast differentiation by modulating NF-kappaB and interferon signaling: implications for Paget’s disease. Cell Rep. 2015;13:1096–102.

  11. 11.

    Slowicka K, Vereecke L, van Loo G. Cellular functions of optineurin in health and disease. Trends Immunol. 2016;37:621–33.

  12. 12.

    Zhu G, Wu CJ, Zhao Y, Ashwell JD. Optineurin negatively regulates TNFalpha- induced NF-kappaB activation by competing with NEMO for ubiquitinated RIP. Curr Biol. 2007;17:1438–43.

  13. 13.

    Chibalina MV, Roberts RC, Arden SD, Kendrick-Jones J, Buss F. Rab8-optineurin-myosin VI: analysis of interactions and functions in the secretory pathway. Methods Enzymol. 2008;438:11–24.

  14. 14.

    Chibalina MV, Poliakov A, Kendrick-Jones J, Buss F. Myosin VI and optineurin are required for polarized EGFR delivery and directed migration. Traffic. 2010;11:1290–303.

  15. 15.

    Munitic I, Giardino Torchia ML, Meena NP, Zhu G, Li CC, Ashwell JD. Optineurin insufficiency impairs IRF3 but not NF-kappaB activation in immune cells. J Immunol. 2013;191:6231–40.

  16. 16.

    Meena NP, Zhu G, Mittelstadt PR, Giardino Torchia ML, Pourcelot M, Arnoult D, et al. The TBK1-binding domain of optineurin promotes type I interferon responses. FEBS Lett. 2016;590:1498–508.

  17. 17.

    Chalasani ML, Radha V, Gupta V, Agarwal N, Balasubramanian D, Swarup G. A glaucoma-associated mutant of optineurin selectively induces death of retinal ganglion cells which is inhibited by antioxidants. Invest Ophthalmol Vis Sci. 2007;48:1607–14.

  18. 18.

    Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, Li Y, et al. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science . 2016;353:603–8.

  19. 19.

    Toth RP, Atkin JD. Dysfunction of optineurin in amyotrophic lateral sclerosis and glaucoma. Front Immunol. 2018;9:1017.

  20. 20.

    Ma HL, Blanchet TJ, Peluso D, Hopkins B, Morris EA, Glasson SS. Osteoarthritis severity is sex dependent in a surgical mouse model. Osteoarthr Cartil. 2007;15:695–700.

  21. 21.

    Huang H, Skelly JD, Ayers DC, Song J. Age-dependent changes in the articular cartilage and subchondral bone of C57BL/6 mice after surgical destabilization of medial meniscus. Sci Rep. 2017;7:42294.

  22. 22.

    Xiu Y, Xu H, Zhao C, Li J, Morita Y, Yao Z, et al. Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation. J Clin Invest. 2014;124:297–310.

  23. 23.

    Lee DJ, Tseng HC, Wong SW, Wang Z, Deng M, Ko CC. Dopaminergic effects on in vitro osteogenesis. Bone Res. 2015;3:15020.

  24. 24.

    Dillon CP, Weinlich R, Rodriguez DA, Cripps JG, Quarato G, Gurung P, et al. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell . 2014;157:1189–202.

  25. 25.

    Seitz S, Priemel M, Zustin J, Beil FT, Semler J, Minne H, et al. Paget’s disease of bone: histologic analysis of 754 patients. J Bone Min Res. 2009;24:62–9.

  26. 26.

    Dutta S, Sengupta P. Men and mice: relating their ages. Life Sci. 2016;152:244–8.

  27. 27.

    Al Nofal AA, Altayar O, BenKhadra K, Qasim Agha OQ, Asi N, Nabhan M, et al. Bone turnover markers in Paget’s disease of the bone: a systematic review and meta-analysis. Osteoporos Int. 2015;26:1875–91.

  28. 28.

    Teramachi J, Zhou H, Subler MA, Kitagawa Y, Galson DL, Dempster DW, et al. Increased IL-6 expression in osteoclasts is necessary but not sufficient for the development of Paget’s disease of bone. J Bone Min Res. 2014;29:1456–65.

  29. 29.

    Lin NY, Beyer C, Giessl A, Kireva T, Scholtysek C, Uderhardt S, et al. Autophagy regulates TNFalpha-mediated joint destruction in experimental arthritis. Ann Rheum Dis. 2013;72:761–8.

  30. 30.

    Abu-Amer Y. NF-kappaB signaling and bone resorption. Osteoporos Int. 2013;24:2377–86.

  31. 31.

    Krebs DL, Hilton DJ. SOCS: physiological suppressors of cytokine signaling. J Cell Sci. 2000;113(Pt 16):2813–9.

  32. 32.

    Lehtonen A, Matikainen S, Julkunen I. Interferons up-regulate STAT1, STAT2, and IRF family transcription factor gene expression in human peripheral blood mononuclear cells and macrophages. J Immunol. 1997;159:794–803.

  33. 33.

    Takayanagi H, Kim S, Matsuo K, Suzuki H, Suzuki T, Sato K, et al. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature . 2002;416:744–9.

  34. 34.

    Hanada R, Hanada T, Sigl V, Schramek D, Penninger JM. RANKL/RANK-beyond bones. J Mol Med (Berl). 2011;89:647–56.

  35. 35.

    Slowicka K, Vereecke L, Mc Guire C, Sze M, Maelfait J, Kolpe A, et al. Optineurin deficiency in mice is associated with increased sensitivity to Salmonella but does not affect proinflammatory NF-kappaB signaling. Eur J Immunol. 2016;46:971–80.

  36. 36.

    Tseng HC, Riday TT, McKee C, Braine CE, Bomze H, Barak I, et al. Visual impairment in an optineurin mouse model of primary open-angle glaucoma. Neurobiol Aging. 2015;36:2201–12.

  37. 37.

    Roodman GD, Windle JJ. Paget disease of bone. J Clin Invest. 2005;115:200–8.

  38. 38.

    Jaco I, Annibaldi A, Lalaoui N, Wilson R, Tenev T, Laurien L, et al. MK2 phosphorylates RIPK1 to prevent TNF-induced cell death. Mol Cell. 2017;66:698–710. e5.

  39. 39.

    Herbert BA, Valerio MS, Gaestel M, Kirkwood KL. Sexual dimorphism in MAPK-activated protein kinase-2 (MK2) regulation of RANKL-induced osteoclastogenesis in osteoclast progenitor subpopulations. PLoS One. 2015;10:e0125387.

  40. 40.

    Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14:36–49.

  41. 41.

    Kurihara N, Zhou H, Reddy SV, Garcia Palacios V, Subler MA, Dempster DW, et al. Expression of measles virus nucleocapsid protein in osteoclasts induces Paget’s disease-like bone lesions in mice. J Bone Min Res. 2006;21:446–55.

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We would like to thank Danielle Callaway of the University of Texas, Brendan Boyce of the University of Rochester, and Kim Mansky of University of Minnesota for their help on osteoclast primary culture. We thank the staff in Biomedical Research Imaging Center and Maya Styner at University of North Carolina for their imaging technical support. We also thank Kevin Gerrish and Rick Fannin in the Molecular Genomics Core at the National Institute of Environmental Health Sciences for microarray support. We also thank Michael Fessler (NIEHS), Donald N. Cook (NIEHS), Kevin Byrd (UNC School of Dentistry), and Richard Loeser (UNC School of Medicine) for their careful assistance with this manuscript. This work was supported in part by the NIH Intramural Research Program 1ZIAES10328601 (to J.M.), NIH/NIDCR R01DE022816 (to C.K.) and R90DE022527 (to SW.W.), Butler Pioneer Award (to H.T.), Alcon Research Institute (to H.T.), American Glaucoma Society (to H.T.), K08-EY021520 (to H.T.), and NEI core grant P30-EY005722 (to Duke Eye Center).

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Correspondence to Jennifer Martinez.

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