title: Characterization of the response of primary cells relevant to dialysis-related amyloidosis to β2-microglobulin monomer and fibrils.
abstract: The formation of insoluble amyloid fibrils is associated with an array of devastating human diseases. Dialysis-related amyloidosis (DRA) is a severe complication of hemodialysis that results in the progressive destruction of the bones and joints. Elevated concentrations of β(2)-microglobulin (β(2)m) in the serum of subjects on hemodialysis promote the formation of amyloid fibrils in the osteoarticular tissues, but the cellular basis for the destruction of these tissues in DRA is poorly understood. In this study we performed a systematic analysis of the interaction of monomeric and fibrillar β(2)m with primary human cells of the types present in the synovial joints of subjects with DRA. Building upon observations that macrophages infiltrate β(2)m amyloid deposits in vivo we demonstrate that monocytes, the precursors of macrophages, cannot degrade β(2)m fibrils, and that both monomeric β(2)m and fibrillar β(2)m are cytotoxic to these cells. β(2)m fibrils also impair the formation of bone resorbing osteoclasts from monocytes and reduce the viability of osteoblasts, the cell type that produces bone. As a consequence, we predict that β(2)m amyloid will disrupt the remodelling of the bone, which is critical for the maintenance of this tissue. Moreover, we show that β(2)m fibrils reduce the viability of chondrocytes, rationalizing the loss of cartilage in DRA. Together, our observations demonstrate that β(2)m cytotoxicity has multiple cellular targets in the osteoarticular tissues and is likely to be a key factor in the bone and joint destruction characteristic of DRA.
authors.affiliation: Astbury Centre for Structural Molecular Biology and Institute of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Morwenna Y
authors.initials: MY
authors.lastname: Porter
authors.forename: Katy E
authors.initials: KE
authors.lastname: Routledge
authors.forename: Sheena E
authors.initials: SE
authors.lastname: Radford
authors.forename: Eric W
authors.initials: EW
authors.lastname: Hewitt
mesh_terms: D000686:Amyloidosis / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D007963:Leukocytes, Mononuclear / Q000166:cytology; D046529:Microscopy, Electron, Transmission; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001613:beta 2-Microglobulin
references.citation: Nephron. 1996;72(1):9-26
references.pmid: 8903856
references.citation: Amyloid. 2009;16(3):151-73
references.pmid: 19657763
references.citation: J Bone Miner Res. 2011 Jun;26(6):1368-76
references.pmid: 21611975
references.citation: Nephron. 1990;56(4):357-63
references.pmid: 1706823
references.citation: Haematologica. 2008 Jun;93(6):955-6
references.pmid: 18515883
references.citation: J Clin Invest. 1985 Dec;76(6):2425-9
references.pmid: 3908488
references.citation: J Biol Chem. 2006 Jun 16;281(24):16521-9
references.pmid: 16601119
references.citation: Eur J Biochem. 1998 Nov 15;258(1):61-7
references.pmid: 9851692
references.citation: Protein Sci. 2005 Mar;14(3):696-702
references.pmid: 15689502
references.citation: Biochemistry. 2006 Feb 21;45(7):2311-21
references.pmid: 16475820
references.citation: J Mol Biol. 2005 Aug 26;351(4):850-64
references.pmid: 16024039
references.citation: Neurobiol Dis. 2010 Mar;37(3):503-9
references.pmid: 19833208
references.citation: J Mol Biol. 2009 Mar 13;386(5):1312-26
references.pmid: 19452600
references.citation: J Bone Miner Metab. 2006;24(2):182-4
references.pmid: 16502130
references.citation: Semin Dial. 2001 Mar-Apr;14(2):80-5
references.pmid: 11264771
references.citation: J Biol Chem. 2008 Feb 22;283(8):4912-20
references.pmid: 18056266
references.citation: Protein Sci. 2000 May;9(5):831-45
references.pmid: 10850793
references.citation: J Mol Biol. 2007 Feb 2;365(5):1337-49
references.pmid: 17134716
references.citation: Biophys J. 2008 May 1;94(9):3635-46
references.pmid: 18199664
references.citation: Pathol Int. 2001 Jan;51(1):1-10
references.pmid: 11148456
references.citation: Nephrol Dial Transplant. 1994;9(6):662-7
references.pmid: 7970093
references.citation: PLoS One. 2011;6(5):e20244
references.pmid: 21625461
references.citation: FEBS J. 2011 Oct;278(20):3868-83
references.pmid: 21595827
references.citation: Kidney Int. 1997 Dec;52(6):1543-9
references.pmid: 9407499
references.citation: Semin Dial. 2009 Jul-Aug;22(4):378-80
references.pmid: 19708985
references.citation: J Biol Chem. 2009 Dec 4;284(49):34272-82
references.pmid: 19808677
references.citation: Kidney Int. 1999 May;55(5):1983-90
references.pmid: 10231463
references.citation: J Biol Chem. 2011 Jan 21;286(3):2121-31
references.pmid: 21068391
references.citation: J Biol Chem. 2006 May 12;281(19):13828-13836
references.pmid: 16554307
references.citation: Am J Kidney Dis. 2001 Oct;38(4 Suppl 1):S156-60
references.pmid: 11576944
references.citation: Kidney Int. 1999 Mar;55(3):899-906
references.pmid: 10027926
references.citation: Ann N Y Acad Sci. 2006 Apr;1068:100-9
references.pmid: 16831910
references.citation: Science. 2003 Apr 18;300(5618):486-9
references.pmid: 12702875
references.citation: Nephrol Dial Transplant. 2002 Jun;17(6):1136-8
references.pmid: 12032213
references.citation: J Biol Chem. 2008 Jun 20;283(25):17279-86
references.pmid: 18424782
references.citation: J Biol Chem. 2010 Aug 13;285(33):25103-8
references.pmid: 20501658
references.citation: Enzyme. 1985;34(3):140-3
references.pmid: 3833541
references.citation: Clin Chem. 2005 Jul;51(7):1177-84
references.pmid: 15890888
references.citation: Kidney Int. 2008 Jun;73(11):1275-81
references.pmid: 18368032
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1485-90
references.pmid: 11818542
references.citation: Kidney Int. 2007 Jul;72(2):174-81
references.pmid: 17495865
references.citation: Annu Rev Biochem. 2006;75:333-66
references.pmid: 16756495
references.citation: J Am Soc Nephrol. 2004 Jan;15(1):126-33
references.pmid: 14694164
references.citation: J Mol Biol. 2001 Oct 26;313(3):559-71
references.pmid: 11676539
references.citation: Scand J Rheumatol. 1997;26(1):61-4
references.pmid: 9057805
references.citation: Nephrol Dial Transplant. 2009 Apr;24(4):1176-81
references.pmid: 19008236
references.citation: Amyloid. 1998 Dec;5(4):247-54
references.pmid: 10036582
references.citation: J Mol Biol. 2010 Oct 8;402(5):783-96
references.pmid: 20624399
references.citation: Bone. 2007 Feb;40(2):251-64
references.pmid: 17098490
references.citation: Nephrol Dial Transplant. 1995 Nov;10(11):2077-82
references.pmid: 8643171
references.citation: Nat Rev Immunol. 2005 Dec;5(12):953-64
references.pmid: 16322748
references.citation: Science. 2005 Jan 14;307(5707):262-5
references.pmid: 15653506
references.citation: J Biol Chem. 2010 May 28;285(22):17137-47
references.pmid: 20335170
references.citation: Mol Cell. 2011 Jan 21;41(2):161-72
references.pmid: 21255727
references.citation: Biochem Biophys Res Commun. 1985 Jun 28;129(3):701-6
references.pmid: 3893430
references.citation: Kidney Int Suppl. 2001 Feb;78:S164-71
references.pmid: 11169004
references.citation: J Biol Chem. 2007 Oct 5;282(40):29691-700
references.pmid: 17686767
references.citation: Autoimmunity. 2008 Apr;41(3):218-23
references.pmid: 18365835
references.citation: Cell Stress Chaperones. 2010 Nov;15(6):1013-26
references.pmid: 20632140