title: Irreversible heavy chain transfer to hyaluronan oligosaccharides by tumor necrosis factor-stimulated gene-6.
abstract: The covalent transfer of heavy chains (HCs) from inter-α-inhibitor (IαI) to hyaluronan (HA) via the protein product of tumor necrosis factor-stimulated gene-6 (TSG-6) forms the HC-HA complex, a pathological form of HA that promotes the adhesion of leukocytes to HA matrices. The transfer of HCs to high molecular weight (HMW) HA is a reversible event whereby TSG-6 can shuffle HCs from one HA molecule to another. Therefore, HMW HA can serve as both an HC acceptor and an HC donor. In the present study, we show that transfer of HCs to low molecular weight HA oligosaccharides is an irreversible event where subsequent shuffling does not occur, i.e. HA oligosaccharides from 8 to 21 monosaccharide units in length can serve as HC acceptors, but are unable to function as HC donors. We show that the HC-HA complex is present in the synovial fluid of mice subjected to systemic and monoarticular mouse models of rheumatoid arthritis. Furthermore, we demonstrate that HA oligosaccharides can be used, with TSG-6, to irreversibly shuffle HCs from pathological, HMW HC-HA to HA oligosaccharides, thereby restoring HC-HA matrices from the inflamed joint to their normal state, unmodified with HCs. This process was also effective for HC-HA in the synovial fluid of human rheumatoid arthritis patients (in vitro).
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Lauer
authors.forename: Tibor T
authors.initials: TT
authors.lastname: Glant
authors.forename: Katalin
authors.initials: K
authors.lastname: Mikecz
authors.forename: Paul L
authors.initials: PL
authors.lastname: DeAngelis
authors.forename: F Michael
authors.initials: FM
authors.lastname: Haller
authors.forename: M Elaine
authors.initials: ME
authors.lastname: Husni
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Hascall
authors.forename: Anthony
authors.initials: A
authors.lastname: Calabro
mesh_terms: D000510:Alpha-Globulins / Q000737:chemistry; D000818:Animals; D002241:Carbohydrates / Q000737:chemistry; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D004586:Electrophoresis / Q000379:methods; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry; D007249:Inflammation; D007700:Kinetics; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009844:Oligosaccharides / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D000510:Alpha-Globulins; D002241:Carbohydrates; D015815:Cell Adhesion Molecules; D007143:Immunoglobulin Heavy Chains; D009844:Oligosaccharides; D011994:Recombinant Proteins; C072273:TNFAIP6 protein, human; C513057:Tnfaip6 protein, mouse; C016001:alpha-1-microglobulin; D006820:Hyaluronic Acid