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J. Biol. Chem., Vol. 281, Issue 24, 16521-16529, June 16, 2006

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Collagen Plays an Active Role in the Aggregation of ₂-Microglobulin under Physiopathological Conditions of Dialysis-related Amyloidosis^*

Annalisa Relini¹, Claudio Canale, Silvia De Stefano, Ranieri Rolandi, Sofia Giorgetti, Monica Stoppini, Antonio Rossi, Federico Fogolari^¶, Alessandra Corazza^¶, Gennaro Esposito^¶, Alessandra Gliozzi, and Vittorio Bellotti

From the Department of Physics, University of Genoa, I-16146 Genoa, Italy, the Department of Biochemistry, University of Pavia, Laboratori di Biotecnologie Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy, and the ^¶Department of Biomedical Sciences and Technologies, University of Udine, I-33100 Udine, Italy

Dialysis-related amyloidosis is characterized by the deposition of insoluble fibrils of₂-microglobulin (₂-m) in the musculoskeletal system. Atomic force microscopy inspection of ex vivo amyloid material reveals the presence of bundles of fibrils often associated to collagen fibrils. Aggregation experiments were undertaken in vitro with the aim of reproducing the physiopathological fibrillation process. To this purpose, atomic force microscopy, fluorescence techniques, and NMR were employed. We found that in temperature and pH conditions similar to those occurring in periarticular tissues in the presence of flogistic processes, ₂-m fibrillogenesis takes place in the presence of fibrillar collagen, whereas no fibrils are obtained without collagen. Moreover, the morphology of₂-m fibrils obtained in vitro in the presence of collagen is extremely similar to that observed in the ex vivo sample. This result indicates that collagen plays a crucial role in ₂-m amyloid deposition under physiopathological conditions and suggests an explanation for the strict specificity of dialysis-related amyloidosis for the tissues of the skeletal system. We hypothesize that positively charged regions along the collagen fiber could play a direct role in₂-m fibrillogenesis. This hypothesis is sustained by aggregation experiments performed by replacing collagen with a poly-L-lysine-coated mica surface. As shown by NMR measurements, no similar process occurs when poly-L-lysine is dissolved in solution with ₂-m. Overall, the findings are consistent with the estimates resulting from a simplified collagen model whereby electrostatic effects can lead to high local concentrations of oppositely charged species, such as ₂-m, that decay on moving away from the fiber surface.

Received for publication, December 28, 2005 , and in revised form, March 13, 2006.

^* This work was supported by grants from the Italian Ministero dell' Istruzione, dell' Università e della Ricerca (Fondo per gli Investimenti della Ricerca di Base project RBNE01S29H, Programmi di ricerca di Rilevante Interesse Nazionale 2003051399 and 2004050405), Fondazione Cassa di Risparmio di Genova e Imperia and Fondazione Cassa di Risparmio della Province Lombarde (Progetto Nobel), and Ricerca Finalizzata IRCCS Policlinico San Matteo. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

¹ To whom correspondence should be addressed: Dept. of Physics, University of Genoa, Via Dodecaneso 33, I-16146 Genova, Italy. Tel.: 39-010-3536427; Fax: 39-010-314218; E-mail: relini{at}mail.fisica.unige.it.

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