ES2565838T3 - Biomarcador de la osteoartritis y uso del mismo - Google Patents
Biomarcador de la osteoartritis y uso del mismo Download PDFInfo
- Publication number
- ES2565838T3 ES2565838T3 ES09757339.8T ES09757339T ES2565838T3 ES 2565838 T3 ES2565838 T3 ES 2565838T3 ES 09757339 T ES09757339 T ES 09757339T ES 2565838 T3 ES2565838 T3 ES 2565838T3
- Authority
- ES
- Spain
- Prior art keywords
- concentration
- osteoarthritis
- subjects
- polypeptide
- spot
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 201000008482 osteoarthritis Diseases 0.000 title abstract description 7
- 239000000090 biomarker Substances 0.000 title 1
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 4
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 4
- 210000002700 urine Anatomy 0.000 abstract description 4
- 229920001184 polypeptide Polymers 0.000 abstract 3
- 125000003275 alpha amino acid group Chemical group 0.000 abstract 1
- 239000012472 biological sample Substances 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 abstract 1
- 239000008280 blood Substances 0.000 abstract 1
- 238000003745 diagnosis Methods 0.000 abstract 1
- 238000000034 method Methods 0.000 abstract 1
- 210000002381 plasma Anatomy 0.000 abstract 1
- 239000013074 reference sample Substances 0.000 abstract 1
- 210000002966 serum Anatomy 0.000 abstract 1
- 230000003349 osteoarthritic effect Effects 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 102100031814 EGF-containing fibulin-like extracellular matrix protein 1 Human genes 0.000 description 7
- 101710176517 EGF-containing fibulin-like extracellular matrix protein 1 Proteins 0.000 description 7
- 208000001132 Osteoporosis Diseases 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 238000002349 difference gel electrophoresis Methods 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 101710199744 Anionic trypsin-2 Proteins 0.000 description 1
- 101710081722 Antitrypsin Proteins 0.000 description 1
- 101000797623 Homo sapiens Protein AMBP Proteins 0.000 description 1
- 102000009112 Mannose-Binding Lectin Human genes 0.000 description 1
- 108010087870 Mannose-Binding Lectin Proteins 0.000 description 1
- 102100032859 Protein AMBP Human genes 0.000 description 1
- 101710151381 Serine protease 2 Proteins 0.000 description 1
- 102100034392 Trypsin-2 Human genes 0.000 description 1
- 102100021144 Zinc-alpha-2-glycoprotein Human genes 0.000 description 1
- 108010000711 Zn-Alpha-2-Glycoprotein Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001475 anti-trypsic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000013383 initial experiment Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6887—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids from muscle, cartilage or connective tissue
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/10—Musculoskeletal or connective tissue disorders
- G01N2800/105—Osteoarthritis, e.g. cartilage alteration, hypertrophy of bone
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Urology & Nephrology (AREA)
- Cell Biology (AREA)
- General Health & Medical Sciences (AREA)
- Biotechnology (AREA)
- Pathology (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- General Physics & Mathematics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Rehabilitation Therapy (AREA)
- Rheumatology (AREA)
- Peptides Or Proteins (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
Un metodo para diagnosticar la osteoartritis en un sujeto, que comprende las etapas de: (i) determinar la concentracion en una muestra biologica seleccionada entre el grupo que comprende orina, sangre completa, suero sanguineo y plasma sanguineo, de un polipeptido que consiste en una secuencia de aminoacidos definida por la SEQ ID NO: 1; (ii) comparar la concentracion determinada en la etapa (i) con uno o mas valores de referencia definidos por una concentracion de referencia del polipeptido obtenido en una muestra de referencia de uno o mas sujetos normales en donde un aumento en la concentracion del polipeptido en comparacion con los valores de referencia es un diagnostico de la osteoartritis.
Description
- 343
- 189 4,18 Beta-actina
- 348
- 21 192 2 Precursor de la Zn-α-2glucoproteína P25311
- 349
- 8 195 -2,44 Serpina B3 P29508
- 351
- 6 115 -5,84 Serpina B1 P30740
- 352
- 5 130 73 2,2 Fibulina 3 Factor 2 inductor de la apoptosis (dos proteínas identificadas en la misma mancha) Q12805 Q9BRQ8
- 356
- 8 2 110 45 2,01 Zn-α-2-glucoproteína FIBULINA3 P25311 Q12805
- 386
- 10 197 1,54 GP36b Q12907
- 398
- 5 187 2,28 Precursor de la proteína AMBP P02760
- 485
- 8 289 -2,3 Lectina de unión a manano Precursor de la serina proteasa 2 O00187 E.C 3.4.21.104
Como se puede ver, a partir de la Tabla 2, se identificaron varias proteínas con cambios significativos en su concentración en las muestras de osteoartritis en comparación con las muestras de sujetos normales. Se sabe que algunas de las proteínas identificadas están implicadas en el proceso inflamatorio, por ejemplo, el precursor del
5 quininógeno o la antitripsina alfa-1. Esta observación coincide con la patología de la osteoartritis.
Se observó un aumento significativo en la concentración de un fragmento de fibulina 3 específico en sujetos con osteoartritis en comparación con sujetos normales como se muestra en la Tabla 2 y las Figuras 1A y 1B. En la Figura 1A se muestra una ampliación de la zona que rodea de la mancha 352 (indicado por un lado de la flecha 10 doble) en la cartografía 2D-DIGE de las proteínas extraídas de la orina de sujetos con osteoartritis (derecha) en comparación con sujetos normales (izquierda). Se ha mostrado mediante espectrometría de masas que la mancha 352 contiene un fragmento de fibulina-3. En la Figura 1B, la misma mancha (mancha 352) se representa mediante la variación de volumen de la mancha (indicada por la otra cabeza de la flecha doble, equivalente a la mancha de la Figura 1A) entre muestras de sujetos con OA (derecha) y sujetos NO (izquierda). En la Figura 2 se muestra también
15 una vista gráfica de la modificación de la abundancia basándose en el aumento de volumen de la mancha 352.
Se identificaron fragmentos trípticos de la mancha 352 mediante análisis por espectrometría de masas como se muestra en la Figura 3A. Estos fragmentos se identificaron como fragmentos de la proteína fibulina-3, como se muestra en la Figura 3B. La Figura 3B muestra la secuencia de la proteína derivada mediante la traducción del
20 ARNm de la fibulina-3 y en negrita la secuencia específica identificada mediante espectrometría de masas. Cada fragmento típico estudiado recibió una puntuación, que es -10 log (P), donde P es la probabilidad de que la correspondencia observada sea un acontecimiento aleatorio. Las puntuaciones de iones individuales > 50 indican la identidad o una extensa homología. En el caso de la Figura 3A, los péptidos trípticos recibieron una puntuación de 58 y 72, respectivamente, indicando una amplia homología.
25 Además de los experimentos que comparaban sujetos OA y sujetos NO, se han realizado estudios adicionales para comparar sujetos OA y con osteoporosis (OP). En estos estudios, se usaron muestras de orina obtenidas de cuatro mujeres con osteoporosis grave. Se prepararon tres geles, como se muestra en la Tabla 3, para comparar sujetos OA y OP. Se marcaron las proteínas de las diferentes muestras con Cy3 o Cy5 CyDye DIGE Fluor y se cargaron en
30 geles como se ha indicado en la Tabla 3. Un patrón interno (MIX) que comprendía cantidades iguales de muestras OA y OP se marcó con Cy2 CyDye DIGE Fluory se cargó en cada gel. Se llevó a cabo la primera separación con un intervalo de centrado isoeléctrico de pH 4-7 y una carga de 37,5 µg de proteínas.
Tabla 3
- Gel 1
- Gel 2 Gel 3
- Cy3
- OA OA OP
- Cy5
- OP OP OA
- Cy2
- MIX MIX MIX
35 El análisis de los geles muestra que la mancha que contenía el fragmento de fibulina-3 (como se ha descrito con referencia a las Figuras 3A y 3B) muestra una disminución de la abundancia en la muestra de OP en comparación con muestras de OA, con una relación de 6,72. En las Figuras 7A y 7B se ilustran estos resultados.
40 En un segundo experimento, se compararon proteínas extraídas de la orina de poblaciones osteoartríticas (OA) y de control (NO) utilizadas en el experimento inicial (descrito con referencia a las Figuras 1 a 6) y procedentes de la
9
Claims (1)
-
imagen1
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08157521A EP2131199A1 (en) | 2008-06-03 | 2008-06-03 | Biomarker for osteoarthritis and/or other ageing-related diseases, and use thereof |
| EP08157521 | 2008-06-03 | ||
| EP09153804 | 2009-02-26 | ||
| EP09153804 | 2009-02-26 | ||
| PCT/EP2009/052392 WO2009146956A1 (en) | 2008-06-03 | 2009-02-27 | Biomarker for osteoarthritis and/or other ageing-related diseases, and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2565838T3 true ES2565838T3 (es) | 2016-04-07 |
Family
ID=40613112
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES09757339.8T Active ES2565838T3 (es) | 2008-06-03 | 2009-02-27 | Biomarcador de la osteoartritis y uso del mismo |
Country Status (5)
| Country | Link |
|---|---|
| US (3) | US8771968B2 (es) |
| EP (3) | EP2975411A1 (es) |
| DK (1) | DK2286240T3 (es) |
| ES (1) | ES2565838T3 (es) |
| WO (2) | WO2009146957A1 (es) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2975411A1 (en) * | 2008-06-03 | 2016-01-20 | Universite De Liege | Biomarker for osteoarthritis and use thereof |
| CN105755146A (zh) * | 2016-04-29 | 2016-07-13 | 北京致成生物医学科技有限公司 | Serpinb3基因在制备骨关节炎诊断制剂中的应用 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7011952B2 (en) | 2000-02-22 | 2006-03-14 | University Of Iowa Research Foundation | Diagnostics and therapeutics for macular degeneration-related disorders |
| US7416849B2 (en) * | 2001-05-11 | 2008-08-26 | Oscient Pharmaceuticals Corporation | HBM variants that modulate bone mass and lipid levels |
| JP2003135075A (ja) * | 2001-11-05 | 2003-05-13 | Research Association For Biotechnology | 新規な全長ｃＤＮＡ |
| AU2003207738A1 (en) * | 2002-01-29 | 2003-09-02 | Quark Biotech, Inc. | Islr gene and its association with osteoarthritis and other bone and cartilage disorders, expression products derived therefrom, and uses thereof |
| WO2006004066A1 (ja) * | 2004-07-02 | 2006-01-12 | Locomogene, Inc. | S1-5を含有するタンパク質製剤 |
| JPWO2006006477A1 (ja) * | 2004-07-09 | 2008-04-24 | 国立大学法人三重大学 | 骨疾患又は関節疾患に関与するポリペプチド及びそのｄｎａ |
| US20060094054A1 (en) * | 2004-11-04 | 2006-05-04 | National Jewish Medical And Research Center | Fibulin-3 and uses thereof |
| CA2615947A1 (en) * | 2005-06-17 | 2006-12-28 | Brigham And Women's Hospital, Inc. | Protein profile for osteoarthritis |
| WO2008012362A2 (en) * | 2006-07-27 | 2008-01-31 | Oxford Genome Sciences (Uk) Ltd | New protein isoforms and uses thereof |
| EP2975411A1 (en) * | 2008-06-03 | 2016-01-20 | Universite De Liege | Biomarker for osteoarthritis and use thereof |
-
2009
- 2009-02-27 EP EP15180470.5A patent/EP2975411A1/en not_active Ceased
- 2009-02-27 US US12/737,051 patent/US8771968B2/en not_active Expired - Fee Related
- 2009-02-27 WO PCT/EP2009/052396 patent/WO2009146957A1/en active Application Filing
- 2009-02-27 ES ES09757339.8T patent/ES2565838T3/es active Active
- 2009-02-27 EP EP20090757340 patent/EP2297582A1/en not_active Withdrawn
- 2009-02-27 WO PCT/EP2009/052392 patent/WO2009146956A1/en active Application Filing
- 2009-02-27 DK DK09757339.8T patent/DK2286240T3/en active
- 2009-02-27 US US12/737,050 patent/US20110159607A1/en not_active Abandoned
- 2009-02-27 EP EP09757339.8A patent/EP2286240B1/en not_active Not-in-force
-
2014
- 2014-06-27 US US14/316,921 patent/US9052313B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| WO2009146957A1 (en) | 2009-12-10 |
| EP2297582A1 (en) | 2011-03-23 |
| WO2009146956A1 (en) | 2009-12-10 |
| US9052313B2 (en) | 2015-06-09 |
| US20150037823A1 (en) | 2015-02-05 |
| US8771968B2 (en) | 2014-07-08 |
| EP2975411A1 (en) | 2016-01-20 |
| US20110159607A1 (en) | 2011-06-30 |
| DK2286240T3 (en) | 2016-04-11 |
| US20110159514A1 (en) | 2011-06-30 |
| EP2286240A1 (en) | 2011-02-23 |
| EP2286240B1 (en) | 2016-01-06 |
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