Stanični i molekularni posrednici subhondralnoga koštanoga razaranja u artritisu

doctoral thesis

• Title (english): Cellular and molecular mediators of subchondral bone destruction in arthritis
• Author: Nina Lukač; VIAF: 32161096730629102742
• Mentor: Nataša Kovačić (mentor); MBZ: 236221
• Committee member: Danka Grčević (predsjednik povjerenstva); MBZ: 210400
• Committee member: Alenka Gagro (član povjerenstva); MBZ: 183764
• Committee member: Sabina Rabatić (član povjerenstva); MBZ: 74965
• Granter: University of Zagreb; School of Medicine; Zagreb
• Defense date and country: 2020-10-23, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Anatomy
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Immunology
• Universal decimal classification (UDC): 612 - Physiology

Abstract

Reumatoidni artritis (RA) je kronična sustavna autoimuna bolest koja zahvaća sinovijalne
zglobove te uzrokuje razaranje zglobne hrskavice i kosti, što dovodi do trajne invalidnosti.
Iako postojeća terapija ublažuje tijek bolesti, za liječenje koštanog razaranja nije u potpunosti
učinkovita, a dio bolesnika na terapiju ne odgovara.
Cilj ovog istraživanja bio je u mišjem modelu RA, artritisu potaknutom antigenom (AIA),
uspoređivanjem miševa divljega tipa (WT) s resorptivnim artritisom, te miševa s izbačenim
genom za receptor Fas (Fas –/–), zaštićenih od koštanog gubitka u artritisu, odrediti koja
stanična populacija u zglobovima ili periartikularnoj koštanoj srži posreduje lokalno
razaranje kosti te u toj populaciji odrediti molekularne posrednike koštane resorpcije.
Blaži oblik artritisa u miševa Fas –/– karakteriziran je promijenjenim staničnim sastavom
zglobnog odjeljka. Smanjen je udio zglobnih mijeloidnih (CD11b+Gr-1+) stanica, čije je
nakupljanje u resorptivnom artritisu miševa WT povezano s gubitkom subhondralnih
koštanih gredica i karakterizirano pojačanim izražajem Mid1. Izražaj Mid1 u zglobu povezan
je s intenzitetom artritisa i izražajem proupalnih citokina. In vitro inhibicija Mid1 smanjuje
upalnu aktivaciju stanica urođene imunosti iz koštane srži, a in vivo ublažuje tijek artritisa te
štiti od gubitaka subhondralnih koštanih gredica.
Zaključno, ovo istraživanje opisuje proupalno djelovanje receptora Fas u artritisu putem
novootkrivene signalne osi u kojoj aktivacija Fas na stanicama urođene imunosti potiče
izražaj Mid1, koji potičući razgradnju PP2A pojačava signalizaciju proupalnih citokina i time
omogućuje stvaranje upalnog mikrookoliša koji je nužan za razvoj zglobnog oštećenja.

Abstract (english)

Rheumatoid arthritis is a chronic systemic autoimmune disease affecting synovial joints,
characterized by cartilage and bone destruction, and subsequent permanent disability.
Available therapeutics improve prognosis but have a limited effect on bone destruction.
The aim of this study was to define joint and periarticular bone marrow cell populations and
population-specific molecular mediators driving local bone destruction in a murine model,
antigen induced arthritis (AIA), by comparing wild type (WT) mice with destructive arthritis,
and mice deficient for Fas gene (Fas –/–), protected from subchondral bone loss in AIA.
Ameliorated arthritis in Fas –/– mice is characterized by altered cell population frequencies in
the affected joint. Fas –/– mice lack accumulation of myeloid cells. In WT mice, myeloid cell
accumulation is associated with loss of subchondral bone and is marked by up-regulation of
Mid1 in the joint, which is associated with arthritis intensity. In vitro inhibition of Mid1
decreases inflammatory activation of innate immune cells. In vivo, it attenuates the course of
AIA and protects from subchondral bone loss.
In conclusion, this study describes a proinflammatory effect of Fas in arthritis through
upregulation Mid1, which enhances cytokine secretion and enables development of
microenvironment necessary for development of joint destruction.

• Keywords: Miševi; Životinje; Modeli bolesti; Životinje; Zglobovi; Artritis; reumatoidni; Hrskavica; Kost i kosti; Mijeloidne stanice; Stanice koštane srži; Citokini; Imunitet; urođeni
• Keywords (english): Mice; Animals; Disease Models; Animal; Joints; Arthritis; Rheumatoid; Cartilage; Bone and Bones; Myeloid Cells; Bone Marrow Cells; Cytokines; Immunity; Innate
• Language: croatian
• URN:NBN: urn:nbn:hr:105:300204
• Project: Number: IP-2014-09-7406; Title: Molekularni posrednici koštane resorpcije uvjetovane receptorom Fas u artritisu; Title: Molecular mediators of Fas-driven osteoresorption in arthritis; Acronym: MEFRA; Leader: Nataša Kovačić; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• Project: Number: DOK-2015-10-9897; Title: Molekularni posrednici koštane resorpcije uvjetovane receptorom Fas u artritisu; Title: Molecular mediators of Fas-driven osteoresorption in arthritis; Acronym: MEFRA; Leader: Nataša Kovačić; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: DOK
• Study programme: Title: Biomedicine and Health Sciences; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstvo (doktor/doktorica znanosti, područje biomedicine i zdravstvo)
• Catalog URL: https://katalog.nsk.hr/F/19IT7Y755V1NXQJPHCLYSQGPF6BLAPPF179HQ7FAXXMYBYGMV5-25370?func=find-e&request=Stani%C4%8Dni+i+molekularni+posrednici+subhondralnoga+ko%C5%A1tanoga+razaranja+u+artritisu&find_scan_code=FIND_NAS&adjacent=N&local_base=MF_WEB&x=48&y=18&filter_code_1=WLN&filter_request_1=&filter_code_2=WYR&filter_request_2=&filter_code_3=WYR&filter_request_3=&filter_code_4=WFM&filter_request_4=
• Type of resource: Text
• Extent: 181 str.
• File origin: Born digital
• Access conditions: Open access
• Repository: Dr Med - University of Zagreb School of Medicine Digital Repository
• Created on: 2021-04-08 09:09:38