Karakterizacija reakcije osteoklastnih progenitora i pojačane osteoresorpcije u mišjem modelu reumatoidnoga artritisa [Characterization of osteoclast progenitor responses and increased osteoresorption in mouse model of rheumatoid arthritis]

Flegar, Darja (2019) Karakterizacija reakcije osteoklastnih progenitora i pojačane osteoresorpcije u mišjem modelu reumatoidnoga artritisa [Characterization of osteoclast progenitor responses and increased osteoresorption in mouse model of rheumatoid arthritis]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Osteoclasts, specialized bone resorbing cells of hematopoietic origin, become overactive in rheumatoid arthritis, leading to bone loss and joint destruction. Osteoclast progenitor cells (OCP) arise from myeloid precursors of monocyte/macrophage lineage and are normally present in the bone marrow and among circulatory monocytes. Under inflammatory conditions their subpopulations get attracted to inflamed sites by yet unknown mechanisms and chemotactic signals. Here, we investigated frequencies and chemokine receptor expression of OCP subpopulations in circulation and periarticular bone marrow (PBM) of C57BL/6 mice with collagen induced arthritis (CIA). We found both lymphoid-negative CD45+CD11b+CD115+ and lymphoid-negative CD45+CD11b-/loCD115+ subsets of OCPs to be increased in blood and PBM of affected joints in CIA. Chemokine receptors were increasingly expressed by both mentioned OCP subsets in CIA, with substantial expression of CCR2 and CX3CR1, and lower expression of CCR1, CCR3, CCR5, CCR9 and CXCR4. CCL2 serum levels, and gene expression for TNF-α, IL-1β, IL-6 and CCL2 in affected areas and spleen were significantly increased in CIA. PBM population of OCP increasingly migrated toward CCL2 chemotactic gradient, whereas down-regulation of CCR2 expression by siRNA significantly reduced the migration potential. Intravascular in vivo staining demonstrated increased recirculation of CD45+CD11b+ cells through PBM and hind paws in CIA, with the ability of tissue homing after adoptive transfer. These results suggest that highly induced OCP subpopulations in CIA migrate to inflamed joints due to chemotaxis and therefore blocking of chemokine signaling may reduce osteoclast activity in arthritis.

Abstract in Croatian

Osteoklasti, stanice hematopoetskog podrijetla specijalizirane za resorpciju kosti, pojačano su aktivni u reumatoidnom artritisu, dovodeći do gubitka kosti i razaranja zglobova. Osteoklastni progenitori (OCP) potječu iz mijeloidnih progenitora monocitno/makrofagne loze te su normalno prisutni u koštanoj srži i među cirkulirajućim monocitima. U upalnim uvjetima, zasad još nedovoljno razjašnjeni mehanizmi i kemotaktični signali privlače subpopulacije OCP na mjesta upale. U ovom radu istražili smo brojnost i izražaj kemokinskih receptora na subpopulacijama OCP u cirkulaciji i periartikularnoj koštanoj srži (PBM) C57Bl/6 miševa s artritisom potaknutim kolagenom (CIA). Uočili smo da su subpopulacije CD3-B220-NK1.1-CD45+CD11b+CD115+ i CD3-B220-NK1.1-CD45+CD11b-/loCD115+ povećane brojnosti u krvi i PBM zahvaćenih zglobova u CIA, sa značajnim izražajem CCR2 i CX3CR1, te slabijim izražajem CCR1, CCR3, CCR5, CCR9 i CXCR4. Serumska koncentracija CCL2 i genski izražaj TNF-α, IL-1β, IL-6 te CCL2 značajno su povećani u zahvaćenim područjima i slezeni u CIA. Subpopulacija OCP iz PBM pojačano migrira prema CCL2-kemotaktičnom gradijentu, dok utišavanje CCR2, uporabom siRNA, smanjuje njezin migracijski potencijal. Intravaskularno in vivo bojenje pokazuje povećanu recirkulaciju CD45+CD11b+ stanica kroz PBM i stražnje šape u CIA, sa sposobnošću navođenja u tkiva nakon adoptivnog transfera. Ovi rezultati sugeriraju mogućnost privlačenja umnožene OCP-subpopulacije u upaljene zglobove kemokinima, stoga blokada kemokinske signalizacije predstavlja obećavajući terapijski pristup za smanjenje osteoklastne aktivnosti u artitisu.

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