SEMA4A ja osteoartroosi

https://www.ncbi.nlm.nih.gov/pubmed/30685700

Nyt on Sema4A todettu uudeksi NF-kB-.stä riippuvien katabolisten tapahtumien säätelijäksi kondrosyyteissä ja tämä saattaa olla osteoartriitin patogeneesin taustalla.   Sema4A aktivoi NFkB tekijää  kiihdyttämällä Rac1/AKT- riippuvaista IkBalfa fosforylaatiota ja  siitä seuraavaa hajoittamista. NF-kB-aktivaatio taas vaaditaan Sema4A:n ylössöätymiseen.  Sema4A:n ylössäätymistä välittävä interleukiini on IL-1beta. IL-1beta omaa katabolista vaikutusta  kondrosyytteihin ja Sema4A vielä pahentaa tätä vaikutusta johtuen lisääntyneestä NFkB aktivaatiosta. NF-kB inhibitio taas  lieventää tilannetta ja poistaa IL-beta-vaikutuksen.

Int Immunopharmacol. 2019 Jan 24;69:88-94. doi: 10.1016/j.intimp.2019.01.006. [Epub ahead of print]

Semaphorin 4A acts in a feed-forward loop with NF-κB pathway to exacerbate catabolic effect of IL-1β on chondrocytes.

Zhang H¹, Wei Q², Xiang X¹, Zhou B¹, Chen J¹, Li J¹, Li Q¹, Xiong H¹, Liu F¹.

Abstract

Inflammation is fundamental in osteoarthritis (OA) pathogenesis. Semaphorin 4A (Sema4A) has been implicated in immune-associated diseases, however, its role in OA remains unclear. In this study, we show that Sema4A is upregulated in knee OA articular cartilage as well as in chondrocytes exposed to IL-1β treatment in vitro. Moreover, IL-1β-induced Sema4A upregulation is abrogated in the presence of BAY 11-7082, a specific inhibitor of NF-κB pathway, suggesting that the activation of NF-κB is required for Sema4A upregulation under this pathological condition. Intriguingly, Sema4A in turn activates NF-κB through facilitating Rac1/AKT-dependent IκBα phosphorylation and subsequent degradation. Functionally, Sema4A aggravates the catabolic effect of IL-1β on chondrocytes, which can be largely attributed to exacerbated NF-κB activation, since NF-κB inhibition remarkably abolishes this effect. In conclusion, our study suggests that Sema4A is a novel regulator of NF-κB-dependent catabolic events in chondrocytes, which may underlie OA pathogenesis.

Copyright © 2019. Published by Elsevier B.V.

KEYWORDS:

Chondrocyte catabolism; IL-1β; NF-κB; Osteoarthritis; Semaphorin 4A

PMID:

30685700

DOI:

10.1016/j.intimp.2019.01.006