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

Semaforiinien osuus Sema3 geeniperhe, luokan III semaforiinit) osallistuvat luun homeostaasiin.

https://www.ncbi.nlm.nih.gov/pubmed/28189595/
SEMA3A
SEMA3B säätyy ylös D3 vitamiinista
SEMA3C säätyy ylös D3 vitamiinista
SEMA3D säätyy alas D3 vitamiinsita
SEMA3E indudoituu vahvimmin  D3-vitamiinista
SEMA3F  indusoituu vahvimmin D3 vitamiinista
SEMA3G säätyy alas D3 vitamiinista

J Steroid Biochem Mol Biol. 2017 Oct;173:185-193. doi: 10.1016/j.jsbmb.2017.02.005. Epub 2017 Feb 9.

Class 3 semaphorins are transcriptionally regulated by 1,25(OH)₂D₃ in osteoblasts.

Ryynänen J¹, Kriebitzsch C², Meyer MB³, Janssens I⁴, Pike JW⁵, Verlinden L⁶, Verstuyf A⁷.

Abstract

The vitamin D endocrine system is essential for calcium metabolism and skeletal integrity. 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] regulates bone mineral homeostasis and acts directly on osteoblasts. In the present study we characterized the transcriptional regulation of the class 3 semaphorin (Sema3) gene family by 1,25(OH)₂D₃ in osteoblastic cells.

 Class 3 semaphorins are secreted proteins that regulate cell growth, morphology and migration, and were recently shown to be involved in bone homeostasis. 

 In ST2, MC3T3-E1 and primary calvarial osteoblast cell cultures we found that all members of the Sema3 gene family were expressed, and that Sema3e and Sema3f were the most strongly induced 1,25(OH)₂D₃ target genes among the studied cell types.

 In addition, transcription of Sema3b and Sema3c was upregulated,
whereas Sema3d and Sema3g was downregulated by 1,25(OH)₂D₃ in different osteoblastic cells.

Chromatin immunoprecipitation analysis linked to DNA sequencing (ChIP-seq analysis) revealed the presence of the vitamin D receptor at multiple genomic loci in the proximity of Sema3 genes, demonstrating that the genes are primary 1,25(OH)₂D₃ targets. Furthermore, we showed that recombinant SEMA3E and SEMA3F protein were able to inhibit osteoblast proliferation. However, recombinant SEMA3s did not affect ST2 cell migration. The expression of class 3 semaphorins in osteoblasts together with their regulation by 1,25(OH)₂D₃ suggests that these genes, involved in the regulation of bone homeostasis, are additional mediators for 1,25(OH)₂D₃ signaling in osteoblasts.

Muistiin sematoforiinien  eräästä osuudesta luun homeostaasiin 25.2. 2019
 

Semaforiinien KROMOSOMISIJAINNIT

Kromosomi 1:

SEMA4A (1q22)

SEMA6C (1q21.3)

Kromosomi 2

SEMA4C (3q11.2)

SEMA4F (2p13.1)

Kromosomi 3:

SEMA3B (3p21.31)

SEMA5B, (3q21.1)

SEMA3G (3p21.1)

SEMA3F (3p21.31)

Kromosomi 5:

SEMA5A (5p15.31)

SEMA6A(5q23.1)

Kromosomi 7

SEMA3A (7q21.11)

SEMA3C (7q21.11)

SEMA3E (7q21.11)

SEMA3D (7q21.11)

Kromosomi 9

SEMA4D (9q22.7)

Kromosomi 10

SEMA4G (10q24.31)

Kromosomi 15:

SEJMA6D (15q21.1)

SEMA4B (15q26.1)

Kromosomi 19

SEMA6B (19p13.3)