Paper - Review

DOI: 10.1038/s41586-020-2222-z

Abstract

The synovium
→ is a mesenchymal tissue ← composed mainly of fibroblasts
← with (a lining & sub-lining) ← that surround the joints

The synovial tissues
← in rheumatoid arthritis
→ 1⃣ undergoes (marked hyperplasia) 2⃣ becomes → inflamed & invasive 3⃣ destroys → the joint

A subset of fibroblasts ← in the sub-lining
→ undergoes → a major expansion ← in rheumatoid arthritis
→ that is linked → to disease activity

❓: the molecular mechanism
← by by which these fibroblasts → differentiate & expand
→ is unknown

Identify → a critical role → for NOTCH3 signalling
← in the differentiation of 1⃣ perivascular 2⃣ sub-lining fibroblasts
← that express CD90

NOTCH3 signalling
→ drives → both 1⃣ transcriptional 2⃣ spatial gradients
← emanating ← from vascular endothelial cells outwards
← in fibroblasts

1⃣ NOTCH3 2⃣ Notch target genes
→ are markedly up-regulated ← in synovial fibroblasts
← in active rheumatoid arthritis

1⃣ the genetic deletion ← of Notch3 2⃣ the blockade of NOTCH3 signalling
→ attenuates inflammation
→ prevents joint damage ← in inflammatory arthritis

❗: synovial fibroblasts
→ exhibits → a positional identity
← that is regulated ← by endothelium-derived Notch signalling

❗: this stromal crosstalk pathway
→ underlies → inflammation & pathology
← in inflammatory arthritis

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