Creb5 establishes the competence forPrg4expression in articular cartilage

Abstract

AbstractA hallmark of cells comprising the superficial zone of articular cartilage is their expression of lubricin, encoded by thePrg4gene, that lubricates the joint and protects against the development of arthritis. Here, we identify Creb5 as a transcription factor that is specifically expressed in superficial zone articular chondrocytes and is required for TGF-β and EGFR signaling to inducePrg4expression. Notably, forced expression of Creb5 in chondrocytes derived from the deep zone of the articular cartilage confers the competence for TGF-β and EGFR signals to inducePrg4expression. Chromatin-IP and ATAC-Seq analyses have revealed that Creb5 directly binds to twoPrg4promoter-proximal regulatory elements, that display an open chromatin conformation specifically in superficial zone articular chondrocytes; and which work in combination with a more distal regulatory element to drive induction ofPrg4by TGF-β. Our results indicate that Creb5 is a critical regulator ofPrg4/lubricin expression in the articular cartilage.