Creb5 establishes the competence for Prg4 expression in articular cartilage

Abstract

<jats:title>Abstract</jats:title><jats:p>A hallmark of cells comprising the superficial zone of articular cartilage is their expression of lubricin, encoded by the <jats:italic>Prg4</jats:italic> gene, 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 induce <jats:italic>Prg4</jats:italic> expression. 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 induce <jats:italic>Prg4</jats:italic> expression. Chromatin-IP and ATAC-Seq analyses have revealed that Creb5 directly binds to two <jats:italic>Prg4</jats:italic> promoter-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 of <jats:italic>Prg4</jats:italic> by TGF-β. Our results indicate that Creb5 is a critical regulator of <jats:italic>Prg4</jats:italic>/lubricin expression in the articular cartilage.</jats:p>