Parathyroid hormone-related protein is induced by hypoxia and promotes expression of the differentiated phenotype of human articular chondrocytes

Parathyroid hormone-related protein (PTHrP) is crucial for normal cartilage development and long bone growth and acts to delay chondrocyte hypertrophy and terminal differentiation in the growth plate. After growth plate closure adult human articular chondrocytes still produce PTHrP suggesting a possible role for this factor in the permanent articular cartilage. However, the expression regulation and function of PTHrP in the permanent articular cartilage is unknown. Human articular cartilage is an avascular tissue and functions in a hypoxic environment. The resident chondrocytes have adapted to hypoxia and use it to drive their tissue-specific functions. Here we explored directly in normal articular chondrocytes isolated from a range of human donors the effect of hypoxia on PTHrP expression and whether PTHrP can regulate expression of the permanent articular chondrocyte phenotype. We show that in human articular chondrocytes PTHrP is upregulated by hypoxia in a HIF-1α and HIF-2α dependent manner. Using recombinant PTHrP, siRNA-mediated depletion of endogenous PTHrP and by blocking signaling through its receptor (PTHR1), we show that hypoxia-induced PTHrP is a positive regulator of the key cartilage transcription factor SOX9, leading to increased COL2A1 expression. Our findings thus identify PTHrP as a potential factor for cartilage repair therapies through its ability to promote the differentiated human articular chondrocyte phenotype.
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research