Articular Cartilage Endurance and Resistance to Osteoarthritic Changes Require Transcription Factor Erg

Abstract

Objective To determine whether and how transcription factor Erg participates in the genesis, establishment and maintenance of articular cartilage. Methods Floxed Erg mice were mated with Gdf5-Cre mice to create conditional mutants lacking Erg in their joints. Mutant and control joints were subjected to morphological and molecular characterization and also experimental osteoarthritis (OA) surgery. Gene expression, promoter reporter assays and gain- and loss-of-function in vitro tests were used to characterize molecular mechanisms of Erg action. Results Conditional Erg ablation did not elicit obvious changes in limb joint development and overall phenotype in juvenile mice. Over aging, however, mutant joints became spontaneously deranged and exhibited clear OA-like phenotypic defects. Mutant joints in juvenile mice were more sensitive to surgically induced OA and became defective sooner than operated control joints. Global gene expression data and other studies identified PTHrP and lubricin as possible downstream effectors and mediators of Erg action in articular chondrocytes. Reporter assays using control and mutated promoter/enhancer constructs did indicate that Erg acted on ets DNA binding sites to stimulate PTHrP expression. ERG was up-regulated in severely affected areas in human OA articular cartilage, but remained barely appreciable in less affected cartilage areas. Conclusion The study shows for the first time that Erg is a critical molecular regulator of articular cartilage’s endurance over postnatal life and ability to mitigate spontaneous and experimental OA. Erg appears to do so through its regulation of PTHrP and lubricin expression, factors known for their protective roles in joints.

Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant

“…Our EMSA analyses implicated the Ets family of transcription factors as positive regulators of expression. Members of this family have previously been reported to have a role in OA via regulation of the expression of chondrogenic genes . Detailed analysis of these Ets transcription factors in the context of the ALDH1A2 association signal and ALDH1A2 expression is now warranted.…”

Transcriptional control of chondrocyte specification and differentiation

“…ERG is strongly expressed in PCs and JPs [132]. Its inactivation in JPs ( Gdf5Cre ) does not affect joint formation [133], but its transgenic overexpression ( Col2a1 ) prevents GPC maturation and induces expression of the ACC marker tenascin-C. Interestingly, mice inactivating ERG in JPs develop osteoarthritis as they age and are more sensitive to surgically induced osteoarthritis than wild-type mice. Molecular studies have suggested that the genes for PTHrP and lubricin (encoded by Prg4 , a superficial ACC marker) might be part of the ERG targetome.…”

Building and maintaining joints by exquisite local control of cell fate

“…Cux1 and the C‐1‐1 isoform of the Ets factor Erg are both expressed at developing murine joints and can repress cartilage differentiation upon misexpression. Loss of Erg in Gdf5 + joint precursors did not, however, alter joint specification in mice, although it did lead to increased susceptibility to age‐ and injury‐induced osteoarthritis of the knee . Recent work in zebrafish has found roles for the Iroquois family of transcriptional repressors in joint specification.…”