Hematopoietic PBX-interacting protein mediates cartilage degeneration during the pathogenesis of osteoarthritis

<jats:title>Abstract</jats:title><jats:p>Osteoarthritis (OA) has been recognized as the most common chronic age-related disease. Cartilage degeneration influences OA therapy. Here we report that hematopoietic pre-B cell leukemia transcription factor-interacting protein (<jats:italic>HPIP</jats:italic>) is essential for OA development. Elevated <jats:italic>HPIP</jats:italic> levels are found in OA patients. <jats:italic>Col2a1-CreER</jats:italic><jats:sup><jats:italic>T2</jats:italic></jats:sup><jats:italic>/HPIP</jats:italic><jats:sup>f/f</jats:sup> mice exhibit obvious skeletal abnormalities compared with their <jats:italic>HPIP</jats:italic><jats:sup>f/f</jats:sup> littermates. <jats:italic>HPIP</jats:italic> deficiency in mice protects against developing OA. Moreover, intra-articular injection of adeno-associated virus carrying <jats:italic>HPIP</jats:italic>-specific short hairpin RNA in vivo attenuates OA histological signs. Notably, in vitro RNA-sequencing and chromatin immunoprecipitation sequencing profiles identify that <jats:italic>HPIP</jats:italic> modulates OA cartilage degeneration through transcriptional activation of <jats:italic>Wnt</jats:italic> target genes. Mechanistically, <jats:italic>HPIP</jats:italic> promotes the transcription of <jats:italic>Wnt</jats:italic> targets by interacting with lymphoid enhancer binding factor 1 (<jats:italic>LEF1</jats:italic>). Furthermore, <jats:italic>HPIP</jats:italic> potentiates the transcriptional activity of <jats:italic>LEF1</jats:italic> and acetylates histone H3 lysine 56 in the promoters of <jats:italic>Wnt</jats:italic> targets, suggesting that <jats:italic>HPIP</jats:italic> is an attractive target in OA regulatory network.</jats:p>