5’ HOXD genes differentially regulate gene expression of Synovial Fibroblasts in hand joints

We previously demonstrated that Homeobox (HOX) transcription factors are differentially expressed between joint locations and can accurately assign synovial fibroblasts (SFs) to their correct joint location. We show here that the expression of the 5’HOXD transcription factors HOXD10, HOXD11, and HOXD13 in SFs strikingly overlaps with predilection sites for the development of rheumatoid arthritis (RA). Changes in SFs gene expression after silencing 5’HOXDs aligned with joint-specific differences of RA SFs. In particular, we identify HOXD13 as regulator or primary cilia function in SFs modulating cell cycle, DNA damage and proteasome activity. Accordingly, we show joint specific differences in primary cilia morphology, DNA damage repair and proteasome activity. We thus propose that HOXD13 and primary cilia play a role in shaping joint-specific SFs functions that might underlie the pathognomic pattern of joint involvement in RA.