Osteoarthritis (OA) has been considered non-reversible as articular cartilage wears down with limited repair capacity. Enhanced chondrocyte hypertrophy and increased type X collagen gene (

COL10A1

) expression have been associated with OA. Therefore

regulators controlling collagen X expression and chondrocyte hypertrophy may play a role in OA intervention. Here

we investigated how Distal-less homeobox 5 (DLX5)

the distal-less homeobox family member

controls murine

Col10a1

gene expression and chondrocyte hypertrophy in chondrogenic cell models and its role in a murine OA model. Through qRT-PCR and Western blot analyses

we detected significantly increased levels of COL10A1 and DLX5 in hypertrophic MCT and ATDC5 cells compared to their proliferative stage. Forced expression of

Dlx5

further increases

while knockdown of

Dlx5

decreases COL10A1 expression in hypertrophic MCT cells. We have performed dual-luciferase reporter and ChIP assays and demonstrated that DLX5 promotes reporter activity through direct interaction with

Col10a1

cis-enhancer. We established a murine OA model and detected markedly increased COL10A1 and DLX5 in the articular cartilage and subchondral bone of the OA mice compared with the controls. Notably

forced overexpression of DLX5 in hypertrophic MCT cells up-regulates RUNX2

and adjacent DLX5 and RUNX2 binding sites have previously been found within the

Col10a1

cis-enhancer. Together

our data suggest that DLX5 may cooperate with RUNX2 to control cell-specific

Col10a1

expression and chondrocyte hypertrophy and is involved in OA pathogenesis.