Runx1 overexpression induces early onset of intervertebral disc degeneration

Intervertebral disc degeneration (IDD) is closely associated with aging. Although the Runt-related transcription factor 1 (<i>RUNX1</i>) is well known for its role in skeletal development and other musculoskeletal related diseases such as osteoarthritis, its involvement in IDD pathogenesis remains elusive. In this study, we examined the function of <i>Runx1</i> specifically in the nucleus pulposus (NP) <i>in vivo</i>. To achieve NP-specific postnatal overexpression of <i>Runx1</i>, we crossed <i>Krt19</i>^CreERT mice with <i>Rosa26</i>-<i>Runx1</i> transgenic mice previously generated in our laboratory. Mice with NP specific <i>Runx1</i> overexpression displayed early onset and progressive disc degeneration beginning at 5 months of age. This was characterized by a phenotypic shift from notochordal cells to hypertrophic chondrocyte-like cells, accompanied by extracellular matrix remodeling, including reduced expression of aggrecan and type II collagen as well as increased type X collagen. In addition, NP cells from these transgenic mice showed increased expression of senescence markers P16 and P21 without significant changes in apoptosis levels. Notably, the severity of degeneration correlated with the number of tamoxifen injections, suggesting a direct association between the level of <i>Runx1</i> expression and IVD degeneration. Early histological signs of degeneration in <i>Runx1</i> overexpression mice highlighted its potential role as a key IDD initiator. Taken together, these findings reveal a novel role of Runx1 in maintaining disc health and regulating age-related degenerative processes.