Role of IL3RA in a Family with Lumbar Spinal Stenosis

Lumbar spinal stenosis (LSS) is a degenerative spinal condition characterized by the narrowing of the spinal canal, resulting in low back pain (LBP) and limited leg mobility. Twin and family studies have suggested that genetics contributes to disease progression. However, the genetic causes of familial LSS remain unclear. We performed whole-exome and direct sequencing on seven female patients from a Han Chinese family with LBP, among whom four developed LSS. Based on our genetic findings, we performed gene knockdown studies in human chondrocytes to study possible pathological mechanisms underlying LSS. We found a novel nonsense mutation, c.417C > G (NM_002183, p.Y139X), in <i>IL3RA</i>, shared by all the LBP/LSS cases. Knockdown of <i>IL3RA</i> led to a reduction in the total collagen content of 81.6% in female chondrocytes and 21% in male chondrocytes. The expression of <i>MMP-1</i>, <i>-3</i>, and/or <i>-10</i> significantly increased, with a more pronounced effect observed in females than in males. Furthermore, <i>EsRb</i> expression significantly decreased following <i>IL3RA</i> knockdown. Moreover, the knockdown of <i>EsRb</i> resulted in increased <i>MMP-1</i> and <i>-10</i> expression in chondrocytes from females. We speculate that <i>IL3RA</i> deficiency could lead to a reduction in collagen content and intervertebral disk (IVD) strength, particularly in females, thereby accelerating IVD degeneration and promoting LSS occurrence. Our results illustrate, for the first time, the association between <i>IL3RA</i> and estrogen receptor beta, highlighting their importance and impact on MMPs and collagen in degenerative spines in women.