Bulk RNA sequencing of primary osteoblasts harvested from matched convex, concave, and non-curve vertebral sites in adolescent idiopathic scoliosis (AIS) patients revealed distinct transcriptional profiles clustering by anatomical location — independent of patient-specific variables. The mTOR pathway emerged as among the most dysregulated, with convex osteoblasts showing elevated mTOR expression yet paradoxically reduced downstream translation signalling, suggesting an uncoupled rather than simply overactive pathway. Rapamycin suppressed alkaline phosphatase activity, osteoprotegerin secretion, and mineralization while sustaining RUNX2 and COL1A1 upregulation, with convex AIS cells showing amplified sensitivity to mTOR inhibition versus controls. Critically, mTOR expression magnitude correlated directly with Cobb angle severity.
AIS affects 2–3% of adolescents, yet its molecular drivers remain poorly characterized despite decades of research. This study's site-matched osteoblast design is methodologically elegant — controlling for systemic confounders while isolating local mechanobiological differences. The uncoupled mTOR phenotype is a genuinely novel mechanistic observation: elevated receptor expression without proportional downstream output implies pathway dysregulation beyond simple overactivation, possibly involving feedback inhibition or scaffold protein dysfunction. Rapamycin's complex dual effects — suppressing mineralization while sustaining osteogenic transcription factors — caution against straightforward therapeutic translation. This is human primary cell data, which adds clinical relevance, but sample sizes in scoliosis surgical cohorts are inherently small. Overall, this represents a meaningful mechanistic advance that repositions mTOR as a site-specific driver of curve progression rather than a systemic skeletal regulator.