LBX1 alters polyamine pathway in adolescent idiopathic scoliosis – a new therapeutic target to mitigate curve progression

Abstract

Background

Adolescent idiopathic scoliosis (AIS) is the most common three-dimensional (3D) spinal deformity occurring during puberty, with girls at a higher risk of curve progression to the surgical threshold. Ladybird homeobox 1 (LBX1) is the most promising AIS predisposing gene based on GWAS studies, but its role in curve progression remains elusive.

Methods

The role of LBX1 in muscle phenotype and curve progression was investigated in clinical samples and mouse models. Additionally, metabolomic analysis was used to explore signaling pathway and potential therapeutic target.

Results

In this study, we found elevated LBX1 and myogenic genes expression, along with increased proportion of type I muscle fibers, in the convex paraspinal muscle (PSM) of AIS patients. Notably, the concave/convex LBX1 ratio in PSM negatively correlates with curve severity. Using a 3D-printed asymmetric hypokyphosing thoracic restrainer, we established AIS-like 3D spinal deformities in young female mice, consistently inducing a thoracic right curve. AAV-mediated Lbx1 knockdown in concave PSM of Lbx1^fl/fl mice exacerbated curve progression by 50%. Mechanistically, Lbx1 knockdown inhibited myogenesis and muscle regeneration, and altered polyamine synthesis pathway. Key polyamine pathway enzymes ODC1 and SAT1 were reduced in concave PSM of AIS patients. The resultant lower serum level of spermidine, a key polyamine metabolite, was found in progressive AIS patients at their initial clinical visits. Importantly, daily spermidine supplementation significantly mitigated curve progression in scoliosis-like mice.

Conclusion

Our findings provide new evidence that differential Lbx1 expression in bilateral PSM exacerbates curve progression. The associated altered polyamine pathway and reduced circulating spermidine level represent novel therapeutic target and prognostic biomarker, respectively.

The translational potential of this article

This study presents a straightforward and reproducible protocol for establishing a mouse model of spinal deformity with consistent curvature pattern for AIS research, and illustrates the potential role of the LBX1-mediated polyamine pathway in driving curve progression in AIS, which can be ameliorated by oral spermidine administration. Our findings highlight the modulation of paraspinal muscles as a viable approach to halting curve progression.