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

Zhe Zhang; Yujia Wang; Zongshan Hu; Wenlin Tian; Mengheng Li; Ziyang Tang; Liang Chang; Hok-Him Tang; Gen Tang; Jie Li; Zhichong Wu; Haixia Xu; Elvis Chun-Sing Chui; Zhen Liu; Adam Yiu-Chung Lau; Tsz-Ping Lam; Daniel Kam-Wah Mok; Huanxiong Chen; Yong Qiu; Jack Chun-Yiu Cheng; Zezhang Zhu; Wayne Yuk-Wai Lee

doi:10.1016/j.jot.2026.101063

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

J Orthop Translat. 2026 Feb 25:57:101063. doi: 10.1016/j.jot.2026.101063. eCollection 2026 Mar.

Authors

Zhe Zhang^{1

2

3

4}, Yujia Wang^{1

2

3}, Zongshan Hu⁵, Wenlin Tian⁶, Mengheng Li⁷, Ziyang Tang⁸, Liang Chang², Hok-Him Tang⁷, Gen Tang^{1

2

3}, Jie Li⁵, Zhichong Wu⁵, Haixia Xu⁶, Elvis Chun-Sing Chui², Zhen Liu⁵, Adam Yiu-Chung Lau^{1

2}, Tsz-Ping Lam^{1

2}, Daniel Kam-Wah Mok⁷, Huanxiong Chen⁶, Yong Qiu⁵, Jack Chun-Yiu Cheng^{1

2}, Zezhang Zhu⁵, Wayne Yuk-Wai Lee^{1

2

3}

Affiliations

¹ SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China.
² Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China.
³ Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region of China.
⁴ Department of Orthopaedics, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu Province, China.
⁵ Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
⁶ Department of Spine Surgery, Hainan Province Clinical Medical Center, The First Affiliated Hospital of Hainan Medical University, Haikou, China.
⁷ Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Hong Kong Special Administrative Region of China.
⁸ Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, the Clinical College of Nanjing Medical University, Nanjing, 210008, China.

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.

Keywords: Adolescent idiopathic scoliosis; Animal model; LBX1; Paraspinal muscle; Polyamine pathway; Translational research.