Abstract
Adolescent Idiopathic Scoliosis (AIS) is the most common form of spinal deformity among adolescents. To explore its etiology of progression and scoliosis-modifying drugs, chondrocytic senescence was confirmed in AIS facet joint cartilage by analyzing clinical specimen. Furthermore, through 4D/480 label-free proteomics analysis, we identified an exosome-mediated positive feedback loop during scoliosis progression, which driving the elevation of cholesterol flow between spinal cartilage and vertebra. To further investigate the pathological significance of the loop in vivo, high-cholesterol flow was reconstructed in C57BL/6 J mice by injecting with recombinant adeno-associated virus rAAV9-Runx2-HMGCR. Our results confirmed the important role of the positive feedback loop in the development of scoliosis. Meanwhile, Avasimibe or/and Corylin were used to delay the scoliosis progression by targeting the key exosomal proteins APOB (Apolipoprotein B-100) or/and HSP90β (Heat Shock Protein 90-beta). This research extends the etiology of scoliosis progression and provides an alternative perspective for scoliosis non-surgical treatment.
Data availability
The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository (accession: PXD070507, https://www.iprox.cn/page/PSV023.html;?url=177280350316<div class="pi">show [QJ]3kMce, Password: HqjF). The newly generated plasmid ID number is GV657 from GENECHEM. The source data underlying the graphs presented in the main figures can be obtained from Supplementary Data 1. Uncropped and unedited western blot images can be obtained from Supplementary information file (Supplementary Figs. 9–33). All other data are available from the corresponding author on reasonable request.
References
Cheng, J. C. et al. Adolescent idiopathic scoliosis. Nat. Rev. Dis. Prim. 1, 1–20 (2015).
Xu, S. et al. Distribution of scoliosis in 2.22 million adolescents in mainland China: a population-wide analysis. J. Glob. Health 14, 04117 (2024).
Campbell, M. et al. Burden of care in families of patients with early onset scoliosis. J. Pediatr. Orthop. B 29, 567–571 (2019).
Chen, F. et al. Compressive stress induces spinal vertebral growth plate chondrocytes apoptosis via Piezo1. J. Orthop. Res. 41, 1792–1802 (2023).
Yu, H. et al. Association of genetic variation in with adolescent idiopathic scoliosis. Elife 12, RP89762 (2024).
Iwahashi, S. et al. Conditional inactivation of the L-type amino acid transporter lat1 in chondrocytes models idiopathic scoliosis in mice. J. Cell Physiol. 237, 4292–4302 (2022).
Yahara, Y. et al. Asymmetric load transmission induces facet joint subchondral sclerosis and hypertrophy in patients with idiopathic adolescent scoliosis: evaluation using finite element model and surgical specimen. JBMR Plus https://doi.org/10.1002/jbm4.10812 (2023).
Bisson, D. G. et al. Axial rotation and pain are associated with facet joint osteoarthritis in adolescent idiopathic scoliosis. Osteoarthr. Cartil. 31, 1101–1110 (2023).
Zhang, H. et al. Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating fbxw7. Ann. Rheum. Dis. 81, 676–686 (2022).
Bisson, D. G. et al. Toll-like receptor involvement in adolescent scoliotic facet joint degeneration. J. Cell. Mol. Med. 24, 11355–11365 (2020).
Zhao, C., Zhu, S. Q., Liang, Y. & Xu, S. Asymmetric osteopenia in adolescent idiopathic scoliosis based on Hounsfield unit of computed tomography. Int. J. Gen. Med. 17, 3945–3953 (2024).
Yang, D. B. et al. Progress, opportunity, and perspective on exosome isolation— efforts for efficient exosome-based theranostics. Theranostics 10, 3684–3707 (2020).
Tan, F. et al. Clinical applications of stem cell-derived exosomes. STTT https://doi.org/10.1038/s41392-023-01704-0 (2024).
Cheng, H. M. et al. Hsp90β promotes osteoclastogenesis by dual-activation of cholesterol synthesis and nf-κb signaling. Cell Death Differ. 30, 673–686 (2023).
Akhmetshina, A., Kratky, D. & Rendina-Ruedy, E. Influence of cholesterol on the regulation of osteoblast function. Metabolites 13, 578 (2023).
Duan, Y. J. et al. Regulation of cholesterol homeostasis in health and diseases: From mechanisms to targeted therapeutics. STTT 7, 265 (2022).
He, Y. et al. Flipped c-terminal ends of apoa1 promote abca1-dependent cholesterol efflux by small HDLs. Circulation 149, 774–787 (2023).
Zimetti, F., Weibel, G. K., Duong, M. & Rothblat, G. H. Measurement of cholesterol bidirectional flux between cells and lipoproteins. J. Lipid Res. 47, 605–613 (2006).
Choi, W. S. et al. The ch25h-cyp7b1-rorα axis of cholesterol metabolism regulates osteoarthritis. Nature 566, 254–258 (2019).
Papathanasiou, I., Anastasopoulou, L. & Tsezou, A. Cholesterol metabolism related genes in osteoarthritis. Bone 152, 116076 (2021).
Roh, K. et al. Lysosomal control of senescence and inflammation through cholesterol partitioning. Nat. Metab. 5, 398–413 (2023).
Taghibiglou, C., Iderstine, S. C. V., Kulinski, A., Rudy, D. & Adeli, K. Intracellular mechanisms mediating the inhibition of apob-containing lipoprotein synthesis and secretion in HepG2 cells by avasimibe (ci-1011), a novel acyl-coenzyme a: Cholesterol acyltransferase (acat) inhibitor. Biochem. Pharmacol. 63, 349–360 (2002).
G. Bisson, D. et al. Facet joint degeneration in adolescent idiopathic scoliosis. Jor Spine 1, 1–11 (2018).
Margulies, J. Y. et al. The relationship between degenerative changes and osteoporosis in the lumbar spine. Clin. Orthop. Relat. Res. 324, 145–152 (1996).
Kurban M, E. F. J. & Hamie L. Nsdhl-related disorders. In: (eds Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A) GeneReviews®. (University of Washington, Seattle, 1993–2025). Updated 2024 Sep 5.
Bibi, H. et al. Molecular and computational analysis of a novel pathogenic variant in involved in cholesterol biosynthetic pathway causing a rare male EBP disorder with neurologic defects (Mend syndrome). Mol. Biol. Rep. 52, 101 (2025).
Haller, G. et al. A missense variant in is associated with severe idiopathic scoliosis. Nat. Commun. 9, 4171 (2018).
Waterworth, D. M. et al. Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 30, 2264–2276 (2010).
Emmert-Streib, F. et al. Graphical modeling of gene expression in monocytes suggests molecular mechanisms explaining increased atherosclerosis in smokers. PLoS ONE 8, e50888 (2013).
van Vliet-Ostaptchouk, J. V. et al. Pleiotropic effects of obesity-susceptibility loci on metabolic traits: a meta-analysis of up to 37,874 individuals. Diabetologia 56, 2134–2146 (2013).
Nebert, D. W. & Liu, Z. J. Slc39a8 gene encoding a metal ion transporter: Discovery and bench to bedside. Hum. Genomics 13, 51 (2019).
Liu, H. et al. Integrated analysis of summary statistics to identify pleiotropic genes and pathways for the comorbidity of schizophrenia and cardiometabolic disease. Front Psychiatry 11, 256 (2020).
Zhang, J., Yu, Y., Pan, L. L., Yu, T. H. & Luo, G. H. C deletion at the re74650330 locus of the gene(rs74650330) increases the risk of coronary artery disease in individuals with low-density lipoprotein cholesterol levels. Genet. Test. Mol. Biomarkers 25, 660–667 (2021).
Zhao, F. R. et al. Identification of zip8-correlated hub genes in pulmonary hypertension by informatic analysis. Peerj 11, e15939 (2023).
Fanelli, G. et al. Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditions. Transl. Psychiatry 15, 145 (2025).
Beverley, K. M. & Levitan, I. Cholesterol regulation of mechanosensitive ion channels. Front. Cell Dev. Biol. 12, 1352259 (2024).
Ramli, Aramaki, T., Watanabe, M. & Kondo, S. Piezo1 mutant zebrafish as a model of idiopathic scoliosis. Front. Gene.t 14, 1321379 (2024).
Lau, K. K. L., Law, K. K. P., Kwan, K. Y. H., Cheung, J. P. Y. & Cheung, K. M. C. Proprioception-related gene mutations in relation to the aetiopathogenesis of idiopathic scoliosis: a scoping review. J. Orthop. Res. 41, 2694–2702 (2023).
Chen, F. et al. Piezo1-primary cilia axis mediates compressive stress-induced growth plate degeneration and ossification in adolescent idiopathic scoliosis. Jor Spine https://doi.org/10.1002/jsp2.70133 (2025).
Chen, F. et al. Piezo1-gpx4 axis mediates mechanical stress-induced vertebral growth plate dysplasia via ferroptosis activation. Adv Sci https://doi.org/10.1002/advs.202502052 (2025).
Wang, L. et al. Mechanical sensing protein piezo1 regulates bone homeostasis via osteoblast-osteoclast crosstalk. Nat. Commun. 11, 282 (2020).
Wai, M. G. C. et al. A review of pinealectomy-induced melatonin-deficient animal models for the study of etiopathogenesis of adolescent idiopathic scoliosis. IJMS 15, 16484–16499 (2014).
Wu, T. et al. Role of enhanced central leptin activity in a scoliosis model created in bipedal amputated mice. Spine 40, E1041–E1045 (2015).
McCallum-Loudeac, J. et al. Deletion of a conserved genomic region associated with adolescent idiopathic scoliosis leads to vertebral rotation in mice. Hum. Mol. Genet. 33, 787–801 (2024).
John, A. A. et al. Aav-mediated delivery of osteoblast/osteoclast-regulating miRNAs for osteoporosis therapy. Mol. Ther. Nucl. Acids 29, 296–311 (2022).
Yang, Y. S. et al. Bone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis. Nat. Commun. 10, 2958 (2019).
Jin, L. Y. et al. Long-term whole-body vibration induces degeneration of intervertebral disc and facet joint in a bipedal mouse model. Front. Biog. Biotech. 11, 1069568 (2023).
Ao, X. et al. Development and characterization of a novel bipedal standing mouse model of intervertebral disc and facet joint degeneration. Clin. Orthop. Relat. Res. 477, 1492–1504 (2019).
Ao, X. et al. Angiopoietin-2 promotes mechanical stress-induced extracellular matrix degradation in annulus fibrosus the hif-1α/nf-κb signaling pathway. Orthop. Surg. 15, 2410–2422 (2023).
Acknowledgements
This work was supported by the National Natural Science Foundation of China (grant numbers 82160425, 82160435, and 82360439), the Academic Enhancement Support Program of Hainan Medical University, China (XSTS2025087, XSTS2025065), and the Hainan Province Clinical Medical Center.
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Min Zuo, Haixia Xu, and Yuying Yang: Investigation, Validation, Data curation, Formal analysis. Wenbo Wang, Jianghong Zhou, and Guojun Li: Validation, Data curation, Resources. Jing Zhao: Validation, Data curation. Rangru Liu: Writing—original draft. Huanxiong Chen: Resources, Funding acquisition. Hua Wang: Conceptualization, Writing-review & editing, Supervision, Project administration, Funding acquisition.
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Communications Biology thanks Po-Chih Shen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ophelia Bu. A peer review file is available.
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Zuo, M., Xu, H., Yang, Y. et al. Exosome-mediated cholesterol flow drives scoliosis progression via promoting the spinal cartilage-bone positive feedback. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09960-w
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DOI: https://doi.org/10.1038/s42003-026-09960-w
