| Autor: |
Hao Yu, Anas M. Khanshour, Aki Ushiki, Nao Otomo, Yoshinao Koike, Elisabet Einarsdottir, Yanhui Fan, Lilian Antunes, Yared H. Kidane, Reuel Cornelia, Rory Sheng, Yichi Zhang, Jimin Pei, Nick V. Grishin, Bret M. Evers, Jason Pui Yin Cheung, John A. Herring, Chikashi Terao, You-Qiang Song, Christina A. Gurnett, Paul Gerdhem, Shiro Ikegawa, Jonathan J. Rios, Nadav Ahituv, Carol A. Wise |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
bioRxiv |
| Popis: |
Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than five-fold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near thePAX1gene. Here we sought to define the roles ofPAX1and newly-identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 9,161 individuals with AIS and 80,731 unaffected controls, significant association was identified with a variant inCOL11A1encoding collagen (α1) XI (rs3753841; NM_080629_c.4004C>T; p.(Pro1335Leu); P=7.07e−11, OR=1.118). Using CRISPR mutagenesis we generatedPax1knockout mice (Pax1−/−). In postnatal spines we found that Pax1 and collagen (α1) XI protein both localize within the intervertebral disc (IVD)-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected inPax1−/−spines compared to wildtype. By genetic targeting we found that wildtypeCol11a1expression in growth plate cells (GPCs) suppresses expression ofPax1and ofMmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, this suppression was abrogated in the presence of the AIS-associatedCOL11A1P1335Lmutant. Further, we found that either knockdown of the estrogen receptor geneEsr2, or tamoxifen treatment, significantly alteredCol11a1andMmp3expression in GPCs. These studies support a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering aPax1-Col11a1-Mmp3signaling axis in the growth plate. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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