Association of an estrogen-sensitive Pax1-Col11a1-Mmp3 signaling axis with adolescent idiopathic scoliosis

Wise, C.; Yu, H.; Khanshour, A. M.; Ushiki, A.; Otomo, N.; Koike, Y.; Einarsdottir, E.; Fan, Y.; Antunes, L.; Kidane, Y. H.; Sheng, R.; Zhang, Y.; Pei, J.; Grishin, N. V.; Evers, B. M. V.; Cheung, J. P. Y.; Herring, J. A.; Terao, C.; Song, Y.-Q.; Gurnett, C.; Gerdhem, P.; Ikegawa, S.; Rios, J. J.; Ahituv, N.

doi:10.1101/2023.05.26.542293

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bioRxiv · 10.1101/2023.05.26.542293

Association of an estrogen-sensitive Pax1-Col11a1-Mmp3 signaling axis with adolescent idiopathic scoliosis

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Abstract

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 the PAX1 gene. Here we sought to define the roles of PAX1 and newly-identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); P=7.07e-11, OR=1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1-/-). In postnatal spines we found that PAX1 and collagen (1) XI protein both localize within the intervertebral disc (IVD)-vertebral junction region encompassing the growth plate, with less collagen (1) XI detected in Pax1-/- spines compared to wildtype. By genetic targeting we found that wildtype Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, this suppression was abrogated in the presence of the AIS-associated COL11A1P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2, or tamoxifen treatment, significantly altered Col11a1 and Mmp3 expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a Pax1-Col11a1-Mmp3 signaling axis in spinal chondrocytes.

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Wise, C., Yu, H., Khanshour, A. M., Ushiki, A., Otomo, N., Koike, Y., Einarsdottir, E., Fan, Y., Antunes, L., Kidane, Y. H., Sheng, R., Zhang, Y., Pei, J., Grishin, N. V., Evers, B. M. V., Cheung, J. P. Y., Herring, J. A., Terao, C., Song, Y.-Q., Gurnett, C., Gerdhem, P., Ikegawa, S., Rios, J. J., Ahituv, N.. 2023-05-27. Association of an estrogen-sensitive Pax1-Col11a1-Mmp3 signaling axis with adolescent idiopathic scoliosis. https://doi.org/10.1101/2023.05.26.542293

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