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Association of an e...
Association of an estrogen-sensitive Pax1-Col11a1-Mmp3 signaling axis with adolescent idiopathic scoliosis.
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Yu, Hao (författare)
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Khanshour, Anas M (författare)
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Ushiki, Aki (författare)
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visa fler...
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Otomo, Nao (författare)
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Koike, Yoshinao (författare)
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- Einarsdottir, Elisabet (författare)
- KTH,Genteknologi,Science for Life Laboratory, SciLifeLab
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Fan, Yanhui (författare)
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Antunes, Lilian (författare)
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Kidane, Yared H (författare)
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Cornelia, Reuel (författare)
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Sheng, Rory (författare)
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Zhang, Yichi (författare)
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Pei, Jimin (författare)
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Grishin, Nick V (författare)
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Evers, Bret M (författare)
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Yin Cheung, Jason Pui (författare)
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Herring, John A (författare)
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Terao, Chikashi (författare)
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Song, You-Qiang (författare)
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Gurnett, Christina A (författare)
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Gerdhem, Paul (författare)
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Ikegawa, Shiro (författare)
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Rios, Jonathan J (författare)
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Ahituv, Nadav (författare)
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Wise, Carol A (författare)
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(creator_code:org_t)
- 2023
- Engelska.
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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 9,161 individuals with AIS and 80,731 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629_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 (α1) XI protein both localize within the intervertebral disc (IVD)-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1 -/- spines compared to wildtype. By genetic targeting we found that wildtype Col11a1 expression in growth plate cells (GPCs) 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 COL11A1 P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2 , or tamoxifen treatment, significantly altered Col11a1 and Mmp3 expression in GPCs. These studies support 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 the growth plate.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Ortopedi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Orthopaedics (hsv//eng)
Publikations- och innehållstyp
- vet (ämneskategori)
- ovr (ämneskategori)
- Av författaren/redakt...
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Yu, Hao
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Khanshour, Anas ...
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Ushiki, Aki
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Otomo, Nao
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Koike, Yoshinao
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Einarsdottir, El ...
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visa fler...
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Fan, Yanhui
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Antunes, Lilian
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Kidane, Yared H
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Cornelia, Reuel
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Sheng, Rory
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Zhang, Yichi
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Pei, Jimin
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Grishin, Nick V
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Evers, Bret M
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Yin Cheung, Jaso ...
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Herring, John A
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Terao, Chikashi
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Song, You-Qiang
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Gurnett, Christi ...
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Gerdhem, Paul
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Ikegawa, Shiro
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Rios, Jonathan J
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Ahituv, Nadav
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Wise, Carol A
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Ortopedi
- Av lärosätet
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Kungliga Tekniska Högskolan