Search: onr:"swepub:oai:DiVA.org:kth-333832" >
Association of an e...
Association of an estrogen-sensitive Pax1-Col11a1-Mmp3 signaling axis with adolescent idiopathic scoliosis.
-
Yu, Hao (author)
-
Khanshour, Anas M (author)
-
Ushiki, Aki (author)
-
show more...
-
Otomo, Nao (author)
-
Koike, Yoshinao (author)
-
- Einarsdottir, Elisabet (author)
- KTH,Genteknologi,Science for Life Laboratory, SciLifeLab
-
Fan, Yanhui (author)
-
Antunes, Lilian (author)
-
Kidane, Yared H (author)
-
Cornelia, Reuel (author)
-
Sheng, Rory (author)
-
Zhang, Yichi (author)
-
Pei, Jimin (author)
-
Grishin, Nick V (author)
-
Evers, Bret M (author)
-
Yin Cheung, Jason Pui (author)
-
Herring, John A (author)
-
Terao, Chikashi (author)
-
Song, You-Qiang (author)
-
Gurnett, Christina A (author)
-
Gerdhem, Paul (author)
-
Ikegawa, Shiro (author)
-
Rios, Jonathan J (author)
-
Ahituv, Nadav (author)
-
Wise, Carol A (author)
-
show less...
-
(creator_code:org_t)
- 2023
- English.
- Related links:
-
https://urn.kb.se/re...
-
show more...
-
https://doi.org/10.1...
-
show less...
Abstract
Subject headings
Close
- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Ortopedi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Orthopaedics (hsv//eng)
Publication and Content Type
- vet (subject category)
- ovr (subject category)
To the university's database
- By the author/editor
-
Yu, Hao
-
Khanshour, Anas ...
-
Ushiki, Aki
-
Otomo, Nao
-
Koike, Yoshinao
-
Einarsdottir, El ...
-
show more...
-
Fan, Yanhui
-
Antunes, Lilian
-
Kidane, Yared H
-
Cornelia, Reuel
-
Sheng, Rory
-
Zhang, Yichi
-
Pei, Jimin
-
Grishin, Nick V
-
Evers, Bret M
-
Yin Cheung, Jaso ...
-
Herring, John A
-
Terao, Chikashi
-
Song, You-Qiang
-
Gurnett, Christi ...
-
Gerdhem, Paul
-
Ikegawa, Shiro
-
Rios, Jonathan J
-
Ahituv, Nadav
-
Wise, Carol A
-
show less...
- About the subject
-
- MEDICAL AND HEALTH SCIENCES
-
MEDICAL AND HEAL ...
-
and Clinical Medicin ...
-
and Orthopaedics
- By the university
-
Royal Institute of Technology