Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States; Institute for Human Genetics, University of California, San Francisco, San Francisco, United States
Nao Otomo
Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan
Yoshinao Koike
Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan; Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Elisabet Einarsdottir
Science for Life Laboratory, Department of Gene Technology, KTH-Royal Institute of Technology, Solna, Sweden
Yanhui Fan
School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China
Lilian Antunes
Department of Neurology, Washington University in St. Louis, St. Louis, United States
Yared H Kidane
Center for Translational Research, Scottish Rite for Children, Dallas, United States
Reuel Cornelia
Center for Translational Research, Scottish Rite for Children, Dallas, United States
Rory R Sheng
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States; Institute for Human Genetics, University of California, San Francisco, San Francisco, United States
Yichi Zhang
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States; Institute for Human Genetics, University of California, San Francisco, San Francisco, United States; School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
Jimin Pei
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
Nick V Grishin
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States; Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, United States
Department of Orthopaedics and Traumatology LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
John A Herring
Department of Orthopedic Surgery, Scottish Rite for Children, Dallas, United States; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, United States
School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China
Christina A Gurnett
Department of Neurology, Washington University in St. Louis, St. Louis, United States
Paul Gerdhem
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Department of Orthopaedics and Hand Surgery, Uppsala University Hospital, Uppsala, Sweden; Department of Clinical Science, Intervention & Technology (CLINTEC), Karolinska Institutet, Stockholm, Uppsala University, Uppsala, Sweden
Shiro Ikegawa
Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan
Center for Translational Research, Scottish Rite for Children, Dallas, United States; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, United States; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States; Institute for Human Genetics, University of California, San Francisco, San Francisco, United States
Center for Translational Research, Scottish Rite for Children, Dallas, United States; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, United States; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States
Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than fivefold 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 (α1) 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 (α1) XI protein both localize within the intervertebral disc-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1-/- spines compared to wild-type. By genetic targeting we found that wild-type Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, the latter 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.
