Contributors

Abraham, John A.; Adams, Robert M.; Birch, John G.; Carter, Peter R.; Copley, Lawson A.; Cummings, Donald; Dempsey, Molly; Dodge, Nancy Noble; Ezaki, Marybeth; Gebhardt, Mark C.; Herring, John A.; Johnston, Charles E.; Karol, Lori A.; Lake, Amy; Moody, Marilyn K.; Nurenberg, Pamela; Oishi, Scott N.; Rathjen, Karl E.; Richards, Brandon; Safavi, Fay Z.; Sheffield, Eugene G.; Sucato, Daniel J.; Tachdjian, Mihran O.; Wilkes, David; Wilson, Philip L.

doi:10.1016/b978-1-4160-2221-3.50001-3

Cited by 2 publications

(9 citation statements)

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“…In regions of the cartilage endplate (CEP)-vertebral bone transition, collagen α1(XI) was detected in columnar chondrocytes, particularly in the hypertrophic zone adjacent to condensing bone ( Figure 2c ). We also examined collagen α1(XI) expression in ribs, as these structures are also involved in the scoliotic deformity 1 . In P28 rib growth plates, as in spine, a biphasic pattern was observed in which collagen α1(XI) reactivity was most pronounced around cells of the presumed resting and pre-hypertrophic/hypertrophic zones ( Figure 2 – figure supplement a,b ).…”

Section: Resultsmentioning

confidence: 99%

“…The three-dimensional nature of the deformity results in torsion in the spine that is most significant at the apex of the major curve, and changes in the structures of the vertebrae and ribs may develop as the curve worsens or progresses 1 . Children with thoracic curves, with larger curves at first presentation, and/or with greater remaining growth potential are at increased risk of progression, but this risk decreases sharply after skeletal maturity 1 . Sex is a recognized risk factor for AIS, with girls having at least a five-fold greater risk of progressive deformity requiring treatment compared to boys 4 .…”

Section: Introductionmentioning

confidence: 99%

“…The human spinal column is a dynamic, segmented, bony and cartilaginous structure that is essential for integrating the brain and nervous system with the axial skeleton while simultaneously providing flexibility in three dimensions 1 . Idiopathic scoliosis is the most common developmental disorder of the spine, typically appearing during the adolescent growth spurt.…”

Section: Introductionmentioning

confidence: 99%

“…Children with AIS usually present with a characteristic right-thoracic major curve pattern and a compensatory lumbar curve. Major thoracolumbar and lumbar curves are less frequent 1 . The three-dimensional nature of the deformity results in torsion in the spine that is most significant at the apex of the major curve, and changes in the structures of the vertebrae and ribs may develop as the curve worsens or progresses 1 .…”

Section: Introductionmentioning

confidence: 99%

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Association of genetic variation inCOL11A1with adolescent idiopathic scoliosis

Wise

Khanshour

et al. 2023

Preprint

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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 (alpha1) 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 (alpha1) XI protein both localize within the intervertebral disc (IVD)-vertebral junction region encompassing the growth plate, with less collagen (alpha1) 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 COL11A1P1335L 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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Association of genetic variation inCOL11A1with adolescent idiopathic scoliosis

Wise

Khanshour

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The human spinal column is a dynamic, segmented, bony, and cartilaginous structure that is essential for integrating the brain and nervous system with the axial skeleton while simultaneously providing flexibility in three dimensions ( Richards et al, 2020 ). Idiopathic scoliosis is the most common developmental disorder of the spine, typically appearing during the adolescent growth spurt.…”

Section: Introductionmentioning

confidence: 99%

Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis

Yu,

Khanshour,

Ushiki

et al. 2024

eLife

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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.

show abstract

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Cited by 2 publications

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Association of genetic variation inCOL11A1with adolescent idiopathic scoliosis

Association of genetic variation inCOL11A1with adolescent idiopathic scoliosis

Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis

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