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Dystrophic spinal deformities in a neurofibromatosis type 1 murine model.

Rhodes SD, Zhang W, Yang D, Yang H, Chen S, Wu X, Li X, Yang X, Mohammad KS, Guise TA, Bergner AL, Stevenson DA, Yang FC - PLoS ONE (2015)

Bottom Line: Despite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1), the pathogenesis of these defects remains largely unknown.Here, we present two murine models: Nf1flox/-;PeriCre and Nf1flox/-;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease.Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.

ABSTRACT
Despite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1), the pathogenesis of these defects remains largely unknown. Here, we present two murine models: Nf1flox/-;PeriCre and Nf1flox/-;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease. Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis. Intriguingly, 36-60% of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice exhibit segmental vertebral fusion anomalies with boney obliteration of the intervertebral disc (IVD). While analogous findings have not yet been reported in the NF1 patient population, we herein present two case reports of IVD defects and interarticular vertebral fusion in patients with NF1. Collectively, these data provide novel insights regarding the pathophysiology of dystrophic spinal anomalies in NF1, and provide impetus for future radiographic analyses of larger patient cohorts to determine whether IVD and vertebral fusion defects may have been previously overlooked or underreported in the NF1 patient population.

No MeSH data available.


Related in: MedlinePlus

Interarticular fusion in Nf1flox/−;Col2.3Cre mice.(A) Representative μCT reconstructions of dystrophic vertebral segments in coronal (top, i and ii) or sagittal (bottom, iii and iv) cross-section. Dysplastic bone growth within the intervertebral disc space has led to interarticular fusion of the dystrophic vertebrae. (B) Representative H&E stained histological sections characterize progressive boney dysplasia within the intervertebral disc space of mice at one month (i and ii), two months (iii and iv), six months (v and vi), and 12 months (vii and viii) of age.
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pone.0119093.g005: Interarticular fusion in Nf1flox/−;Col2.3Cre mice.(A) Representative μCT reconstructions of dystrophic vertebral segments in coronal (top, i and ii) or sagittal (bottom, iii and iv) cross-section. Dysplastic bone growth within the intervertebral disc space has led to interarticular fusion of the dystrophic vertebrae. (B) Representative H&E stained histological sections characterize progressive boney dysplasia within the intervertebral disc space of mice at one month (i and ii), two months (iii and iv), six months (v and vi), and 12 months (vii and viii) of age.

Mentions: Representative sagittal and parasagittal μCT reconstructions further demonstrate vertebral asymmetry and ossification of the IVD space with cancellous bone in Nf1flox/−;Col2.3Cre mice (Fig. 5A, ii and iv). Histological sections acquired from mice one, two, six, and 12 months of age illustrate the phenotype in varying stages of progression in Nf1flox/−;Col2.3Cre mice (Fig. 5). Atrophy of the AF was evident in Nf1flox/−;Col2.3Cre mice beginning from one month of age (Fig. 5B, i-ii). Between two to six months of age, there is evidence of significant degeneration of both the AF and NP with intervertebral fusion beginning from the lateral margins of the disc in Nf1flox/−;Col2.3Cre mice as compared to WT control mice (Fig. 5B, iii-vi). Finally, by 12 months of age, complete obliteration of the physiologic IVD architecture is evident in Nf1flox/−;Col2.3Cre mice, and the IVD space has been replaced with infiltrating cancellous bone and marrow cells, resulting in interarticular fusion of the adjacent segments (Fig. 5B, vii-viii).


Dystrophic spinal deformities in a neurofibromatosis type 1 murine model.

Rhodes SD, Zhang W, Yang D, Yang H, Chen S, Wu X, Li X, Yang X, Mohammad KS, Guise TA, Bergner AL, Stevenson DA, Yang FC - PLoS ONE (2015)

Interarticular fusion in Nf1flox/−;Col2.3Cre mice.(A) Representative μCT reconstructions of dystrophic vertebral segments in coronal (top, i and ii) or sagittal (bottom, iii and iv) cross-section. Dysplastic bone growth within the intervertebral disc space has led to interarticular fusion of the dystrophic vertebrae. (B) Representative H&E stained histological sections characterize progressive boney dysplasia within the intervertebral disc space of mice at one month (i and ii), two months (iii and iv), six months (v and vi), and 12 months (vii and viii) of age.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4364663&req=5

pone.0119093.g005: Interarticular fusion in Nf1flox/−;Col2.3Cre mice.(A) Representative μCT reconstructions of dystrophic vertebral segments in coronal (top, i and ii) or sagittal (bottom, iii and iv) cross-section. Dysplastic bone growth within the intervertebral disc space has led to interarticular fusion of the dystrophic vertebrae. (B) Representative H&E stained histological sections characterize progressive boney dysplasia within the intervertebral disc space of mice at one month (i and ii), two months (iii and iv), six months (v and vi), and 12 months (vii and viii) of age.
Mentions: Representative sagittal and parasagittal μCT reconstructions further demonstrate vertebral asymmetry and ossification of the IVD space with cancellous bone in Nf1flox/−;Col2.3Cre mice (Fig. 5A, ii and iv). Histological sections acquired from mice one, two, six, and 12 months of age illustrate the phenotype in varying stages of progression in Nf1flox/−;Col2.3Cre mice (Fig. 5). Atrophy of the AF was evident in Nf1flox/−;Col2.3Cre mice beginning from one month of age (Fig. 5B, i-ii). Between two to six months of age, there is evidence of significant degeneration of both the AF and NP with intervertebral fusion beginning from the lateral margins of the disc in Nf1flox/−;Col2.3Cre mice as compared to WT control mice (Fig. 5B, iii-vi). Finally, by 12 months of age, complete obliteration of the physiologic IVD architecture is evident in Nf1flox/−;Col2.3Cre mice, and the IVD space has been replaced with infiltrating cancellous bone and marrow cells, resulting in interarticular fusion of the adjacent segments (Fig. 5B, vii-viii).

Bottom Line: Despite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1), the pathogenesis of these defects remains largely unknown.Here, we present two murine models: Nf1flox/-;PeriCre and Nf1flox/-;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease.Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.

ABSTRACT
Despite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1), the pathogenesis of these defects remains largely unknown. Here, we present two murine models: Nf1flox/-;PeriCre and Nf1flox/-;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease. Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis. Intriguingly, 36-60% of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice exhibit segmental vertebral fusion anomalies with boney obliteration of the intervertebral disc (IVD). While analogous findings have not yet been reported in the NF1 patient population, we herein present two case reports of IVD defects and interarticular vertebral fusion in patients with NF1. Collectively, these data provide novel insights regarding the pathophysiology of dystrophic spinal anomalies in NF1, and provide impetus for future radiographic analyses of larger patient cohorts to determine whether IVD and vertebral fusion defects may have been previously overlooked or underreported in the NF1 patient population.

No MeSH data available.


Related in: MedlinePlus