Intervertebral disc degeneration in adult mice with hereditary kyphoscoliosis

Mason, Roger M.; Palfrey, A. J.

doi:10.1002/jor.1100020405

Cited by 29 publications

(13 citation statements)

References 11 publications

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“…However, on routine staining, chondrocytes were only sparsely present in the inner annulus. This observation is consistent with that of Mason [13]. In the outer annulus the magnitude of the compressive stress is higher than in the inner annulus in a bent disc [25] and static compressive stress has been reported either to enhance (low stress) or decrease (high stress) chondrocytes metabolism [6,7,10].…”

Section: Discussionsupporting

confidence: 90%

Biological and mechanical consequences of transient intervertebral disc bending

et al. 2007

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Degenerative mechanisms for the intervertebral disc are unclear, particularly those associated with cumulative trauma. This research focuses on how mechanical loading at levels below those known to cause acute trauma can lead to cellular injury. Mouse-tail discs were subjected to static bending for 1 week, then allowed to recover unloaded for 3 weeks and 3 months. Discs were analyzed using histology, in situ hybridization (collagen and aggrecan gene expression), TUNEL assay for apoptotic cell death, and biomechanics. The bent discs demonstrated loss of annular cellularity on the concave (compressed) side, while the nucleus and convex annulus appeared normal. Chondrocyte-like cells were apparent within the inner, concave annulus on the recovered discs, with evidence of proliferation at the annulus/endplate interface. However, annular architecture and biomechanical properties for the recovered discs were not different from controls, suggesting that restoration of physiologic tissue stress prevents the inner annular degradation noted in previous compressioninduced degeneration models. These data demonstrate that cellular injury can be induced by transient compressive stress, and that recellularization is slow in this avascular tissue. Taken together, this suggests that cellular damage accumulation may be an important injury mechanism that is distinct from acute mechanical failure.

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Section: Discussionsupporting

confidence: 90%

Biological and mechanical consequences of transient intervertebral disc bending

et al. 2007

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“…The mutants have been extensively investigated as a possible model of idiopathic kyphoscoliosis in humans, but there was no evidence of a primary disease of the spine. 2,17 A neuromuscular cause for the deformities was found by systematic histological investigation of mutant mouse muscles at various ages. Necrosis, regeneration, and subsequent fibrosis and atrophy of muscles were identified from about 1 week of age, indicating a primary muscular dystrophy.…”

Section: Discussionmentioning

confidence: 99%

“…1 In this model, kyphoscoliosis develops due to atrophy of postural muscles during postnatal growth. 2,3 The muscle phenotype of the ky/ky was morphologically characterized by muscle fiber regeneration, necrosis, and internally located nuclei in the soleus, gracilis, paraspinal, and back muscles. 3 The Ky locus was mapped to a small region of the distal part of the mouse chromosome 9 that is homologous to human chromosome 3q21.…”

Section: Introductionmentioning

confidence: 99%

A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency

et al. 2016

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We describe a new early-onset neuromuscular disorder due to a homozygous loss-of-function variant in the kyphoscoliosis peptidase gene (KY). A 7.5-year-old girl with walking difficulties from 2 years of age presented with generalized muscle weakness; mild contractures in the shoulders, hips and feet; cavus feet; and lordosis but no scoliosis. She had previously been operated with Achilles tendon elongation. Whole-body MRI showed atrophy and fatty infiltration in the calf muscles. Biopsy of the vastus lateralis muscle showed variability in fiber size, with some internalized nuclei and numerous very small fibers with variable expression of developmental myosin heavy chain isoforms. Some small fibers showed abnormal sarcomeres with thickened Z-discs and small nemaline rods. Whole-exome sequencing revealed a homozygous one-base deletion (c.1071delG, p.(Thr358Leufs*3)) in KY, predicted to result in a truncated protein. Analysis of an RNA panel showed that KY is predominantly expressed in skeletal muscle in humans. A recessive variant in the murine ortholog Ky was previously described in a spontaneously generated mouse mutant with kyphoscoliosis, which developed postnatally and was caused by dystrophy of postural muscles. The abnormal distribution of Xin and Ky-binding partner filamin C in the muscle fibers of our patient was highly similar to their altered localization in ky/ky mouse muscle fibers. We describe the first human case of disease associated with KY inactivation. As in the mouse model, the affected child showed a neuromuscular disorder -but in contrast, no kyphoscoliosis.

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“…In addition, null mice displayed a prominent kyphosis that intensified with age, a relatively common phenotype in mouse models of neuromuscular diseases such as the mdx mouse (22) and the kyphoscoliosis (ky) mouse (23). Because normal extension by the animal or gentle manipulation by a handler corrected the curvature, it is likely that the inherent skeletal muscle weakness also underlies this phenotype.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Hexose-6-phosphate Dehydrogenase Activates the Unfolded Protein Response Pathway and Induces Skeletal Myopathy

Lavery

Walker

Turan

et al. 2008

Journal of Biological Chemistry

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Hexose-6-phosphate dehydrogenase (H6PD) is the initial component of a pentose phosphate pathway inside the endoplasmic reticulum (ER) that generates NADPH for ER enzymes. In liver H6PD is required for the 11-oxoreductase activity of 11␤-hydroxysteroid dehydrogenase type 1, which converts inactive 11-oxo-glucocorticoids to their active 11-hydroxyl counterparts; consequently, H6PD null mice are relatively insensitive to glucocorticoids, exhibiting fasting hypoglycemia, increased insulin sensitivity despite elevated circulating levels of corticosterone, and increased basal and insulin-stimulated glucose uptake in muscles normally enriched in type II (fast) fibers, which have increased glycogen content. Here, we show that H6PD null mice develop a severe skeletal myopathy characterized by switching of type II to type I (slow) fibers. Running wheel activity and electrically stimulated force generation in isolated skeletal muscle are both markedly reduced. Affected muscles have normal sarcomeric structure at the electron microscopy level but contain large intrafibrillar membranous vacuoles and abnormal triads indicative of defects in structure and function of the sarcoplasmic reticulum (SR). SR proteins involved in calcium metabolism, including the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), calreticulin, and calsequestrin, show dysregulated expression. Microarray analysis and real-time PCR demonstrate overexpression of genes encoding proteins in the unfolded protein response pathway. We propose that the absence of H6PD induces a progressive myopathy by altering the SR redox state, thereby impairing protein folding and activating the unfolded protein response pathway. These studies thus define a novel metabolic pathway that links ER stress to skeletal muscle integrity and function. H6PD3 is a bifunctional enzyme that catalyzes the first two steps of the pentose phosphate pathway (1). It is distinct from its cytosolic homolog, glucose-6-phosphate dehydrogenase, in being localized exclusively to the lumen of the endoplasmic reticulum (ER). H6PD converts glucose 6-phosphate to 6-phosphogluconolactonate with the concomitant production of NADPH, thereby maintaining adequate levels of reductive cofactors in the oxidizing environment of the ER (2, 3).One critical role for H6PD is providing NADPH to 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1), a bi-directional enzyme highly expressed in liver and adipose tissue. 11␤-HSD1 catalyzes both dehydrogenation and oxo-reduction of glucocorticoids, but in vivo it acts predominantly as a NADPHdependent oxoreductase that converts hormonally inactive cortisone to active cortisol (in rodents, 11-dehydrocorticosterone to corticosterone) (4). To investigate the functional interactions of H6PD and 11␤-HSD1 in vivo, we produced mice with a targeted inactivation of H6PD and showed that 11␤-HSD1 predominantly acts as a dehydrogenase in these mice (6). The resulting cellular resistance to corticosterone leads to activation of the hypothalamic-pituitary-adrenal axis and elevat...

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Intervertebral disc degeneration in adult mice with hereditary kyphoscoliosis

Cited by 29 publications

References 11 publications

Biological and mechanical consequences of transient intervertebral disc bending

Biological and mechanical consequences of transient intervertebral disc bending

A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency

Deletion of Hexose-6-phosphate Dehydrogenase Activates the Unfolded Protein Response Pathway and Induces Skeletal Myopathy

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