Regulation of terminal hypertrophic chondrocyte differentiation in <i>Prmt5</i> mutant mice modeling infantile idiopathic scoliosis

Liu, Zhaoyang; Ramachandran, Janani; Vokes, Steven A.; Gray, Ryan S.

doi:10.1242/dmm.041251

Cited by 16 publications

(5 citation statements)

References 84 publications

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“…However, the Sko mice are a novel and useful animal model that shows scoliosis with features similar to syndromic scoliosis since most genetically altered models of scoliosis are unclear about which type of scoliosis they resemble in humans or die soon after birth. [21,22] Furthermore, this is the first basic science report to demonstrate the causal relationship between scoliosis and reduced bone density and quality, to our knowledge. Therefore, we believe that the insights gained from this study provide a clue to elucidating the etiology of scoliosis, which may lead to new treatment development for the disease.…”

Section: Characteristics Of Scoliosis In Mice • Handa Et Almentioning

confidence: 76%

“…The incidence of scoliosis due to cartilage-related abnormalities has recently attracted much attention, and loci associated with cartilage, such as GPR126 and PAX1, have been detected in genome-wide association studies 3,21 . Furthermore, it has been reported that chondrocyte-specific inactivation of Prmt5 and SHP2 in mice results in IS 22,23 . Growth plate thickening has also been observed in scoliosis in mice with Prmt5 inactivation, and impaired endochondral ossification causes scoliosis.…”

Section: Discussionmentioning

confidence: 99%

“…3,21 Furthermore, it has been reported that chondrocyte-specific inactivation of Prmt5 and SHP2 in mice results in IS. 22,23 Growth plate thickening has also been observed in scoliosis in mice with Prmt5 inactivation, and impaired endochondral ossification causes scoliosis. We also confirmed the thickening of the growth plate in this study, as reported by Iwahashi et al 7 In the Sd-type growth plate, no difference was found between the left and right sides (thickening of the growth plate was observed), whereas the scoliosis-type growth plate exhibited thickening with differences in laterality.…”

Section: Characteristics Of Scoliosis In Mice • Handa Et Almentioning

confidence: 99%

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Characteristics of Scoliosis in Mice Induced by Chondrocyte-specific Inactivation of L-type Amino Acid Transporter 1

Handa,

Demura,

Yokogawa

et al. 2023

Spine

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Study Design. A mouse study of the Slc7a5 gene using conditional knockout to assess the effects of its inactivation on spinal deformity. Objectives. This study aimed to investigate whether the mice with scoliosis (induced by chondrocyte-specific inactivation of L-type amino acid transporter 1 [LAT1]) show a developmental process similar to that of pediatric scoliosis and to examine the relationship between reduced bone mineral density (BMD) and scoliosis. Furthermore, we aimed to obtain insights into elucidating the etiology and pathophysiology of scoliosis. Summary of Background Data. The etiology and pathogenesis of scoliosis are not fully understood despite substantial investigative efforts. LAT1 is an amino acid transporter that mediates the cellular uptake of large neutral amino acids. A recent study revealed that chondrocyte-specific inactivation of LAT1 in mice results in scoliosis (Col2a1-Cre;Slc7a5fl/fl mice: “Sko mice”). Methods. Body length, body weight, Cobb angle, vertebral body rotation angle, and BMD at 1, 2, 4, 6, and 8 weeks of age were examined and statistically compared with those of normal control mice. Pathological and morphological evaluation was performed on specimens from 10-week-old euthanized mice. Results. The Sko mice developed thoracic scoliosis in infancy without congenital malformations. This spinal deformity progressed rapidly during growth, with diverse curve patterns and hypoplastic vertebral bodies.　Pathological examination revealed thickening of the growth plates and decreased osteoblasts, suggesting that impaired endochondral ossification was the cause of the scoliosis.　Sko mice were also observed to have decreased BMD and degraded bone microstructure. Reduced BMD and bone quality may not be the causes of the onset and progression of scoliosis in the Sko mice. Conclusions. In Sko mice, the characteristics of scoliosis and vertebral pathology showed many similarities with syndromic scoliosis in humans. Endochondral ossification defects may impair growth, leading to scoliosis and decreased BMD.

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Section: Characteristics Of Scoliosis In Mice • Handa Et Almentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Characteristics Of Scoliosis In Mice • Handa Et Almentioning

confidence: 99%

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Characteristics of Scoliosis in Mice Induced by Chondrocyte-specific Inactivation of L-type Amino Acid Transporter 1

Handa,

Demura,

Yokogawa

et al. 2023

Spine

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“…Skeletal preparations were performed as previously described 65 . Briefly, P1 pups were skinned and fixed in 10% neutral-buffered formalin for 1 day at 4°C, stained with 0.3% Alcian blue and 0.1% Alizarin red at 37°C for 3 days, and cleared with 1% KOH.…”

Section: Analyses Of Micementioning

confidence: 99%

Spatial Transcriptomics Reveals the Requirement of ADGRG6 in Maintaining Chondrocyte Homeostasis in Mouse Growth Plates

Bian,

Hansen,

Feng

et al. 2023

Preprint

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The growth plate is essential for maintaining skeletal growth; however, the mechanisms governing postnatal growth plate homeostasis are poorly understood. Here we show that ADGRG6/GPR126, a cartilage-enriched G protein-coupled receptor (GPCR), is dispensable for embryonic limb development but is required for postnatal growth plate homeostasis. Adgrg6 ablation in osteochondral progenitor cells or postnatal chondrocytes leads to reduced cellularity and impaired maintenance of the resting zone in the growth plate, coupled with increased cell death and reduced cell proliferation. Adgrg6 mutant growth plates also exhibit disorganized extracellular matrix structures and dysregulated hypertrophic differentiation. Furthermore, using a novel spatial transcriptomics workflow that applies to FFPE tissue sections of mineralized mouse knee joints, we demonstrate that Adgrg6 ablation leads to reduced SOX9 expression, induced Indian hedgehog (IHH) signaling, and a precocious chondrogenic-to-osteogenic conversion of the growth plate chondrocytes that may be driven by increased POSTN/integrin receptor signaling. We further demonstrated that ADGRG6 regulates the proper formation of the resting zone growth plate by maintaining the PTHrP and SOX9-positive cell populations. Altogether, our findings elucidate the essential role of ADGRG6 in maintaining chondrocyte fate, survival, and homeostasis of the postnatal growth plates.

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“…Congenital disorders can specifically affect single-organ systems, such as the heart (reviewed by Rufaihah et al, 2021), kidneys (reviewed by Blackburn and Miller, 2019), as well as skeleton and muscles (Liu et al, 2019;Rios et al, 2021;Wong et al, 2020). Patients with congenital bicuspid aortic valve have two instead of three flaps in this valve, which can lead to disease of this major artery.…”

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confidence: 99%

Developmental disorders Journal Meeting: a collaboration between Development and Disease Models & Mechanisms

Hooper

Justice

Patton

2021

Disease Models &Amp; Mechanisms

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Developmental disorders present at birth or arise during childhood, leading to physical or intellectual disabilities with long-term effects on morbidity. According to a study from the Centers for Disease Control and Prevention, one in six children in the USA has a developmental disability that affects their education and lifestyle (Zablotsky et al., 2019). These disorders encompass a wide range of conditions, and are caused by genetic and/or environmental factors. Expanding research in this area is fundamental to improving diagnosis, preventing progression and treating these conditions. At Disease Models & Mechanisms (DMM), we have a strong interest in research that delineates the mechanisms that underlie developmental disorders, with a dedicated collection of Reviews, Perspectives and Research articles. We pursue pre-clinical modelling to discover new mechanistic insights with a view towards how this can support children and their families, and inform their care.

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Regulation of terminal hypertrophic chondrocyte differentiation in Prmt5 mutant mice modeling infantile idiopathic scoliosis

Cited by 16 publications

References 84 publications

Characteristics of Scoliosis in Mice Induced by Chondrocyte-specific Inactivation of L-type Amino Acid Transporter 1

Characteristics of Scoliosis in Mice Induced by Chondrocyte-specific Inactivation of L-type Amino Acid Transporter 1

Spatial Transcriptomics Reveals the Requirement of ADGRG6 in Maintaining Chondrocyte Homeostasis in Mouse Growth Plates

Developmental disorders Journal Meeting: a collaboration between Development and Disease Models & Mechanisms

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