Expression Data from Sms-G56S Osteoblasts
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE275891 | GEO | 2025/08/25
REPOSITORIES: GEO
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Project description:The polyamines (putrescine, spermidine, and spermine) are essential molecules for normal cellular functions and are subject to strict metabolic regulation. Mutations in the gene encoding spermine synthase (SMS) lead to accumulation of spermidine in an X-linked recessive disorder known as Snyder-Robinson syndrome (SRS). Presently, no treatments exist for this rare disease that manifests with a spectrum of symptoms including intellectual disability, developmental delay, thin habitus, and low muscle tone. The development of therapeutic interventions for SRS will require a suitable disease-specific animal model that recapitulates many of the abnormalities observed in patients. Here, we characterize the molecular, behavioral, and neuroanatomical features of a mouse model with a missense mutation in the Sms gene that results in a glycine-to-serine substitution at position 56 (G56S) of the SMS protein. Mice harboring this mutation exhibit a complete loss of SMS protein and elevated spermidine/spermine ratio in skeletal muscles and the brain. In addition, the G56S mice demonstrate increased anxiety, impaired learning, and decreased explorative behavior in fear conditioning, Morris water maze, and open field tests, respectively. Furthermore, these mice failed to gain weight over time and exhibit abnormalities in brain structure and bone density. Transcriptomic analysis of the cerebral cortex revealed downregulation of genes associated with mitochondrial oxidative phosphorylation and ribosomal protein synthesis. Our findings also revealed impaired mitochondrial bioenergetics in fibroblasts isolated from the G56S mice, indicating a correlation between these processes in the affected mice. Collectively, our findings establish the first in-depth characterization of an SRS preclinical mouse model that identifies cellular processes that could be targeted for future therapeutic development
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Project description:Osteoarthritis (OA) is the most common joint disease and this is a major cause of joint pain and disability in the aging population. Its etiology is multifactorial (i.e., age, obesity, joint injury, genetic predisposition), and the pathophysiologic process affects the entirety of the joint (Martel-Pelletier J et al. Osteoarthritis. Nature reviews Disease primers. 2016;2:16072). Although it is not yet clear if it precedes or occurs subsequently to cartilage damage, subchondral bone sclerosis is an important feature in OA pathophysiology (Goldring SR et al. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk. Nat Rev Rheumatol. 2016;12:632-44). It is characterized by local bone resorption and the accumulation of weakly mineralized osteoid substance (Bailey AJ et al. Phenotypic expression of osteoblast collagen in osteoarthritic bone: production of type I homotrimer. Int J Biochem Cell Biol. 2002;34:176-82). Subchondral bone sclerosis is suspected to be linked to cartilage degradation, not only by modifying the mechanical stresses transmitted to the cartilage, but also by releasing biochemical factors with an activity on cartilage metabolism (Sanchez C et al. Osteoblasts from the sclerotic subchondral bone downregulate aggrecan but upregulate metalloproteinases expression by chondrocytes. This effect is mimicked by interleukin-6, -1beta and oncostatin M pre-treated non-sclerotic osteoblasts. Osteoarthritis Cartilage. 2005;13:979-87; Sanchez C et al. Subchondral bone osteoblasts induce phenotypic changes in human osteoarthritic chondrocytes. Osteoarthritis Cartilage. 2005;13:988-97; Westacott CI et al J. Alteration of cartilage metabolism by cells from osteoarthritic bone. Arthritis Rheum. 1997;40:1282-91. We have previously demonstrated that osteoblasts isolated from subchondral OA bone exhibited an altered phenotype. More precisely, we showed that osteoblasts coming from the thickening (called sclerotic, SC) of subchondral bone located just below a cartilage lesion produced higher levels of alkaline phosphatase, interleukin (IL)-6, IL-8, prostaglandinE2, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-9 and transforming growth factor(TGF)-β1 and type I collagen than osteoblasts coming from the non-thickening neighboring area (called non-sclerotic area, NSC) (Sanchez C et al. Phenotypic characterization of osteoblasts from the sclerotic zones of osteoarthritic subchondral bone. Arthritis Rheum. 2008;58:442-55; Sanchez C et al. Regulation of subchondral bone osteoblast metabolism by cyclic compression. Arthritis Rheum. 2012;64:1193-203.) To compare secretome of cells living in different in vivo conditions is useful, not only to better understand the pathological mechanisms underlying changes in OA subchondral bone, but also to identify soluble biomarkers potentially reflecting these changes. Using our well-characterised human subchondral osteoblast culture model, we compared the secretome of osteoblasts coming from sclerotic and non sclerotic OA subchondral bone. This approach allowed to identify changes in secretome that contribute to explain some subchondral bone abnormalities in OA and to propose osteomodulin and fibulin-3 as potential biomarkers of OA subchondral bone remodelling.
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Project description:Type I diabetes (T1D) impairs bone accrual in patients, but the mechanism is unclear. Here in a murine monogenic model for T1D, we demonstrate that diabetes suppresses bone formation resulting in a rapid loss of both cortical and trabecular bone. Single-cell RNA sequencing uncovers metabolic dysregulation in bone marrow osteogenic cells of the diabetic mice. In vivo stable isotope tracing reveals impaired glycolysis in diabetic bone that is highly responsive to insulin stimulation. Remarkably, deletion of the insulin receptor reduces cortical but not trabecular bone. Increasing glucose uptake by overexpressing Glut1 in osteoblasts exacerbates bone defects in T1D mice. Conversely, activation of glycolysis by Pfkfb3 overexpression preserves both trabecular and cortical bone mass in the face of diabetes. The study identifies defective glucose metabolism in osteoblasts as a pathogenic mechanism for osteopenia in T1D, and furthermore implicates boosting osteoblast glycolysis as a potential anabolic therapy.
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Project description:In SMS-CTR cells, the overexpression of CASZ1b in SMS-CTR cells led to a modification of regional chromation accessibility.
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Project description:Mucolipidosis type II (MLII) is a severe inherited multisystemic disorder caused by mutations in the GNPTAB gene. Skeletal abnormalities are a predominant feature of MLII. Here we investigate the gene expression in a knock-in mouse model for mucolipidosis type II, generated by the insertion of a cytosine in the murine Gnptab gene (c.3082insC) that is homologous to a homozygous mutation in an MLII patient. Since osteoblasts are critically involved in regulating bone development and remodeling, a genome-wide expression analysis was performed with RNA isolated from primary cultures of osteoblasts originating from MLII knock-in mice (KI) compared to RNA from wild-type (WT) osteoblasts to identify dysregulated genes involved in pathogenic mechanisms.
2014-01-29 | GSE43854 | GEO
Project description:Mucolipidosis type II (MLII) is a severe inherited multisystemic disorder caused by mutations in the GNPTAB gene. Skeletal abnormalities are a predominant feature of MLII. Here we investigate the gene expression in a knock-in mouse model for mucolipidosis type II, generated by the insertion of a cytosine in the murine Gnptab gene (c.3082insC) that is homologous to a homozygous mutation in an MLII patient. Since osteoblasts are critically involved in regulating bone development and remodeling, a genome-wide expression analysis was performed with RNA isolated from primary cultures of osteoblasts originating from MLII knock-in mice (KI) compared to RNA from wild-type (WT) osteoblasts to identify dysregulated genes involved in pathogenic mechanisms. Primary osteoblasts were isolated from calvaria of 5-day-old wild-type (WT) and MLII knock-in littermates (KI). RNA was extracted at day 10 of differentiation induced by ascorbic acid and beta-glycerophosphate and hybridization on Affymetrix microarrays. We used preparations of RNA from two individual primary cultures of osteoblasts for every genotype (WT_OB_I, WT_OB_II, KI_OB_I, KI_OB_II) and compared WT vs KI samples.
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