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Abcc6 null mice a model mineralization disorder PXE show vertebral osteopenia without enhanced intervertebral disc calcification with aging

ABSTRACT: Abcc6 null mice a model mineralization disorder PXE show vertebral osteopenia without enhanced intervertebral disc calcification with aging

PROVIDER: PRJNA780873 | ENA |

REPOSITORIES: ENA

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Abcc6 null mice a model mineralization disorder PXE show vertebral osteopenia without enhanced intervertebral disc calcification with aging

Project description:Transcriptomic analysis of annulus fibrosus (AF) tissues from intervertebral discs of 7-month-old mice with the global deletion of ABCC6. ABCC6 is an efflux transporter of ATP in hepatic cells and loss of function results in metabolic ectopic mineralization disorder pseudoxanthoma elsaticum. To understand the role of ABCC6 and ectopic mineralization in the disc, we examined the transcriptomic profiles of annulus fibrosus cells in control and ABCC6 knock-out mice using microarrays.

2021-11-17 | GSE188943 | GEO

Oral Citrate Supplementation Mitigates Age-Associated Pathological Intervertebral Disc Calcification in LG/J Mice

Project description:Despite the high prevalence of age-dependent intervertebral disc calcification, there is a glaring lack of treatment options for this debilitating pathology. Here, we investigate the efficacy of long-term oral K3Citrate supplementation in ameliorating disc calcification in LG/J mice, a model of spontaneous age-associated disc calcification. K3Citrate successfully reduced the incidence of disc calcification in LG/J mice without deleterious effects on vertebral bone structure, plasma chemistry, and locomotion. Notably, a positive effect on grip strength, a marker of frailty, was evident in treated mice. Spectroscopic investigation of the persisting calcified nodules indicated K3Citrate did not alter the mineral composition, and collagen 10 and aggrecan staining revealed that reactivation of an endochondral differentiation program in endplates may drive LG/J disc calcification. Importantly, K3Citrate reduced calcification incidence without altering the abundance of endplate hypertrophic chondrocytes, suggesting mitigation of disc calcification through Ca2+ chelation. This was further supported by the inability of K3Citrate to inhibit hypertrophic differentiation of chondrogenic ATDC5 cells and minimal effects on their metabolic status. Overall, this study sheds light on the pathogenesis of intervertebral disc calcification in LG/J mice and underscores the therapeutic potential of K3Citrate as a systemic intervention strategy for disc calcification.

2024-08-16 | GSE270561 | GEO

<i>Abcc6</i> Null Mice-a Model for Mineralization Disorder PXE Shows Vertebral Osteopenia Without Enhanced Intervertebral Disc Calcification With Aging.

Project description:Chronic low back pain is a highly prevalent health condition intricately linked to intervertebral disc degeneration. One of the prominent features of disc degeneration that is commonly observed with aging is dystrophic calcification. ATP-binding cassette sub-family C member 6 (ABCC6), a presumed ATP efflux transporter, is a key regulator of systemic levels of the mineralization inhibitor pyrophosphate (PPi). Mutations in ABCC6 result in pseudoxanthoma elasticum (PXE), a progressive human metabolic disorder characterized by mineralization of the skin and elastic tissues. The implications of ABCC6 loss-of-function on pathological mineralization of structures in the spine, however, are unknown. Using the Abcc6 -/- mouse model of PXE, we investigated age-dependent changes in the vertebral bone and intervertebral disc. Abcc6 -/- mice exhibited diminished trabecular bone quality parameters at 7 months, which remained significantly lower than the wild-type mice at 18 months of age. Abcc6 -/- vertebrae showed increased TRAP staining along with decreased TNAP staining, suggesting an enhanced bone resorption as well as decreased bone formation. Surprisingly, however, loss of ABCC6 resulted only in a mild, aging disc phenotype without evidence of dystrophic mineralization. Finally, we tested the utility of oral K3Citrate to treat the vertebral phenotype since it is shown to regulate hydroxyapatite mechanical behavior. The treatment resulted in inhibition of the osteoclastic response and an early improvement in mechanical properties of the bone underscoring the promise of potassium citrate as a therapeutic agent. Our data suggest that although ectopic mineralization is tightly regulated in the disc, loss of ABCC6 compromises vertebral bone quality and dysregulates osteoblast-osteoclast coupling.

| S-EPMC8850990 | biostudies-literature

Loss of function mutation in progressive ankylosis (Ank) gene causes aberrant mineralization and acquisition of osteoblast-like-phenotype by annulus fibrosus cells in the intervertebral disc

Project description:Transcriptomic analysis of nucleus pulposus (NP) and annulus fibrosus (AF) tissues from intervertebral discs of 3-month-old mice with loss of function mutation of Ank gene. Regulator of extracellular inorganic pyrophosphate, Ank is essential for preventing ectopic mineralization in the extracellular matrices, maintaining the health of the intervertebral disc of mice. We examined the transcriptomic profiles of nucleus pulposus and annulus fibrosus cells in control and Ank mutant mice using microarrays.

2023-06-01 | GSE206997 | GEO

Sdc4 deletion perturbs intervertebral disc matrix homeostasis and promotes early osteopenia in the aging mouse spine

Project description:Sdc4 deletion perturbs intervertebral disc matrix homeostasis and promotes early osteopenia in the aging mouse spine

| PRJNA1018948 | ENA

Oral Citrate Supplementation Mitigates Age-Associated Pathological Intervertebral Disc Calcification in LG/J Mice

Project description:Oral Citrate Supplementation Mitigates Age-Associated Pathological Intervertebral Disc Calcification in LG/J Mice

| PRJNA1127505 | ENA

Sdc4 deletion perturbs intervertebral disc matrix homeostasis and promotes early osteopenia in the aging mouse spine

Project description:Transcriptional analysis of 6-month-old primary nucleus pulposus (NP) mouse disc tissues from wild-type (WT) and SDC4 KO mice, which harbor deletions of exon 2 to part of exon 5 that endcodes the N-terminal coding region. Breeder mice were provided by Dr. Michael Simons. SDC4's regulation of cytokine-dependent activation of the aggrecanse ADAMTS-5 is linked with inflammation-associated intervertebral disc degeneration. In this study, we aim to establish the role of SDC4 in matrix homeostasis under the context of aging.

2024-09-01 | GSE243573 | GEO

Loss of Runx3 in osteoblasts provokes severe congenital osteopenia

2014-05-01 | GSE57195 | GEO

Loss of Runx3 in osteoblasts provokes severe congenital osteopenia

Project description:Murine Runx3 is expressed in developing bone osteoblasts (OBLs) and its deletion in these cells culminates in severe congenital osteopenia. We demonstrate that Runx3 is non-redundantly involved in the proliferation of early pre-committed OBL progenitor cells, a critical step in the generation of adequate numbers of bone-forming OBLs. Thus, in the absence of Runx3 in cells of this lineage, the number of mature/active OBLs is significantly diminished, providing a mechanistic explanation to the observed osteopenia. This experiment was aimed at identifying genes that are likely regulated by Runx3 along osteoblastogenesis. To elucidate the Runx3-mediated transcriptional program along OBL differentiation, we compared gene expression profile in WT and Runx3f/f/Col1a1-cre calvarial OBLs. Progenitor cells were purified and RNA extracted, reverse-transcribed, fragmented, labeled and hybridized to GeneChipÂ® Mouse Gene 2.0 ST Array.

2014-05-01 | E-GEOD-57195 | biostudies-arrayexpress

Exploring molecular profiles of calcification in aortic vascular smooth muscle cells and aortic valvular interstitial cells

Project description:Cardiovascular calcification can occur in vascular and valvular structures and is commonly associated with calcium deposition and tissue mineralization leading to stiffness and dysfunction. Based on shared risk factors and end stage pathologies, calcific aortic valve disease (CAVD) and coronary artery calcification (CAC) are often considered as one disease, and similarly treated. However, the clinical conditions associated with each phenotype can be different, suggesting multifaceted pathologies. To better understand diversity in molecular and cellular processes that underlie calcification in vascular and valvular structures, we exposed aortic vascular smooth muscle cells (AVSMCs) and aortic valve interstitial cells (AVICs) to calcific stimuli including high (2.5mM) phosphate and osteogenic media (OM) treatments in vitro. Consistent with clinical observations made by others, we show that AVSMCs are more susceptible to calcification than AVICs, and this process is mediated by cell-specific and treatment-specific molecular responses. RNA-seq analysis demonstrates that in response to calcific-stimuli, both AVSMCs and AVICs activate a robust ossification-program, although the signaling pathways, cellular processes and osteogenic-associated markers involved are diverse. In addition, VIC-mediated calcification appears to involve biological processes related to osteo-chondro differentiation and down regulation of actin cytoskeleton genes, that are not observed in VSMCs. Furthermore, are findings suggest that signaling pathways involved in cardiovascular cell calcification are dependent on the calcific-stimuli, including a requirement of PI3K signaling for OM-induced calcification, and not 2.5mM Phosphate. Together, this study provides a wealth of information suggesting that the pathogenesis of cardiovascular calcifications may be significantly more diverse than previously appreciated.

2023-08-01 | GSE227131 | GEO

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