651 research outputs found
Compounds And Methods For Treating Bone Disorders And Controlling Weight
The present invention provides peptides and methods of their use in treating bone disorders and bone-related conditions and in treating obesity
The Effect of High Fat Diet on Marrow Adipocytes from C57BL/6J (B6) Mice
In mice models, the administration of a high fat diet (HFD) is an accelerating factor for metabolic syndrome, impaired glucose tolerance, and early type 2 diabetes mellitus (T2DM) (1)https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1049/thumbnail.jp
Plasma concentrations of per- and polyfluoroalkyl substances and body composition from mid-childhood to early adolescence
BACKGROUND
ā¢ Per- and polyfluoroalkyl substances (PFAS) may alter body composition by lowering anabolic hormones and increasing inflammation.
Prior studies have found positive, inverse, and null associations of PFAS concentrations with adiposity among children and adolescents.
Few studies have examined associations of PFAS concentrations with changes in body composition longitudinally.
No study has examined the association of PFAS plasma concentrations with lean mass.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1038/thumbnail.jp
IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation: IRS-1 SCAFFOLD FOR IGF-I/IGFBP-2 SIGNALING IN OB DIFFERENTIATION
Insulin like growth factor I (IGF-I) and insulin like growth factor binding protein-2 (IGFBP-2) function coordinately to stimulate AKT and osteoblast differentiation. IGFBP-2 binding to receptor protein tyrosine phosphatase Ī² (RPTPĪ²) stimulates polymerization and inactivation of phosphatase activity. Because phosphatase and tensin homolog (PTEN) is the primary target of RPTPĪ², this leads to enhanced PTEN tyrosine phosphorylation and inactivation. However RPTPĪ² inactivation also requires IGF-I receptor activation. The current studies were undertaken to determine the mechanism by which IGF-I mediates changes in RPTPĪ² function in osteoblasts. IGFBP-2/IGF-I stimulated vimentin binding to RPTPĪ² and this was required for RPTPĪ² polymerization. Vimentin serine phosphorylation mediated its binding to RPTPĪ² and PKCĪ¶ was identified as the kinase that phosphorylated vimentin. To determine the mechanism underlying IGF-I stimulation of PKCĪ¶-mediated vimentin phosphorylation, we focused on insulin receptor substrateā1 (IRS-1). IGF-I stimulated IRS-1 phosphorylation and recruitment of PKCĪ¶ and vimentin to phospho-IRS-1. IRS-1 immunoprecipitates containing PKCĪ¶ and vimentin were used to confirm that activated PKCĪ¶ directly phosphorylated vimentin. PKCĪ¶ does not contain a SH-2 domain that is required to bind to phospho-IRS-1. To determine the mechanism of PKCĪ¶ recruitment we analyzed the role of p62 (a PKCĪ¶ binding protein) that contains a SH2 domain. Exposure to differentiation medium plus IGF-I stimulated PKCĪ¶/p62 association. Subsequent analysis showed the p62/PKCĪ¶ complex was co-recruited to IRS-1. Peptides that disrupted p62/PKCĪ¶ or p62/IRS-1 inhibited IGF-I/IGFBP-2 stimulated PKCĪ¶ activation, vimentin phosphorylation, PTEN tyrosine phosphorylation, AKT activation, and osteoblast differentiation. The importance of these signaling events for differentiation was confirmed in primary mouse calvarial osteoblasts. These results demonstrate the cooperative interaction between RPTPĪ² and the IGF-I receptor leading to a coordinated series of signaling events that are required for osteoblast differentiation. Our findings emphasize the important role IRS-1 plays in modulating these signaling events and confirm its essential role in facilitating osteoblast differentiation
A High Fat Diet Increases Bone Marrow Adipose Tissue (MAT) But Does Not Alter Trabecular or Cortical Bone Mass in C57BL/6J Mice
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111767/1/jcp24954.pd
IGFBP-2 Directly Stimulates Osteoblast Differentiation: IGFBP-2 DIRECTLY STIMULATES OSTEOBLAST DIFFERENTIATION
Insulin like growth factor binding protein two (IGFBP-2) is important for acquisition of normal bone mass in mice; however, the mechanism by which IGFBP-2 functions is not defined. These studies investigated the role of IGFBP-2 in stimulating osteoblast differentiation. MC-3T3 preosteoblasts expressed IGFBP-2, and IGFBP-2 knockdown resulted in a substantial delay in osteoblast differentiation, reduced osteocalcin expression and Alizarin red staining. These findings were replicated in primary calvarial osteoblasts obtained from IGFBP-2 ā/ā mice and addition of IGFBP-2 rescued the differentiation program. In contrast, overexpression of IGFBP-2 accelerated the time course of differentiation as well as increasing the total number of differentiating cells. By day 6 IGFBP-2 overexpressing cells expressed twice as much osteocalcin as control cultures and this difference persisted. To determine the mechanism by which IGFBP-2 functions, the interaction between IGFBP-2 and receptor tyrosine phosphatase Ī² (RPTPĪ²) was examined. Disruption of this interaction inhibited the ability of IGFBP-2 to stimulate AKT activation and osteoblast differentiation. Knockdown of RPTPĪ² enhanced osteoblast differentiation whereas overexpression of RPTPĪ² was inhibitory. Adding back IGFBP-2 to RPTPĪ² overexpressing cells was able to rescue cell differentiation via enhancement of AKT activation. To determine the region of IGFBP-2 that mediated this effect an IGFBP-2 mutant that contained substitutions of key amino acids in the heparin binding domain-1 (HBD-1) was prepared. This mutant had a major reduction in its ability to stimulate differentiation of calvarial osteoblasts from IGFBP-2 ā/ā mice. Addition of a synthetic peptide that contained the HBD-1 sequence to calvarial osteoblasts from IGFBP-2 ā/ā mice rescued differentiation and osteocalcin expression. In summary, the results clearly demonstrate that IGFBP-2 stimulates osteoblast differentiation and that this effect is mediated through its heparin binding domain-1 interacting with RPTPĪ². The results suggest that stimulation of differentiation is an important mechanism by which IGFBP-2 regulates the acquisition of normal bone mass in mice
Metabolic programming determines the lineage-differentiation fate of murine bone marrow stromal progenitor cells
Enhanced bone marrow adipogenesis and impaired osteoblastogenesis have been observed in obesity, suggesting that the metabolic microenvironment regulates bone marrow adipocyte and osteoblast progenitor differentiation fate. To determine the molecular mechanisms, we studied two immortalized murine cell lines of adipocyte or osteoblast progenitors (BMSC
Association of Receiving Multiple, Concurrent Fracture-Associated Drugs With Hip Fracture Risk
Importance: Many prescription drugs increase fracture risk, which raises concern for patients receiving 2 or more such drugs concurrently. Logic suggests that risk will increase with each additional drug, but the risk of taking multiple fracture-associated drugs (FADs) is unknown.
Objective: To estimate hip fracture risk associated with concurrent exposure to multiple FADs.
Design, Setting, and Participants: This cohort study used a 20% random sample of Medicare fee-for-service administrative data for age-eligible Medicare beneficiaries from 2004 to 2014. Sex-stratified Cox regression models estimated hip fracture risk associated with current receipt of 1, 2, or 3 or more of 21 FADs and, separately, risk associated with each FAD and 2-way FAD combination vs no FADs. Models included sociodemographic characteristics, comorbidities, and use of non-FAD medications. Analyses began in November 2018 and were completed April 2019.
Exposure: Receipt of prescription FADs.
Main Outcomes and Measures: Hip fracture hospitalization.
Results: A total of 11.3 million person-years were observed, reflecting 2,646,255 individuals (mean [SD] age, 77.2 [7.3] years, 1,615,613 [61.1%] women, 2,136,585 [80.7%] white, and 219āÆ579 [8.3%] black). Overall, 2,827,284 person-years (25.1%) involved receipt of 1 FAD; 1,322,296 (11.7%), 2 FADs; and 954,506 (8.5%), 3 or more FADs. In fully adjusted, sex-stratified models, an increase in hip fracture risk among women was associated with the receipt of 1, 2, or 3 or more FADs (1 FAD: hazard ratio [HR], 2.04; 95% CI, 1.99-2.11; P\u3c.001; 2 FADs: HR, 2.86; 95% CI, 2.77-2.95; P\u3c.001; ā„3 FADs: HR, 4.50; 95% CI, 4.36-4.65; P\u3c.001). Relative risks for men were slightly higher (1 FAD: HR, 2.23; 95% CI, 2.11-2.36; P\u3c.001; 2 FADs: HR, 3.40; 95% CI, 3.20-3.61; P\u3c.001; ā„3 FADs: HR, 5.18; 95% CI, 4.87-5.52; P\u3c.001). Among women, 2 individual FADs were associated with HRs greater than 3.00; 80 pairs of FADs exceeded this threshold. Common, risky pairs among women included sedative hypnotics plus opioids (HR, 4.90; 95% CI, 3.98-6.02; P\u3c.001), serotonin reuptake inhibitors plus benzodiazepines (HR, 4.50; 95% CI, 3.76-5.38; P\u3c.001), and proton pump inhibitors plus opioids (HR, 4.00; 95% CI, 3.56-4.49; P\u3c.001). Receipt of 1, 2, or 3 or more non-FADs was associated with a small, significant reduction in fracture risk compared with receipt of no non-FADs among women (1 non-FAD: HR, 0.93; 95% CI, 0.90-0.96; P\u3c.001; 2 non-FADs: HR, 0.84; 95% CI, 0.81-0.87; P\u3c.001; ā„3 non-FADs: HR, 0.74; 95% CI, 0.72-0.77; P\u3c.001).
Conclusions and Relevance: Among older adults, FADs are commonly used and commonly combined. In this cohort study, the addition of a second and third FAD was associated with a steep increase in fracture risk. Many risky pairs of FADs included potentially avoidable drugs (eg, sedatives and opioids). If confirmed, these findings suggest that fracture risk could be reduced through tighter adherence to long-established prescribing guidelines and recommendations
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Deficiency of Retinaldehyde Dehydrogenase 1 Induces BMP2 and Increases Bone Mass In Vivo
The effects of retinoids, the structural derivatives of vitamin A (retinol), on post-natal peak bone density acquisition and skeletal remodeling are complex and compartment specific. Emerging data indicates that retinoids, such as all trans retinoic acid (ATRA) and its precursor all trans retinaldehyde (Rald), exhibit distinct and divergent transcriptional effects in metabolism. Despite these observations, the role of enzymes that control retinoid metabolism in bone remains undefined. In this study, we examined the skeletal phenotype of mice deficient in retinaldehyde dehydrogenase 1 (Aldh1a1), the enzyme responsible for converting Rald to ATRA in adult animals. Bone densitometry and micro-computed tomography (ĀµCT) demonstrated that Aldh1a1-deficient (Aldh1a1ā/ā) female mice had higher trabecular and cortical bone mass compared to age and sex-matched control C57Bl/6 wild type (WT) mice at multiple time points. Histomorphometry confirmed increased cortical bone thickness and demonstrated significantly higher bone marrow adiposity in Aldh1a1ā/ā mice. In serum assays, Aldh1a1ā/ā mice also had higher serum IGF-1 levels. In vitro, primary Aldh1a1ā/ā mesenchymal stem cells (MSCs) expressed significantly higher levels of bone morphogenetic protein 2 (BMP2) and demonstrated enhanced osteoblastogenesis and adipogenesis versus WT MSCs. BMP2 was also expressed at higher levels in the femurs and tibias of Aldh1a1ā/ā mice with accompanying induction of BMP2-regulated responses, including expression of Runx2 and alkaline phosphatase, and Smad phosphorylation. In vitro, Rald, which accumulates in Aldh1a1ā/ā mice, potently induced BMP2 in WT MSCs in a retinoic acid receptor (RAR)-dependent manner, suggesting that Rald is involved in the BMP2 increases seen in Aldh1a1 deficiency in vivo. Collectively, these data implicate Aldh1a1 as a novel determinant of cortical bone density and marrow adiposity in the skeleton in vivo through modulation of BMP signaling
Coastal Geology and Geomorphology of Cape Cod - An Aerial and Ground View
Guidebook for field trips to the Boston area and vicinity : 68th annual meeting, New England Intercollegiate Geological Conference, October 8-10, 1976: Trip A-10; B-1
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