Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment primary cancer, emotional psychosocial factors within this population precipitate time to recurrence death, however underlying mechanism(s) remain unclear. Using a mouse model bone metastasis, we provide experimental evidence that activation sympathetic nervous system, which is one many pathophysiological consequences severe stress depression, promotes MDA-231 cancer cell...

The effects of type 1 diabetes on de novo bone formation during tibial distraction osteogenesis (DO) and intact trabecular cortical were studied using nonobese diabetic (NOD) mice comparably aged nondiabetic NOD mice. Diabetic received treatment with insulin, vehicle, or no a 14-day DO procedure. Distracted tibiae analyzed radiographically, histologically, by microcomputed tomography (μCT). Contralateral μCT. Serum levels osteocalcin, cross-linked C-telopeptide I collagen measured. Total new...

Nonunion is a common complication in open fractures and other severe bone injuries. Recombinant human morphogenetic protein-2 (rhBMP-2) delivered on collagen sponge enhances healing of fractures. However, the burst release rhBMP-2 necessitates supra-physiological doses to achieve robust osteogenic effect, which introduces risk ectopic formation inflammation increases cost. Although concept that ideal pharmacokinetics for includes both sustained generally accepted, investigations into effects...

Abstract Silent information regulator T1 (SirT1) is linked to longevity and negatively controls NF-κB signaling, a crucial mediator of survival both osteoclasts osteoblasts. Here we show that repression by SirT1 in osteoblasts necessary for proper bone remodeling may contribute the mechanisms linking aging loss. Osteoclast- or osteoblast-specific deletion using Sirtflox/flox mice crossed lysozyme M-cre 2.3 kb col1a1-cre transgenic mice, respectively, resulted decreased mass caused increased...

IL-17A (IL-17), a driver of the inflammatory phase fracture repair, is produced locally by several cell lineages including γδ T cells and Th17 cells. However, origin these their relevance for repair are unknown. Here, we show that fractures rapidly expanded callus cells, which led to increased gut permeability promoting systemic inflammation. When microbiota contained cell-inducing taxon segmented filamentous bacteria (SFB), activation was followed expansion intestinal migration callus,...

Activating transcription factor 4 (Atf4) is a leucine-zipper-containing protein of the cAMP response element-binding (CREB) family. Ablation Atf4 (Atf4−/−) in mice leads to severe skeletal defects, including delayed ossification and low bone mass, short stature limbs. expressed proliferative prehypertrophic growth plate chondrocytes, suggesting an autonomous function chondrocytes during endochondral ossification. In Atf4−/− plate, typical columnar structure disturbed. The zone shortened,...

Type 1 diabetes mellitus is associated with a number of disorders skeletal health, conditions that rely, in part, on dynamic bone formation. A mouse model distraction osteogenesis was used to study the consequences streptozotocin-induced and insulin treatment formation osteoblastogenesis. In diabetic mice compared control mice, new decreased, adipogenesis increased around, respectively, gaps. Although restored levels observed nondiabetic it failed significantly decrease adipogenesis....

Abstract Matrix metalloproteinases (MMPs) are capable of processing certain components bone tissue, including type 1 collagen, a determinant the biomechanical properties and they expressed by osteoclasts osteoblasts. Therefore, we posit that MMP activity can affect ability to resist fracture. To explore this possibility, determined architectural, compositional, bones from wild-type (WT), Mmp2−/−, Mmp9−/− female mice at 16 weeks age. MMP-2 MMP-9 have similar substrates but primarily...

Chronic inflammation-mediated oxidative stress is a common mechanism of implant rejection and failure. Therefore, polymer scaffolds that can degrade slowly in response to this environment may provide viable platform for site-specific, sustained release immunomodulatory agents over long time period. In work, proline oligomers varying lengths (P(n)) were synthesized exposed environments, their accelerated degradation under conditions was verified via high performance liquid chromatography gel...

The heritable form of pulmonary arterial hypertension (PAH) is typically caused by a mutation in bone morphogenic protein receptor type 2 (BMPR2), and mice expressing Bmpr2 mutations develop PAH with features similar to human disease. BMPR2 known interact the cytoskeleton, array studies patients confirm alterations cytoskeletal pathways. goal this study was evaluate defects BMPR2-associated PAH. Expression arrays on our mutant mouse lungs revealed as prominent molecular consequence universal...

Breast cancer often metastasizes to bone causing osteolytic resorption which releases active TGFβ. Because TGFβ favors progression of breast metastasis bone, we hypothesized that treatment using anti-TGFβ antibody may reduce tumor burden and rescue tumor-associated loss in metastatic cancer. In this study have tested the efficacy an 1D11 preventing metastasis. We used two preclinical models, either human cells or murine mammary were injected host mice via left cardiac ventricle. Using...

Longitudinal clinical studies demonstrate that increases in bone turnover occur perimenopausal women correlate better with elevated serum FSH than changes estradiol (E2). This rise is due to a selective decrease ovarian inhibin B (InhB). Our previous demonstration inhibins suppress both osteoblast and osteoclast development suggests may regulate differentiation thereby turnover, independent of sex steroids.The objective this study was determine whether decreased A (InhA) InhB levels markers...

Gonadal function plays a major role in bone homeostasis. It is widely held that the skeletal consequences of hypogonadism are solely due to loss sex steroids; however, increases turnover begin during perimenopause before decreases serum estradiol levels. These data and our demonstration inhibins acutely regulate cell differentiation vitro led us test whether inhibin A (InhA) regulates mass vivo. Using transgenic model inducible human InhA expression, increased total body mineral density,...

Bone metastases are frequent complications of malignant melanoma leading to reduced quality life and significant morbidity. Regulation immune cells by the gut microbiome influences cancer progression, but role in tumor growth bone is unknown. Using intracardiac or intratibial injections B16-F10 into mice, we showed that depletion broad-spectrum antibiotics accelerated intraosseous osteolysis. Microbiome blunted melanoma-induced expansion intestinal NK Th1 their migration from tumor-bearing...

DO was used in an aged mouse model to determine if systemically and/or locally administered rhIGF-I improved osteoblastogenesis and new bone formation. Local systemic treatment increased However, only delivery produced measurable concentrations of the circulation.Human rodent research supports a primary role for IGF-I Significant roles both endocrine paracrine/autocrine have been suggested normal We assessed, using distraction osteogenesis (DO), impact continuous administration recombinant...

ABSTRACT The inner ear vestibular system has numerous projections on central brain centers that regulate sympathetic outflow, and skeletal affect bone remodeling by inhibiting formation osteoblasts promoting resorption osteoclasts. In this study, we show bilateral lesions in mice cause a low mass phenotype associated with decreased increased resorption. This reduction is most pronounced lower limbs, not reduced locomotor activity or chronic inflammation, could be prevented the administration...

Disuse has been shown to cause a rapid and dramatic loss of skeletal mass strength in the load-bearing bones young mature animals humans. However, little is known about effects disuse aged mammals. The present study was designed determine whether are maintained with extreme age. Fischer 344/Brown Norway male rats (6 32 mo old) were hindlimb suspended (HS) or housed individually for 2 wk. Trabecular volume microarchitecture proximal tibia significantly decreased by HS only rats. reduced...

ABSTRACT Neurofibromatosis type I (NF1) is an autosomal dominant disease with incidence of 1/3000, caused by mutations in the NF1 gene, which encodes RAS/GTPase-activating protein neurofibromin. Non-bone union after fracture (pseudarthrosis) children remains a challenging orthopedic condition to treat. Recent progress understanding biology neurofibromin suggested that pseudarthrosis stems primarily from defects bone mesenchymal lineage and hypersensitivity hematopoietic cells TGFβ. However,...