Using Real-Time Cell Metabolic Flux Analyzer to Monitor Osteoblast Bioenergetics.

Bone formation by osteoblasts is an essential process for proper bone acquisition and bone turnover to maintain skeletal homeostasis, and ultimately, prevent fracture. In the interest to both optimize peak bone mass and combat various musculoskeletal diseases (i.e.

Variable Response to Antifibrinolytics Correlates with Blood-loss and Transfusion in Posterior Spinal Fusion.

Purpose: Posterior spinal fusion (PSF) activates the fibrinolytic protease plasmin, which is implicated in blood loss and transfusion. While antifibrinolytic drugs have improved blood loss and reduced transfusion, variable blood loss has been observed in similar PSF procedures treated with the same dose of antifibrinolytics. However, both the cause of this and the appropriate measures to determine antifibrinolytic efficacy during high-blood-loss spine surgery are unknown, making clinical trials to optimize antifibrinolytic dosing in PSF difficult.

Quantitative Analysis of Growth Factors From Cancellous Bone Graft Collected With a Reamer-Irrigator-Aspirator System From Native Long Bones Versus Previously Reamed Long Bones.

Objective: Collection of bone graft with the Reamer-Irrigator-Aspirator (RIA) system has become common practice across the field of orthopaedic surgery. While RIA bone graft is typically obtained from native long bones, grafting material can likewise be harvested from long bones that have previously undergone the placement and removal of an intramedullary nail, a process termed re-reamed RIA (RRR). The purpose of this study was to evaluate the total protein and growth factor concentrations present in native-RIA (NR) compared with RRR samples.

A Perfusion Bioreactor Model of Tumor-Induced Bone Disease Using Human Cells.

Advanced solid tumors often metastasize to bone. Once established in bone, these tumors can induce bone destruction resulting in decreased quality of life and increased mortality. Neither 2D in vitro models nor 3D animal models sufficiently recapitulate the human bone-tumor microenvironment needed to fully understand the complexities of bone metastasis, highlighting the need for new models.

Metabolic Adaptations During and Co-Infection.

Successful pathogens require metabolic flexibility to adapt to diverse host niches. The presence of co-infecting or commensal microorganisms at a given infection site can further influence the metabolic processes required for a pathogen to cause disease. The Gram-positive bacterium and the polymorphic fungus are microorganisms that asymptomatically colonize healthy individuals but can also cause superficial infections or severe invasive disease.

HDAC inhibitors stimulate LIFR when it is repressed by hypoxia or PTHrP in breast cancer.

Breast cancer cells frequently disseminate to the bone marrow, where they either induce osteolysis or enter a dormant state. Downregulation of leukemia inhibitory factor receptor (LIFR), a known breast tumor suppressor, enables otherwise dormant MCF7 human breast cancer cells to become aggressively osteolytic. Hypoxia (low oxygen tensions), which may develop in tumors as a pathological response to the metabolic demands of the proliferating cells and as a physiological state in the bone, downregulates LIFR in breast cancer cells independent of hypoxia-inducible factor (HIF) signaling.

Bruise Location in Supracondylar Humerus Fractures Predicts Specific Neurovascular Injuries.

Purpose: The presence of soft tissue injury in pediatric supracondylar humerus fractures (SCHFs) has been shown to be an independent predictor of any neurovascular injury. Potentially expanding this concept, the specific neurovascular structure injured around the elbow is thought to be dependent upon the direction and magnitude of fracture displacement and subsequent soft tissue injury. Therefore, it was hypothesized that the bruise location following SCHF is indicative of the anatomic location of maximal soft tissue injury and therefore is a specific prognosticator of which neurovascular structure may be injured.

Genetic heterogeneity of heritable ectopic mineralization disorders in a large international cohort.

Purpose: Heritable ectopic mineralization disorders comprise a group of conditions with a broad range of clinical manifestations in nonskeletal connective tissues. We report the genetic findings from a large international cohort of 478 patients afflicted with ectopic mineralization.

Methods: Sequence variations were identified using a next-generation sequencing panel consisting of 29 genes reported in association with ectopic mineralization.

Plasmin drives burn-induced systemic inflammatory response syndrome.

Severe injuries, such as burns, provoke a systemic inflammatory response syndrome (SIRS) that imposes pathology on all organs. Simultaneously, severe injury also elicits activation of the fibrinolytic protease plasmin. While the principal adverse outcome of plasmin activation in severe injury is compromised hemostasis, plasmin also possesses proinflammatory properties.

Effect of Intramedullary Nailing Patterns on Interfragmentary Strain in a Mouse Femur Fracture: A Parametric Finite Element Analysis.

Delayed long bone fracture healing and nonunion continue to be a significant socioeconomic burden. While mechanical stimulation is known to be an important determinant of the bone repair process, understanding how the magnitude, mode, and commencement of interfragmentary strain (IFS) affect fracture healing can guide new therapeutic strategies to prevent delayed healing or nonunion. Mouse models provide a means to investigate the molecular and cellular aspects of fracture repair, yet there is only one commercially available, clinically-relevant, locking intramedullary nail (IMN) currently available for studying long bone fractures in rodents.

Compositional assessment of bone by Raman spectroscopy.

Raman spectroscopy (RS) is used to analyze the physiochemical properties of bone because it is non-destructive and requires minimal sample preparation. With over two decades of research involving measurements of mineral-to-matrix ratio, type-B carbonate substitution, crystallinity, and other compositional characteristics of the bone matrix by RS, there are multiple methods to acquire Raman signals from bone, to process those signals, and to determine peak ratios including sub-peak ratios as well as the full-width at half maximum of the most prominent Raman peak, which is nu1 phosphate (νPO). Selecting which methods to use is not always clear.

Determining the pharmacologic window of bisphosphonates that mitigates severe injury-induced osteoporosis and muscle calcification, while preserving fracture repair.

Unlabelled: Following severe injury, biomineralization is disrupted and limited therapeutic options exist to correct these pathologic changes. This study utilized a clinically relevant murine model of polytrauma including a severe injury with concomitant musculoskeletal injuries to identify when bisphosphonate administration can prevent the paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues, yet not interfere with musculoskeletal repair.

Introduction: Systemic and intrinsic mechanisms in bone and soft tissues help promote biomineralization to the skeleton, while preventing it in soft tissues.

A Mini-Open Approach to Medial Pinning in Pediatric Supracondylar Humeral Fractures May Be Safer Than Previously Thought.

Background: Displaced pediatric supracondylar humeral fractures (SCHFs) are stabilized after reduction by smooth pins. Although some SCHFs are biomechanically stable after lateral-only entry pinning (lateral pinning), an additional medial entry pin (cross-pinning) confers superior stabilization in some SCHFs. There is a recognized risk of iatrogenic ulnar nerve injury with medial entry pinning.

Dormancy in the Tumor Microenvironment.

Tumor cells frequently disseminate to distant organ sites, where they encounter permissive or restrictive environments that enable them to grow and colonize or enter a dormant state. Tumor dormancy is not strictly defined, but generally describes a tumor cell that is non-proliferative or in a state of balanced equilibrium, in which the proliferation rate of the tumor cell or cells is equal to its rate of cell death. The mechanisms that regulate tumor cell entry into and exit from dormancy are poorly understood, but microenvironmental features as well as tumor cell intrinsic factors play an important role in mediating this transition.

Hypoxia inducible factor signaling in breast tumors controls spontaneous tumor dissemination in a site-specific manner.

Hypoxia is a common feature in tumors and induces signaling that promotes tumor cell survival, invasion, and metastasis, but the impact of hypoxia inducible factor (HIF) signaling in the primary tumor on dissemination to bone in particular remains unclear. To better understand the contributions of hypoxia inducible factor 1 alpha (HIF1α), HIF2α, and general HIF pathway activation in metastasis, we employ a PyMT-driven spontaneous murine mammary carcinoma model with mammary specific deletion of Hif1α, Hif2α, or von Hippel-Lindau factor (Vhl) using the Cre-lox system. Here we show that Hif1α or Hif2α deletion in the primary tumor decreases metastatic tumor burden in the bone marrow, while Vhl deletion increases bone tumor burden, as hypothesized.

Inhibition of TGF-β Increases Bone Volume and Strength in a Mouse Model of Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI), is a genetic disorder of bone fragility caused by mutations in collagen I or proteins involved in collagen processing. Previous studies in mice and human OI bones have shown that excessive activation of TGF-β signaling plays an important role in dominant and recessive OI disease progression. Inhibition of TGF-β signaling with a murine pan-specific TGF-β neutralizing antibody (1D11) was shown to significantly increase trabecular bone volume and long bone strength in mouse models of OI.

Staphylococcus aureus infections in children.

Purpose Of Review: Staphylococcus aureus is the most common invasive bacterial pathogen infecting children in the U.S. and many parts of the world.

gp130 Cytokines Activate Novel Signaling Pathways and Alter Bone Dissemination in ER+ Breast Cancer Cells.

Breast cancer cells frequently home to the bone marrow, where they encounter signals that promote survival and quiescence or stimulate their proliferation. The interleukin-6 (IL-6) cytokines signal through the co-receptor glycoprotein130 (gp130) and are abundantly secreted within the bone microenvironment. Breast cancer cell expression of leukemia inhibitory factor (LIF) receptor (LIFR)/STAT3 signaling promotes tumor dormancy in the bone, but it is unclear which, if any of the cytokines that signal through LIFR, including LIF, oncostatin M (OSM), and ciliary neurotrophic factor (CNTF), promote tumor dormancy and which signaling pathways are induced.

Internal Rotation Stress Test Reduces Cross-Pinning and Improves Outcomes in Displaced Pediatric Supracondylar Humeral Fractures.

Unlabelled: Stabilization of the medial column is vital in preventing the loss of fixation and malunion in displaced pediatric supracondylar humeral fractures (SCHFs). The preferred percutaneous pin configuration for medial column fixation remains controversial between medial pinning (cross-pinning) and additional lateral-based pinning. The intraoperative internal rotation stress test (IRST) has been proposed to reliably determine the optimal fixation strategy for each unique fracture.

Factors That Drive Annual Variation in Pediatric Elbow Fracture Occurrence, Severity, and Resource Utilization.

Background: Elbow fractures are the most common pediatric fractures requiring operative treatment. To date, few studies have examined what annual factors drive pediatric elbow fracture incidence and no studies have examined which annual factors drive elbow fracture severity or resource utilization. The goal of this study was to not only document the annual patterns of pediatric elbow fracture incidence and severity but also the impact of these patterns on resource utilization in the emergency department, emergency medical service transportation, and the operating room (OR).

Settable Polymeric Autograft Extenders in a Rabbit Radius Model of Bone Formation.

Autograft (AG) is the gold standard for bone grafts, but limited quantities and patient morbidity are associated with its use. AG extenders have been proposed to minimize the volume of AG while maintaining the osteoinductive properties of the implant. In this study, poly(ester urethane) (PEUR) and poly(thioketal urethane) (PTKUR) AG extenders were implanted in a 20-mm rabbit radius defect model to evaluate new bone formation and graft remodeling.

Measurement of Osteoblast Cytotoxicity Induced by S. aureus Secreted Toxins.

Staphylococcus aureus is a Gram-positive bacterium that is capable of infecting and inducing tissue pathology in nearly every organ system. The pathogenesis of staphylococcal infection is dictated, in part, through the production of toxins that induce cellular death through receptor-dependent and -independent mechanisms, thereby contributing to tissue injury. One common manifestation of invasive staphylococcal infection is osteomyelitis, or infection of bone.

HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer.

Despite advances in breast cancer treatment, residual disease driven by dormant tumor cells continues to be a significant clinical problem. Leukemia inhibitory factor receptor (LIFR) promotes a dormancy phenotype in breast cancer cells and LIFR loss is correlated with poor patient survival. Herein, we demonstrate that histone deacetylase inhibitors (HDACi), which are in phase III clinical trials for breast cancer, epigenetically induced LIFR and activated a pro-dormancy program in breast cancer cells.

Bone marrow adipocytes - Good, bad, or just different?

Skeletal remodeling is essential for proper maintenance of adult bone mass, and due to its heavy energetic demands this process is closely tied to whole body metabolic. Thus, bone formation by the osteoblast, bone resorption by the osteoclast, and mechano-sensing by the osteocyte, are highly coupled processes that are essential for bone turnover. When one experiences a disruption in these processes, over time increased skeletal fragility and fracture can result.