Zoledronic acid improves bone quality and muscle function in a high bone turnover state.

Summary: Zoledronic acid (ZA) prevents muscle weakness in mice with bone metastases; however, its role in muscle weakness in non-tumor-associated metabolic bone diseases and as an effective treatment modality for the prevention of muscle weakness associated with bone disorders, is unknown. We demonstrate the role of ZA-treatment on bone and muscle using a mouse model of accelerated bone remodeling, which represents the clinical manifestation of non-tumor associated metabolic bone disease. ZA increased bone mass and strength and rescued osteocyte lacunocanalicular organization.

Frequently Used Conceptual Frameworks and Design Principles for Extended Reality in Health Professions Education.

Health professions education (HPE) has witnessed a dramatic increase in the use of extended reality (XR), but there is limited evidence that conceptual frameworks are being effectively employed in the design and implementation of XR. This paper introduces commonly utilized conceptual frameworks that can support the integration of XR into the learning process and design principles that can be helpful for the development and evaluation of XR educational applications. Each framework and design principle is summarized briefly, followed by a description of its applicability to XR for HPE and an example of such application.

Implementing Rubric-Based Peer Review for Video Microlecture Design in Health Professions Education.

Efficient and effective instructional materials designed for asynchronous learning are increasingly important in health professions curricula. Video microlectures are an effective instructional method, but many faculty lack training in applying best-practice multimedia principles to development of their own recorded microlectures. Here we report a rubric designed for use in a peer-review process to evaluate and improve microlectures.

Effect of Video Conferencing on Student Academic Performance: Evidence from Preclinical Summative Assessment Scores.

Anecdotal evidence suggests learners experience fatigue and burnout from multiple hours on virtual platforms. We compared summative exam performance data of second year preclinical medical students in a medical neuroscience course over consecutive years in which interactive synchronous activities occurred in-person (2019) or entirely online (2020). Exam items that assessed interactive, synchronously delivered content in 2020 had mean scores that were significantly lower than 2019.

Therapeutic targeting of immune checkpoints with small molecule inhibitors.

Immune checkpoints are known to contribute to tumor progression by enhancing cancer's ability to evade the immune system and metastasize. Immunotherapies, including monoclonal antibodies, have been developed to target specific immunosuppressive molecules on the membranes of cancer cells and have proven revolutionary in the field of oncology. Recently, small molecule inhibitors (SMIs) have gained increased attention in cancer research with potential applications in immunotherapy.

Dehydration: A Multidisciplinary Case-Based Discussion for First-Year Medical Students.

Introduction: As many medical school curricula shift to integrated learning of multiple basic science topics as well as clinical concepts, there is an increasing need for instructional materials that incorporate multiple topics yet are targeted to the knowledge basis of first-year medical students. This interactive case-based session for first-year medical students centers on the clinical presentation and initial evaluation of a patient experiencing dehydration after running a marathon in a high-altitude city.

Methods: After completion of assigned out-of-class preparation, students followed the patient from a healthy state to moderate dehydration over the course of two 2-hour class sessions.

Osteolytic Breast Cancer Causes Skeletal Muscle Weakness in an Immunocompetent Syngeneic Mouse Model.

Muscle weakness and cachexia are significant paraneoplastic syndromes of many advanced cancers. Osteolytic bone metastases are common in advanced breast cancer and are a major contributor to decreased survival, performance, and quality of life for patients. Pathologic fracture caused by osteolytic cancer in bone (OCIB) leads to a significant (32%) increased risk of death compared to patients without fracture.

Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling.

Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current lack of strategies to diagnose or treat bone quality deficits. Transforming growth factor beta (TGF-β) signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown.

The Role of TGFβ in Bone-Muscle Crosstalk.

Purpose Of Review: The role of bone-derived factors in regulation of skeletal muscle function is an important emerging aspect of research into bone-muscle crosstalk. Implications for this area of research are far reaching and include understanding skeletal muscle weakness in cancer, osteoporosis, cachexia, rare diseases of bone, and aging.

Recent Findings: Recent research shows that bone-derived factors can lead to changes in the skeletal muscle.

Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates muscle weakness in vivo.

Aromatase inhibitors (AIs) cause muscle weakness, bone loss, and joint pain in up to half of cancer patients. Preclinical studies have demonstrated that increased osteoclastic bone resorption can impair muscle contractility and prime the bone microenvironment to accelerate metastatic growth. We hypothesized that AI-induced bone loss could increase breast cancer progression in bone and exacerbate muscle weakness associated with bone metastases.

The P2Y nucleotide receptor is an inhibitor of vascular calcification.

Background And Aims: Mutations in the 5'-nucleotidase ecto (NT5E) gene that encodes CD73, a nucleotidase that converts AMP to adenosine, are linked to arterial calcification. However, the role of purinergic receptor signaling in the pathology of intimal calcification is not well understood. In this study, we examined whether extracellular nucleotides acting via P2Y receptor (P2YR) modulate arterial intimal calcification, a condition highly correlated with cardiovascular morbidity.

Differentiated Smooth Muscle Cells Generate a Subpopulation of Resident Vascular Progenitor Cells in the Adventitia Regulated by Klf4.

Rationale: The vascular adventitia is a complex layer of the vessel wall consisting of vasa vasorum microvessels, nerves, fibroblasts, immune cells, and resident progenitor cells. Adventitial progenitors express the stem cell markers, Sca1 and CD34 (adventitial sca1-positive progenitor cells [AdvSca1]), have the potential to differentiate in vitro into multiple lineages, and potentially contribute to intimal lesions in vivo.

Objective: Although emerging data support the existence of AdvSca1 cells, the goal of this study was to determine their origin, degree of multipotency and heterogeneity, and contribution to vessel remodeling.

Skeletal muscle Ca(2+) mishandling: Another effect of bone-to-muscle signaling.

Our appreciation of crosstalk between muscle and bone has recently expanded beyond mechanical force-driven events to encompass a variety of signaling factors originating in one tissue and communicating to the other. While the recent identification of new 'myokines' has shifted some focus to the role of muscle in this partnership, bone-derived factors and their effects on skeletal muscle should not be overlooked. This review summarizes some previously known mediators of bone-to-muscle signaling and also recent work identifying a new role for bone-derived TGF-β as a cause of skeletal muscle weakness in the setting of cancer-induced bone destruction.

Up-regulation of glycolytic metabolism is required for HIF1α-driven bone formation.

The bone marrow environment is among the most hypoxic in the body, but how hypoxia affects bone formation is not known. Because low oxygen tension stabilizes hypoxia-inducible factor alpha (HIFα) proteins, we have investigated the effect of expressing a stabilized form of HIF1α in osteoblast precursors. Brief stabilization of HIF1α in SP7-positive cells in postnatal mice dramatically stimulated cancellous bone formation via marked expansion of the osteoblast population.

Radioactive in situ hybridization to detect gene expression in skeletal tissue sections.

In situ hybridization (ISH) using RNA probes is a valuable technique to characterize gene expression patterns in animal tissues. It provides valuable spatial information about gene expression. Compared to the nonradioactive alternatives,(35)S radioactive ISH generally provides higher sensitivity.

Osx-Cre targets multiple cell types besides osteoblast lineage in postnatal mice.

Osterix (Osx or Sp7) is a zinc-finger-family transcriptional factor essential for osteoblast differentiation in mammals. The Osx-Cre mouse line (also known as Osx1-GFP::Cre) expresses GFP::Cre fusion protein from a BAC transgene containing the Osx regulatory sequence. The mouse strain was initially characterized during embryogenesis, and found to target mainly osteoblast-lineage cells.

Tbx18 regulates development of the epicardium and coronary vessels.

The epicardium and coronary vessels originate from progenitor cells in the proepicardium. Here we show that Tbx18, a T-box family member highly expressed in the proepicardium, controls critical early steps in coronary development. In Tbx18(-/-) mouse embryos, both the epicardium and coronary vessels exhibit structural and functional defects.

Notch signaling and bone remodeling.

Notch signaling plays context-dependent roles in the development and maintenance of many cell types and tissues in mammals. In the skeleton, both osteoblasts and osteoclasts require Notch signaling for proper differentiation and function, and the specific roles of Notch are dependent on the differentiation status of the cell. The recent discovery of activating NOTCH2 mutations as the cause of Hajdu-Cheney syndrome has highlighted the significance of Notch signaling in human bone physiology.

Wnt1/βcatenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair.

Wnts are required for cardiogenesis but the role of specific Wnts in cardiac repair remains unknown. In this report, we show that a dynamic Wnt1/βcatenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair. Acute ischaemic cardiac injury upregulates Wnt1 that is initially expressed in the epicardium and subsequently by cardiac fibroblasts in the region of injury.

Vascular smooth muscle progenitor cells: building and repairing blood vessels.

Molecular pathways that control the specification, migration, and number of available smooth muscle progenitor cells play key roles in determining blood vessel size and structure, capacity for tissue repair, and progression of age-related disorders. Defects in these pathways produce malformations of developing blood vessels, depletion of smooth muscle progenitor cell pools for vessel wall maintenance and repair, and aberrant activation of alternative differentiation pathways in vascular disease. A better understanding of the molecular mechanisms that uniquely specify and maintain vascular smooth muscle cell precursors is essential if we are to use advances in stem and progenitor cell biology and somatic cell reprogramming for applications directed to the vessel wall.

Loss of microRNAs in neural crest leads to cardiovascular syndromes resembling human congenital heart defects.

Objective: Congenital heart defects represent the most common human birth defects. Even though the genetic cause of these syndromes has been linked to candidate genes, the underlying molecular mechanisms are still largely unknown. Disturbance of neural crest cell (NCC) migration into the derivatives of the pharyngeal arches and pouches can account for many of the developmental defects.