• bone defect
• bone union Bone reconstruction
• induced membrane
• open fracture

• Humans
• Male
• Female
• Retrospective Studies
• Fracture Healing/physiology
• Adult
• Bone Transplantation/methods
• Tibial Fractures/surgery
• Tibial Fractures/diagnostic imaging
• Middle Aged
• Tomography, X-Ray Computed
• Young Adult
• Aged
• Fractures, Ununited/surgery
• Fractures, Ununited/diagnostic imaging

• Q202370 Research Project of Wuxi Health Commission

• Bone
• Nonunion
• Prediction model
• Scores
• Tibial fracture
• Trauma

• Aging
• Bone biology
• Bone disease
• Cellular senescence

• Animals
• Male
• Mice
• Biomarkers/metabolism
• Cellular Senescence
• Cyclin-Dependent Kinase Inhibitor p16/metabolism
• Cyclin-Dependent Kinase Inhibitor p16/genetics
• Cyclin-Dependent Kinase Inhibitor p21/metabolism
• Cyclin-Dependent Kinase Inhibitor p21/genetics
• Fracture Healing
• Mesenchymal Stem Cells/metabolism
• Neutrophils/metabolism
• Neutrophils/pathology
• Female

• R01 DK128552 NIDDK NIH HHS
• R01 AG082681 NIA NIH HHS
• R01 AG076515 NIA NIH HHS
• R01 AG082708 NIA NIH HHS
• R01 AG068048 NIA NIH HHS
• UG3 CA268103 NCI NIH HHS
• R01 AG063707 NIA NIH HHS
• UH3 CA268103 NCI NIH HHS
• P01 AG062413 NIA NIH HHS
• National Institute on Aging
• National Institute of Diabetes and Digestive and Kidney Diseases
• National Cancer Institute

• FNDC5/irisin
• M6A
• Maternal
• Mitophagy
• OPTN
• Osteoporosis
• Prednisone
• Skeletal muscle

• Humans
• Mice
• Female
• Animals
• Pregnancy
• Prednisone/metabolism
• Fibronectins/metabolism
• Maternal Exposure
• Mitophagy
• Muscle, Skeletal/metabolism
• Transcription Factors/metabolism
• Osteoporosis/chemically induced

• R01 AG082681 NIA NIH HHS
• T32 AG049672 NIA NIH HHS
• UH3 CA268103 NCI NIH HHS
• R01 AG082708 NIA NIH HHS
• R01 AG068048 NIA NIH HHS
• UG3 CA268103 NCI NIH HHS

• fracture healing
• fracture nonunion
• zucker rats
• type 2 diabetes mellitus
• fracture and of the healing
• gene expression
• rats
• mrna
• inflammation
• fracture callus
• rna
• external fixators
• femoral fractures
• femoral osteotomy

• computational biology and bioinformatics
• systems biology

• Proteomics/methods
• Drug Repositioning
• Proteins
• Biomarkers

• 01ZX2210D Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
• 01ZX1910D Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
• 01ZX1910D Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
• 01ZX1910B Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
• 161L0214A Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
• 161L0214A Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
• 777111 EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
• 101057619 EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
• 13154 Villum Fonden (Villum Foundation)
• 22.00115 Federal Department of Economic Affairs, Education and Research, Switzerland | Staatssekretariat für Bildung, Forschung und Innovation (State Secretariat for Education, Research and Innovation)

• Bisphosphonates
• Drug delivery systems
• Drug effects
• Implant
• Osseointegration

• corticosteroid
• heterophil
• intervertebral disc
• necroptosis
• nucleus pulposus

• Animals
• Birds
• Inflammation
• Biological Evolution
• Spine
• Neutrophils

• P20GM121342 SC-TRIMH
• Gerry Ohrstrom

• Atypical fractures
• Bone abnormalities
• Bone structure
• Disorganized bone tissue
• Fragility fractures
• Ineffective load conduction or transfer

• aging
• bone
• bone healing
• fracture
• fracture healing
• osteoporosis
• senescence

• bracing
• spondylolisthesis
• spondylolysis
• therapeutic exercise

• Humans
• Spondylolysis/complications
• Spondylolysis/diagnosis
• Spondylolisthesis/therapy
• Spondylolisthesis/diagnosis
• Spondylolisthesis/etiology
• Sports
• Exercise Therapy/adverse effects
• Pain
• Lumbar Vertebrae

Forensic anthropologists analyze human remains to assist in the identification of the deceased, predominantly by assessing age-at-death, sex, stature, ancestry and any unique identifying features. Whilst methods have been established to create this biological profile of the skeleton, these may be influenced by a number of factors. This paper, for the first time, provides an overview from a reading of the clinical and pharmacological literature to explore whether the intake of drugs can affect the skeleton and whether these may have implications for forensic anthropology casework. In effect, drugs such as tobacco, heroin, and prescription medications can alter bone mineral density, can increase the risk of fractures, destroy bone and changes to the dentition. By considering how drugs can affect the skeleton, forensic anthropologists can be aware of this when attempting to identify the deceased.

Forensic anthropologists rely on a number of parameters when analyzing human skeletal remains to assist in the identification of the deceased, predominantly age-at-death, sex, stature, ancestry or population affinity, and any unique identifying features. During the examination of human remains, it is important to be aware that the skeletal features considered when applying anthropological methods may be influenced and modified by a number of factors, and particular to this article, prescription drugs (including medical and non-medical use) and other commonly used drugs. In view of this, this paper aims to review the medical, clinical and pharmacological literature to enable an assessment of those drug groups that as side effects have the potential to have an adverse effect on the skeleton, and explore whether or not they can influence the estimation of age-at-death, sex and other indicators of the biological profile. Moreover, it may be that the observation of certain alterations or inconsistencies in the skeleton may relate to the use of drugs or medication, and this in turn may help narrow down the list of missing persons to which a set of human remains could belong. The information gathered from the clinical and medical literature has been extracted with a forensic anthropological perspective and provides an awareness on how several drugs, such as opioids, cocaine, corticosteroids, non-steroidal anti-inflammatory drugs, alcohol, tobacco and others have notable effects on bone. Through different mechanisms, drugs can alter bone mineral density, causing osteopenia, osteoporosis, increase the risk of fractures, osteonecrosis, and oral changes. Not much has been written on the influence of drugs on the skeleton from the forensic anthropological practitioner perspective; and this review, in spite of its limitations and the requirement of further research, aims to investigate the current knowledge of the possible effects of both prescription and recreational drugs on bones, contributing to providing a better awareness in forensic anthropological practice and assisting in the identification process of the deceased.

Pulsed electromagnetic fields (PEMFs) are a type of biophysical stimulation that has been shown to be effective in improving bone regeneration and preventing bone loss. Their use dates back to the 1970s, but a gold standard treatment protocol has not yet been defined. PEMF efficacy relies on the generation of biopotentials, which activate several molecular pathways. There is currently no clear understanding of the effects on bone healing and, in addition, there are several animal models relevant to this issue. Therefore, drawing guidelines and conclusions from the analysis of the studies is difficult. In vivo investigations on PEMF stimulation are reviewed in this paper, focusing on molecular and morphological improvements in bone. Currently, there is little knowledge about the biological mechanism of PEMF and its effect on bone healing. This is due to the variability of crucial characteristics of electro-magnetic fields, such as amplitude and exposure frequency, which may influence the type of biological response. Furthermore, a different responsiveness of cells involved in the bone healing process is documented. Heterogeneous setting parameters and different outcome measures are considered in various animal models. Therefore, achieving comparable results is difficult.

Biophysical energies are a versatile tool to stimulate tissues by generating biopotentials. In particular, pulsed electromagnetic field (PEMF) stimulation has intrigued researchers since the 1970s. To date, many investigations have been carried out in vivo, but a gold standard treatment protocol has not yet been defined. The main obstacles are represented by the complex setting of PEMF characteristics, the variety of animal models (including direct and indirect bone damage) and the lack of a complete understanding of the molecular pathways involved. In the present review the main studies about PEMF stimulation in animal models with bone impairment were reviewed. PEMF signal characteristics were investigated, as well as their effect on molecular pathways and osseous morphological features. We believe that this review might be a useful starting point for a prospective study in a clinical setting. Consistent evidence from the literature suggests a potential beneficial role of PEMF in clinical practice. Nevertheless, the wide variability of selected parameters (frequency, duration, and amplitude) and the heterogeneity of applied protocols make it difficult to draw certain conclusions about PEMF effectiveness in clinical implementation to promote bone healing. Deepening the knowledge regarding the most consistent results reported in literature to date, we believe that this review may be a useful starting point to propose standardized experimental guidelines. This might provide a solid base for further controlled trials, to investigate PEMF efficacy in bone damage conditions during routine clinical practice.

• bone
• cyclin-dependent kinase 5
• fracture healing
• glucocorticoid-induced osteoporosis
• glucocorticoids
• osteoblasts
• osteoclasts
• osteocytes
• roscovitine

Hemophagocytic lymphohistiocytosis (HLH) is an underdiagnosed, rare clinical syndrome, in particular secondary HLH, which mostly affects adults. HLH can be caused by malignancy, infections, autoimmune disorders, and, rarely, trauma. Here, we present the case of a patient who presented with anemia not responding to blood transfusion but improved after treatment with intravenous immunoglobulin. This case aims to highlight a rare presentation of this disease (HLH secondary to trauma) and to discuss the current HLH diagnostic criteria.

Cellular senescence is considered a physiological process along with aging and has recently been reported to be involved in the pathogenesis of many age-related disorders. Cellular senescence was first found in human fibroblasts and gradually explored in many other organs, including endocrine organs. The adrenal cortex is essential for the maintenance of blood volume, carbohydrate metabolism, reaction to stress and the development of sexual characteristics. Recently, the adrenal cortex was reported to harbor some obvious age-dependent features. For instance, the circulating levels of aldosterone and adrenal androgen gradually descend, whereas those of cortisol increase with aging. The detailed mechanisms have remained unknown, but cellular senescence was considered to play an essential role in age-related changes of the adrenal cortex. Recent studies have demonstrated that the senescent phenotype of zona glomerulosa (ZG) acts in association with reduced aldosterone production in both physiological and pathological aldosterone-producing cells, whereas senescent cortical-producing cells seemed not to have a suppressed cortisol-producing ability. In addition, accumulated lipofuscin formation, telomere shortening and cellular atrophy in zona reticularis cells during aging may account for the age-dependent decline in adrenal androgen levels. In adrenocortical disorders, including both aldosterone-producing adenoma (APA) and cortisol-producing adenoma (CPA), different cellular subtypes of tumor cells presented divergent senescent phenotypes, whereby compact cells in both APA and CPA harbored more senescent phenotypes than clear cells. Autonomous cortisol production from CPA reinforced a local cellular senescence that was more severe than that in APA. Adrenocortical carcinoma (ACC) was also reported to harbor oncogene-induced senescence, which compensatorily follows carcinogenesis and tumor progress. Adrenocortical steroids can induce not only a local senescence but also a periphery senescence in many other tissues. Therefore, herein, we systemically review the recent advances related to cellular senescence in adrenocortical biology and its associated disorders.

• adrenal cortex
• aging
• cellular senescence
• compact and clear cells

• extracellular matrix
• extremely low frequency pulsed electromagnetic fields (ELF-PEMFs)
• fracture healing
• macrophages
• mesenchymal stem/stromal cells

• EH 471/2 Deutsche Forschungsgemeinschaft
• Stipend China Scholarship Council

Senescent cells have detrimental effects across tissues with aging but may have beneficial effects on tissue repair, specifically on skin wound healing. However, the potential role of senescent cells in fracture healing has not been defined. Here, we performed an in silico analysis of public mRNAseq data and found that senescence and senescence-associated secretory phenotype (SASP) markers increased during fracture healing. We next directly established that the expression of senescence biomarkers increased markedly during murine fracture healing. We also identified cells in the fracture callus that displayed hallmarks of senescence, including distension of satellite heterochromatin and telomeric DNA damage; the specific identity of these cells, however, requires further characterization. Then, using a genetic mouse model (Cdkn2a^LUC) containing a Cdkn2a^Ink4a-driven luciferase reporter, we demonstrated transient in vivo senescent cell accumulation during callus formation. Finally, we intermittently treated young adult mice following fracture with drugs that selectively eliminate senescent cells (‘senolytics’, Dasatinib plus Quercetin), and showed that this regimen both decreased senescence and SASP markers in the fracture callus and significantly accelerated the time course of fracture healing. Our findings thus demonstrate that senescent cells accumulate transiently in the murine fracture callus and, in contrast to the skin, their clearance does not impair but rather improves fracture healing.

• bone
• callus
• fracture
• medicine
• mouse

• bone healing
• bone inflammation
• fracture repair
• osteomyelitis

• animal model
• delayed union
• fracture
• impaired healing
• nonunion

Osteopenia and osteoporosis are bone disorders characterized by reduced bone mineral density (BMD), altered bone microarchitecture and increased bone fragility. Because of global aging, their incidence is rapidly increasing worldwide and novel treatments that would be more efficient at preventing disease progression and at reducing the risk of bone fractures are needed. Preclinical studies are today a major bottleneck to the collection of new data and the discovery of new drugs, since they are commonly based on rodent in vivo systems that are time consuming and expensive, or in vitro systems that do not exactly recapitulate the complexity of low BMD disorders. In this regard, teleost fish, in particular zebrafish and medaka, have recently emerged as suitable alternatives to study bone formation and mineralization and to model human bone disorders. In addition to the many technical advantages that allow faster and larger studies, the availability of several fish models that efficiently mimic human osteopenia and osteoporosis phenotypes has stimulated the interest of the academia and industry toward a better understanding of the mechanisms of pathogenesis but also toward the discovery of new bone anabolic or antiresorptive compounds. This mini review recapitulates the in vivo teleost fish systems available to study low BMD disorders and highlights their applications and the recent advances in the field.

• bone anabolic compounds
• fish model
• induced osteoporosis
• screening
• teleosts

• Cannabidiol
• cytotoxicity
• dexamethasone
• inflammation
• macrophages

• Autophagy/drug effects
• Cannabidiol/pharmacology
• Chemokine CCL2/metabolism
• Chemokine CCL5/metabolism
• Cyclooxygenase 2/metabolism
• Dexamethasone/pharmacology
• Humans
• Intercellular Signaling Peptides and Proteins/metabolism
• Interleukin-10/metabolism
• Interleukin-1beta/metabolism
• Interleukin-6/metabolism
• Lipopolysaccharides/pharmacology
• Macrophages/drug effects
• Macrophages/metabolism
• Monocytes/metabolism
• Nitric Oxide Synthase/metabolism
• Oxidative Stress/drug effects
• TOR Serine-Threonine Kinases/metabolism
• Tumor Necrosis Factor-alpha/metabolism

• T32 GM067545 NIGMS NIH HHS

• Arthrodesis
• Bilateral
• Metatarsophalangeal joint (MTPJ)
• Sequential

• glucocorticoid receptor
• osteoblast
• osteoclast
• osteoporosis
• transgenic mice

• Glucocorticoids/metabolism
• Homeostasis
• Humans
• Osteoclasts/metabolism
• Osteoporosis/metabolism
• Receptors, Glucocorticoid/metabolism

• Anti-RANKL monoclonal antibody
• Bone regeneration
• Combination therapy
• Glucocorticoid-induced osteoporosis
• Teriparatide

• Animals
• Antibodies, Monoclonal/therapeutic use
• Bone Density
• Bone Density Conservation Agents/therapeutic use
• Bone Regeneration
• Glucocorticoids/adverse effects
• Mice
• Mice, Inbred C57BL
• Osteoporosis/chemically induced
• Osteoporosis/drug therapy
• RANK Ligand/antagonists & inhibitors
• Teriparatide/therapeutic use
• X-Ray Microtomography

As a type of high-frequency electrotherapy, a short-wave can promote the fracture healing process; yet, its underlying therapeutic mechanisms remain unclear.

To observe the effect of Short-Wave therapy on mesenchymal stem cell (MSC) homing and relative mechanisms associated with fracture healing.

For in vivo study, the effect of Short-Wave therapy to fracture healing was examined in a stabilized femur fracture model of 40 SD rats. Radiography was used to analyze the morphology and microarchitecture of the callus. Additionally, fluorescence assays were used to analyze the GFP-labeled MSC homing after treatment in 20 nude mice with a femoral fracture. For in vitro study, osteoblast from newborn rats simulated fracture site was first irradiated by the Short-Wave; siRNA targeting HIF-1 was used to investigate the role of HIF-1. Osteoblast culture medium was then collected as chemotaxis content of MSC, and the migration of MSC from rats was evaluated using wound healing assay and trans-well chamber test. The expression of HIF-1 and its related factors were quantified by q RT-PCR, ELISA, and Western blot.

Our in vivo experiment indicated that Short-Wave therapy could promote MSC migration, increase local and serum HIF-1 and SDF-1 levels, induce changes in callus formation, and improve callus microarchitecture and mechanical properties, thus speeding up the healing process of the fracture site. Moreover, the in vitro results further indicated that Short-Wave therapy upregulated HIF-1 and SDF-1 expression in osteoblast and its cultured medium, as well as the expression of CXCR-4, β-catenin, F-actin, and phosphorylation levels of FAK in MSC. On the other hand, the inhibition of HIF-1α was significantly restrained by the inhibition of HIF-1α in osteoblast, and it partially inhibited the migration of MSC.

These results suggested that Short-Wave therapy could increase HIF-1 in callus, which is one of the crucial mechanisms of chemotaxis MSC homing in fracture healing.

• Fracture
• HIF-1
• Mesenchymal stem cells
• Recruitment
• Short-Wave therapy

• Fracture Healing
• Fractures, Ununited/diagnosis
• Fractures, Ununited/etiology
• Humans
• Osteogenesis
• Risk Factors

• R01 AR077761 NIAMS NIH HHS

Both inflammatory diseases like rheumatoid arthritis (RA) and anti-inflammatory treatment of RA with glucocorticoids (GCs) or non-steroidal anti-inflammatory drugs (NSAIDs) negatively influence bone metabolism and fracture healing. Janus kinase (JAK) inhibition with tofacitinib has been demonstrated to act as a potent anti-inflammatory therapeutic agent in the treatment of RA, but its impact on the fundamental processes of bone regeneration is currently controversially discussed and at least in part elusive. Therefore, in this study, we aimed to examine the effects of tofacitinib on processes of bone healing focusing on recruitment of human mesenchymal stromal cells (hMSCs) into the inflammatory microenvironment of the fracture gap, chondrogenesis, osteogenesis and osteoclastogenesis. We performed our analyses under conditions of reduced oxygen availability in order to mimic the in vivo situation of the fracture gap most optimal. We demonstrate that tofacitinib dose-dependently promotes the recruitment of hMSCs under hypoxia but inhibits recruitment of hMSCs under normoxia. With regard to the chondrogenic differentiation of hMSCs, we demonstrate that tofacitinib does not inhibit survival at therapeutically relevant doses of 10–100 nM. Moreover, tofacitinib dose-dependently enhances osteogenic differentiation of hMSCs and reduces osteoclast differentiation and activity. We conclude from our data that tofacitinib may influence bone healing by promotion of hMSC recruitment into the hypoxic microenvironment of the fracture gap but does not interfere with the cartilaginous phase of the soft callus phase of fracture healing process. We assume that tofacitinib may promote bone formation and reduce bone resorption, which could in part explain the positive impact of tofacitinib on bone erosions in RA. Thus, we hypothesize that it will be unnecessary to stop this medication in case of fracture and suggest that positive effects on osteoporosis are likely.

• bone healing
• chondrogenic differentiation
• hMSC-migration
• osteoclast differentiation
• osteogenic differentiation
• tofacitinib

• Cell Differentiation/drug effects
• Cell Hypoxia
• Cell Movement/drug effects
• Cell Survival/drug effects
• Cells, Cultured
• Chondrogenesis/drug effects
• Collagen Type I/metabolism
• Collagen Type I, alpha 1 Chain
• Core Binding Factor Alpha 1 Subunit/metabolism
• Humans
• Janus Kinase Inhibitors/pharmacology
• Janus Kinases/antagonists & inhibitors
• Janus Kinases/metabolism
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Osteogenesis/drug effects
• Piperidines/pharmacology
• Pyrimidines/pharmacology
• Pyrroles/pharmacology

• arthritis
• conditional knockout mice
• fracture healing
• glucocorticoid receptor
• glucocorticoids
• inflammation
• osteoporosis

• Animals
• Anti-Inflammatory Agents/pharmacology
• Bone and Bones/drug effects
• Bone and Bones/metabolism
• Cell Communication/drug effects
• Disease Susceptibility
• Glucocorticoids/metabolism
• Glucocorticoids/pharmacology
• Hormones/metabolism
• Humans
• Immune System/cytology
• Immune System/immunology
• Immune System/metabolism
• Osteitis/etiology
• Osteitis/metabolism
• Osteitis/pathology
• Osteoarthritis/etiology
• Osteoarthritis/metabolism
• Osteoarthritis/pathology
• Osteocytes/metabolism
• Signal Transduction
• Stress, Physiological
• Stromal Cells/metabolism

• Biological processes
• CKIP-1
• Intrinsic mechanisms
• Molecular functions
• Therapeutic strategies

• Bone fracture healing
• Glucocorticoid
• Medaka
• Osteoblast
• Osteoclast
• Pharyngeal bone

• Autoimmune diseases
• Fracture healing
• Immunosuppressive agents
• Perioperative care
• Transplantation

• Bone union
• metatarsal
• osteotomy
• rheumatoid arthritis
• risk factor