Unique Spatial Transcriptomic Profiling of the Murine Femoral Fracture Callus: A Preliminary Report.

Fracture callus formation is a dynamic stage of bone activity and repair with precise, spatially localized gene expression. Metastatic breast cancer impairs fracture healing by disrupting bone homeostasis and imparting an altered genomic profile. Previous sequencing techniques such as single-cell RNA and in situ hybridization are limited by missing spatial context and low throughput, respectively.

Concurrent targeting of glycolysis in bacteria and host cell inflammation in septic arthritis.

Intracellular infiltration of bacteria into host cells complicates medical and surgical treatment of bacterial joint infections. Unlike soft tissue infections, septic arthritis and infection-associated inflammation destroy cartilage that does not regenerate once damaged. Herein, we show that glycolytic pathways are shared by methicillin-resistant Staphylococcus aureus (MRSA) proliferation and host inflammatory machinery in septic arthritis.

Enhancement of Impaired MRSA-Infected Fracture Healing by Combinatorial Antibiotics and Modulation of Sustained Inflammation.

Fracture healing is impaired in the setting of infection, which begets protracted inflammation. The most problematic causative agent of musculoskeletal infection is methicillin-resistant Staphylococcus aureus (MRSA). We hypothesized that modulation of excessive inflammation combined with cell-penetrating antibiotic treatments facilitates fracture healing in a murine MRSA-infected femoral fracture model.

Inflammatory conversion of quiescent osteoblasts by metastatic breast cancer cells through pERK1/2 aggravates cancer-induced bone destruction.

Disruption of bone homeostasis caused by metastatic osteolytic breast cancer cells increases inflammatory osteolysis and decreases bone formation, thereby predisposing patients to pathological fracture and cancer growth. Alteration of osteoblast function induces skeletal diseases due to the disruption of bone homeostasis. We observed increased activation of pERK1/2 in osteolytic breast cancer cells and osteoblasts in human pathological specimens with aggressive osteolytic breast cancer metastases.

Dual therapeutic targeting of intra-articular inflammation and intracellular bacteria enhances chondroprotection in septic arthritis.

Bacterial infections involving joints and vital organs represent a challenging clinical problem because of the two concurrent therapeutic goals of bacterial eradication and tissue preservation. In the case of septic arthritis, permanent destruction of articular cartilage by intense host inflammation is commonly seen even after successful treatment of bacterial infection. Here, we provide scientific evidence of a novel treatment modality that can protect articular cartilage and enhanced eradication of causative bacteria in septic arthritis.

Re-appraising the potential of naringin for natural, novel orthopedic biotherapies.

Naringin is a naturally occurring flavonoid found in plants of the genus that has historically been used in traditional Chinese medical regimens for the treatment of osteoporosis. Naringin modulates signaling through numerous molecular pathways critical to musculoskeletal development, cellular differentiation, and inflammation. Administration of naringin increases expression of bone morphogenetic proteins (BMPs) and activation of the Wnt/β-catenin and extracellular signal-related kinase (Erk) pathways, thereby promoting osteoblastic proliferation and differentiation from stem cell precursors for bone formation.

Locally delivered adjuvant biofilm-penetrating antibiotics rescue impaired endochondral fracture healing caused by MRSA infection.

Infection is a devastating complication following an open fracture. We investigated whether local rifampin-loaded hydrogel can combat infection and improve healing in a murine model of methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. A transverse fracture was made at the tibia midshaft of C57BL/6J mice aged 10-12 weeks and stabilized with an intramedullary pin.

Smoking Alters Inflammation and Skeletal Stem and Progenitor Cell Activity During Fracture Healing in Different Murine Strains.

Smokers are at a higher risk of delayed union or nonunion after fracture repair. Few specific interventions are available for prevention because the molecular mechanisms that result in these negative sequelae are poorly understood. Murine models that mimic fracture healing in smokers are crucial in further understanding the local cellular and molecular alterations during fracture healing caused by smoking.

Intracellular Staphylococcus aureus in bone and joint infections: A mechanism of disease recurrence, inflammation, and bone and cartilage destruction.

Bone and joint infections are devastating afflictions. Although medical interventions and advents have improved their care, bone and joint infections still portend dismal outcomes. Indeed, bone and joint infections are associated with extremely high mortality and morbidity rates and, generally, occur secondary to the aggressive pathogen Staphylococcus aureus.

Recalcitrant methicillin-resistant infection of bone cells: Intracellular penetration and control strategies.

Aims: To characterize the intracellular penetration of osteoblasts and osteoclasts by methicillin-resistant (MRSA) and the antibiotic and detergent susceptibility of MRSA in bone.

Methods: Time-lapse confocal microscopy was used to analyze the interaction of MRSA strain USA300 with primary murine osteoblasts and osteoclasts. The effects of early and delayed antibiotic treatments on intracellular and extracellular bacterial colony formation and cell death were quantified.

Systemic Parathyroid Hormone Enhances Fracture Healing in Multiple Murine Models of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a multisystemic disease that afflicts more than 415 million people globally-the incidence and prevalence of T2DM continues to rise. It is well-known that T2DM has detrimental effects on bone quality that increase skeletal fragility, which predisposes subjects to an increased risk of fracture and fracture healing that results in non- or malunion. Diabetics have been found to have perturbations in metabolism, hormone production, and calcium homeostasis-particularly PTH expression-that contribute to the increased risk of fracture and decreased fracture healing.

Tendon stem/progenitor cells regulate inflammation in tendon healing JNK and STAT3 signaling.

Tendon stem/progenitor cells (TSCs) have been found in different anatomic locations and showed a promising regenerative potential. We identified a role of TSCs in the regulation of inflammation during healing of acute tendon injuries. Delivery of connective tissue growth factor (CTGF) into full-transected rat patellar tendons significantly increased the number of CD146 TSCs, leading to enhanced healing.

Calreticulin inhibits inflammation-induced osteoclastogenesis and bone resorption.

Osteoclasts play key roles in bone remodeling and pathologic osteolytic disorders such as inflammation, infection, bone implant loosening, rheumatoid arthritis, metastatic bone cancers, and pathological fractures. Osteoclasts are formed by the fusion of monocytes in response to receptor activators of NF-κB-ligand (RANKL) and macrophage colony stimulating factor 1 (M-CSF). Calreticulin (CRT), a commonly known intracellular protein as a calcium-binding chaperone, has an unexpectedly robust anti-osteoclastogenic effect when its recombinant form is applied to osteoclast precursors in vitro or at the site of bone inflammation externally in vivo.