BackgroundMice deficient in the large zinc finger protein, ZAS3, show postnatal increase in bone mass suggesting that ZAS3 is critical in the regulation of bone homeostasis. Although ZAS3 has been shown to inhibit osteoblast differentiation, its role on osteoclastogenesis has not been determined. In this report we demonstrated the role of ZAS3 in bone resorption by examining the signaling mechanisms involved in osteoclastogenesis.Methodology/Principal FindingsComparison of adult wild-type and ZAS3 knockout (ZAS3−/−) mice showed that ZAS3 deficiency led to thicker bones that are more resistant to mechanical fracture. Additionally, ZAS3−/− bones showed fewer osteoclasts and inefficient M-CSF/sRANKL-mediated osteoclastogenesis ex vivo. Utilizing RAW 264.7 pre-osteoclasts, we demonstrated that overexpression of ZAS3 promoted osteoclastogenesis and the expression of crucial osteoclastic molecules, including phospho-p38, c-Jun, NFATc1, TRAP and CTSK. Contrarily, ZAS3 silencing by siRNA inhibited osteoclastogenesis. Co-immunoprecipitation experiments demonstrated that ZAS3 associated with TRAF6, the major receptor associated molecule in RANK signaling. Furthermore, EMSA suggested that nuclear ZAS3 could regulate transcription by binding to gene regulatory elements.Conclusion/SignificanceCollectively, the data suggested a novel role of ZAS3 as a positive regulator of osteoclast differentiation. ZAS3 deficiency caused increased bone mass, at least in part due to decreased osteoclast formation and bone resorption. These functions of ZAS3 were mediated via activation of multiple intracellular targets. In the cytoplasmic compartment, ZAS3 associated with TRAF6 to control NF-kB and MAP kinase signaling cascades. Nuclear ZAS3 acted as a transcriptional regulator for osteoclast-associated genes. Additionally, ZAS3 activated NFATc1 required for the integration of RANK signaling in the terminal differentiation of osteoclasts. Thus, ZAS3 was a crucial molecule in osteoclast differentiation, which might potentially serve as a target in the design of therapeutic interventions for the treatment of bone diseases related to increased osteoclast activity such as postmenopausal osteoporosis, Paget's disease, and rheumatoid arthritis.
Recent studies suggest outpatient therapy, oral antibiotics, or earlier discharge could be appropriate in some pediatric patients admitted with febrile neutropenia; supporting data are lacking. Retrospective chart review of patients admitted from September 2005 through October 2016 identified 131 “early discharge” febrile neutropenia admissions with discharge absolute neutrophil count (ANC) <500/µl and negative cultures. All were afebrile and discharged without outpatient antibiotics. Eleven of 131 patients (8%) were readmitted. Two patients called back for late positive cultures. Nine were readmitted with febrile neutropenia; 2 had positive cultures on readmission. All 4 patients with positive cultures were safely treated with appropriate antibiotics. The remaining 7 patients had uneventful readmissions. Average ANC (SD) at discharge was lower for patients readmitted versus those not readmitted (69 [70] vs. 196 [145], P≤0.001), as was absolute phagocyte count (APC) at discharge (97 [82] vs. 453 [431], P≤0.001). APC on admission was not significantly lower for those readmitted (165 [254] vs. 321 [388], P=0.09). Few patients required readmission; those with bacterial infections were easily identified and appropriately treated. Higher ANC or APC criteria for discharge would increase length of hospital stay without decreasing morbidity. A subset of patients admitted with febrile neutropenia can be safely discharged before count recovery without oral antibiotics.
Osteomyelitis is an infection of the bone; proper management requires prolonged antibiotic treatment. Controversy exists as to when a patient should transition from intravenous to oral antibiotics. However, due to the high bioavailability of some oral antibiotics, optimal time to transition from high to low bioavailability antibiotics is a more valid consideration. Additionally, there are questions surrounding the efficacy of certain antibiotics, specifically trimethoprim-sulfamethoxazole (TMP-SMX), in treating osteomyelitis. After obtaining Institutional Review Board approval from both universities, a retrospective chart review was conducted, utilizing an author-created severity scale, on all patients seen by Pediatric Infectious Diseases at the Universities of Michigan and Toledo with an acute osteomyelitis diagnosis from 2002-2012. There were 133 patients, 106 treated successfully. Success was defined in this study specifically as treatment of <14 weeks without recurrence within 30 days of stopping antibiotics or permanent site disability. Seventeen patients were treated with TMP-SMX at comparable cure rates. Patients with pre-existing bone defects (noted in radiological reports), initial erythrocyte sedimentation rate (ESR)≥70, hematogenous osteomyelitis with soft tissue extension, and skull osteomyelitis were associated with increased failure rate. Switch to low bioavailability antibiotics occurred, on average, at 3.5 weeks; however, switching before then was not associated with decreased cure rate. As prevalence of methicillin-resistant Staphylococcus aureus (MRSA), especially clindamycin-resistant MRSA, increases, TMP-SMX appears to be an acceptable antibiotic. There does not appear to be a minimum length of high bioavailability treatment required for cure. Prior bone defect, extensive infection, ESR≥70, or skull osteomyelitis may be indications for more aggressive management.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.