Although the side effects of radiation therapy vary from mucositis to osteomyelitis depending on the dose of radiation therapy, to date, an experimental animal model has not yet been proposed. The aim of this study was to develop an animal model for assessing complications of irradiated bone, especially to quantify the dose of radiation needed to develop a rat model.Sixteen Sprague-Dawley rats aged seven weeks with a mean weight of 267.59 g were used. Atraumatic extraction of a right mandibular first molar was performed. At one week after the extraction, the rats were randomized into four groups and received a single dose of external radiation administered to the right lower jaw at a level of 14, 16, 18, or 20 Gy, respectively. Clinical alopecia with body weight changes were compared and bony volumetric analysis with micro-computed tomography (CT), histologic analysis with H&E were performed.The progression of the skin alopecia was different depending on the irradiation dose. Micro-CT parameters including bone volume, bone volume/tissue volume, bone mineral density, and trabecular spaces, showed no significant differences. The progression of osteoradionecrosis (ORN) along with that of inflammation, fibrosis, and bone resorption, was found with increased osteoclast or fibrosis in the radiated group. As the radiation dose increases, osteoclast numbers begin to decrease and osteoclast tends to increase. Osteoclasts respond more sensitively to the radiation dose, and osteoblasts are degraded at doses above 18 Gy.A standardized animal model clinically comparable to ORN of the jaw is a valuable tool that can be used to examine the pathophysiology of the disease and trial any potential treatment modalities. We present a methodology for the use of an experimental rat model that incorporates a guideline regarding radiation dose.
Abstract Osteoradionecrosis (ORN) of the jaw is a significant complication of radiotherapy for oral cavity cancer. In addition to antibiotic medication, treatment options such as hyperbaric oxygen therapy, surgical approaches, and combined therapy with pentoxifylline and tocopherol have been recently introduced. In this review article, we will discuss the definition and classifications of osteoradionecrosis, its etiology and pathophysiology, previous treatment options, oral and maxillofacial complications of radiotherapy, basic information on pentoxifylline and tocopherol, recent reports of pentoxifylline and tocopherol combined therapy, and, finally, ORN-induced animal models and future approaches.
The heat shock protein ClpB in Escherichia coli is a protein-activated ATPase and consists of two proteins with sizes of 93 and 79 kDa. By polymerase chain reaction-aided site-directed mutagenesis, both the proteins have been shown to be encoded by the same reading frame of the clpB gene, the 93-kDa protein (ClpB93) from the 5'-end AUG translational initiation site and the 79-kDa protein (ClpB79) from the 149th codon (an internal GUG start site). Both the purified ClpB93 and ClpB79 proteins behave as tetrameric complexes with a very similar size of about 350 kDa upon gel filtration on a Superose-6 column. Both appear to be exclusively localized to the cytosol of E. coli. Both show inherent ATPase activities and have an identical Km of 1.1 mM for ATP. The ATPase activity of ClpB93 is as markedly stimulated by proteins, including casein and insulin, as that of wild-type ClpB, but the same proteins show little or no effect on ClpB79. Because ClpB79 lacks the 148 N-terminal sequence of ClpB93 but retains the two consensus sequences for adenine nucleotide binding, the N-terminal portion appears to contain a site(s) or domain(s) responsible for protein binding. Furthermore, ClpB79 is capable of inhibiting the casein-activated ATPase activity of ClpB93 in a dose-dependent manner but without any effect on its inherent ATPase activity. In addition, ClpB93 mixed with differing amounts of ClpB79 behave as tetrameric molecules, although its protein-activated ATPase activity is gradually reduced. These results suggest that tetramer formation between ClpB93 and ClpB79 may be responsible for the inhibition of the activity.
Bone defects present significant challenges in clinical contexts, particularly among the elderly, and are often linked to altered innate immune responses; however, underlying mechanisms remain to be understood. This study investigates immune changes in early bone healing in aged mice, emphasizing the effects of zinc in modulating inflammatory processes. By exploring the role of zinc and NETosis in this process, we seek to develop novel therapeutic strategies that could improve bone repair in aging populations. Critical-sized calvarial bone defects were induced in young (8-week-old) and aged (18-month-old) mice, with RNA sequencing analysis. Zinc oxide nanoparticle-infused polycaprolactone (ZnPCL) scaffolds were then fabricated using electrospinning, and their effects on intracellular zinc levels, NETosis, M2 polarization, and bone formation were assessed through in vitro and in vivo experiments. In aged mice, bone healing was delayed, inflammation was prolonged, and NETosis was excessive. RNA sequencing identified alterations in zinc ion transport genes, alongside excessive NETosis. Aged mouse neutrophils exhibited low intracellular zinc levels. ZnPCL fibers effectively reduced NETosis and inflammation, promoted M2 macrophage polarization, and enhanced new bone formation, thereby improving bone healing in aged mice. This study demonstrates that ZnO nanoparticle-infused biomaterials, ZnPCL, effectively deliver zinc to neutrophils, reduce NETosis, promote M2 polarization, and enhance bone healing in aged mice.
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