Systemic Dietary Hesperidin Modulation of Osteoclastogenesis, Bone Homeostasis and Periodontal Disease in Mice

Abstract

This study aimed to evaluate the effects of hesperidin (HE) on in vitro osteoclastogenesis and dietary supplem entation on mouse periodontal disease and femoral bone phenotype. RAW 264.7 cells were stimulated with RANKL in the presence or absence of HE (1, 100 or 500 µM) for 5 days, and evaluated by TRAP, TUNEL and Western Blot (WB) analyses. In vivo, C57BL/6 mice were given HE via oral gavage (125, 250 and 500 mg/kg) for 4 weeks. A sterile silk ligature was placed between the first and second right maxillary molars for 10 days and microcomputed tomography (μCT), histopathological and immunohistochemical evaluation were performed. Femoral bones subjected or not to dietary HE (500 mg/kg) for 6 and 12 weeks were evaluated using μCT. In vitro, HE 500 µM reduced formation of RANKL-stimulated TRAP-positive(+) multinucleated cells (500 µM) as well as c-Fos and NFATc1 protein expression (p < 0.05), markers of osteoclasts. In vivo, dietary HE 500 mg/kg increased the alveolar bone resorption in ligated teeth (p < 0.05) and resulted in a significant increase in TRAP+ cells (p < 0.05). Gingival inflammatory infiltrate was greater in the HE 500 mg/kg group even in the absence of ligature. In femurs, HE 500 mg/kg protected trabecular and cortical bone mass at 6 weeks of treatment. In conclusion, HE impaired in vitro osteoclastogenesis, but on the contrary, oral administration of a high concentration of dietary HE increased osteoclast numbers and promoted inflammation-induced alveolar bone loss. However, HE at 500 mg/kg can promote a bone-sparing effect on skeletal bone under physiological conditions.

Mitigation of BMP-induced Inflammation in Craniofacial Bone Regeneration and Improvement of Bone Parameters by Dietary Hesperidin

“…Our results share similarities with prior evidence demonstrating an antiin ammatory effect of HE during bone formation in our mandible model. In contrast, evaluating the systemic effects of HE in a model of periodontal in ammation 23 , this avonoid increased the in ammatory pro le, tissue damage and bone resorption in rats with periodontal disease, which can in part be attributed to the characteristics of the model studied. As previously described by de Paiva Gonçalves et al 23 , the complexity of the diseased environment, local in ammation, as well as avonoid dosage, are crucial factors to be considered in the cell responses to HE.…”

“…In contrast, evaluating the systemic effects of HE in a model of periodontal in ammation 23 , this avonoid increased the in ammatory pro le, tissue damage and bone resorption in rats with periodontal disease, which can in part be attributed to the characteristics of the model studied. As previously described by de Paiva Gonçalves et al 23 , the complexity of the diseased environment, local in ammation, as well as avonoid dosage, are crucial factors to be considered in the cell responses to HE. Nonetheless, the remarkable reduction in the in ammatory cell in ux, the evidence of organized, high quality and non-ectopic healing bone in rats treated with HE at 100mg/kg+BMP2 at 1µg are likely the direct result of a primarily nonhyperin ammatory healing site.…”

“…After mandibles were demineralized and embedded, sections (6 µm) obtained from the mid-cross section of the mandible in the frontal plane were stained by Hematoxylin & Eosin (H&E) for a qualitative gross evaluation and picrosirius red (PSR) for quantitative collagen organization and maturation analysis. Osteoclast numbers were assessed by tartrate-resistant acid phosphatase (TRAP) staining as previously described 10,23 .…”

Mitigation of BMP-induced inflammation in craniofacial bone regeneration and improvement of bone parameters by dietary hesperidin

“…HE (97% purity, ACROS Organics, Belgium) concentration at 100 mg/kg of rat weight was diluted in 0.9% sodium chloride mixed fresh at time of ingestion and administered systemically once daily via oral gavage by experienced personnel as reported 25 . HE treatment started 4 weeks before mandible surgery and was maintained until euthanasia at day 7 or 14 post-surgery.…”

Trans-Resveratrol: From Phytonutrient Supplement, to Novel Nanotherapeutic Agent

“…Additionally, as a supplementary treatment, host modulation therapy (HMT) may be employed to address the dysregulation of the immune system that was triggered by dysbiosis [24]. Some phytochemicals have been identified as potential modulators of dysbiotic oral biofilms as well as mitigators of host inflammatory responses (e.g., Curcumin, Hesperidin, Silymarin, Resveratrol) [25][26][27]. Pharmacognosy, therefore, has been explored as a contributing modality for the mitigation of inflammatory disease.…”