High bone microarchitecture, strength, and resistance to bone loss in MRL/MpJ mice correlates with activation of different signaling pathways and systemic factors

Sun, Xuying; Gao, Xueqin; Deng, Zhenhan; Zhang, Linlin; McGilvray, Kirk C.; Gadomski, Benjamin C.; Amra, Sarah; Bao, Gang; Huard, Johnny

doi:10.1096/fj.201901229rr

Cited by 7 publications

(6 citation statements)

References 67 publications

(178 reference statements)

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“…Maintaining the correct coupling play a crucial part in keeping the health homeostasis of bone mass and bone architecture ( Samsa et al, 2016 ). Under pathological conditions, architectural destroy of the skeleton and bone mass loss occur when the bone coupling activity is disturbed owning to the dominant activities of osteoclasts in osteoporosis or during old age ( Knowles, 2015 ; Sun et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Notopterol Attenuates Estrogen Deficiency-Induced Osteoporosis via Repressing RANKL Signaling and Reactive Oxygen Species

Chen

Wang

et al. 2021

Front. Pharmacol.

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Integrity of the skeleton is sustained through the balanced activities of osteoblasts and osteoclasts in bone remodeling unit. The balance can be disrupted by excessive osteoclasts activation commonly seen in osteoporosis. Notopterol (NOT) is a main component of Notopterygium incisum which exerts a wide spectrum effect on biomedical pharmacology. In our study, we found NOT serves as an inhibitor in regulating RANKL-activated osteoclasts formation and bone resorption function by calculating tartrate resistant acid phosphatase (TRAcP) staining and hydroxyapatite resorption assays. Furthermore, RANKL-mediated signaling pathways including MAPK, NF-κB and calcium ossification were hampered, whereas ROS scavenging enzymes in Nrf2/Keap1/ARE signaling pathways were promoted by NOT. In addition, the activation of the essential transcription factor NFATc1 in RANKL-mediated osteoclastogenesis was almost totally suppressed by NOT. What is more, NOT diminished the loss of bone mass in preclinical model of OVX mice by blocking osteoclastogenesis determined by bone histomorphometry, TRAcP staining and H&E staining. Conclusively, our findings demonstrated that NOT could arrest osteoclastogenesis and bone resorptive activity by attenuating RANKL-mediated MAPK, NF-κB, calcium and NFATc1 signaling transduction pathways and enhancing ROS scavenging enzymes in Nrf2/Keap1/ARE pathways in vitro, and prohibit bone loss induced by OVX in vivo. Taken together, NOT may be identified to be a natural and novel treatment for osteolytic diseases.

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Section: Introductionmentioning

confidence: 99%

Notopterol Attenuates Estrogen Deficiency-Induced Osteoporosis via Repressing RANKL Signaling and Reactive Oxygen Species

Chen

Wang

et al. 2021

Front. Pharmacol.

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“…Cortical bone was analyzed with the following: 50 slices immediately distal to the proximal tibia growth plate, Gauss = 0.8, Sigma = 1, and threshold = 200. Microarchitectural analysis was performed using a direct (no model) approach as previously described [ 47 , 48 ]. For FIS treatments, mice were imaged using the eXplore Locus Ultra Pre-Clinical CT Scanner (GE Healthcare, London, ON) through the pre-Clinical CT Core Facility with the acquisition settings of 140 kVp and 22 mA with 16 s rotation/exposure.…”

Section: Methodsmentioning

confidence: 99%

“…One-way analysis of variance (ANOVA) followed by Tukey's Honestly Significant Different (HSD) post hoc multiple comparison test was used when analyzing quantitative data (multiple) with GraphPad Prism 7. Two-tailed Student T testing was utilized when comparing two groups, and Wilcoxon rank-sum test was used for non-parametric testing as in µ CT and histology scoring which was because of the increased deviation of parameters for these outputs as described previously [ 47 , 48 ].…”

Section: Methodsmentioning

confidence: 99%

The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24−/− Progeria Mouse Model

Hambright

Gao

et al. 2023

Journal of Osteoporosis

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Aging leads to several geriatric conditions including osteoporosis (OP) and associated frailty syndrome. Treatments for these conditions are limited and none target fundamental drivers of pathology, and thus identifying strategies to delay progressive loss of tissue homeostasis and functional reserve will significantly improve quality of life in elderly individuals. A fundamental property of aging is the accumulation of senescent cells. Senescence is a cell state defined by loss of proliferative capacity, resistance to apoptosis, and the release of a proinflammatory and anti-regenerative senescence-associated secretory phenotype (SASP). The accumulation of senescent cells and SASP factors is thought to significantly contribute to systemic aging. Senolytics—compounds which selectively target and kill senescent cells—have been characterized to target and inhibit anti-apoptotic pathways that are upregulated during senescence, which can elicit apoptosis in senescent cells and relieve SASP production. Senescent cells have been linked to several age-related pathologies including bone density loss and osteoarthritis in mice. Previous studies in murine models of OP have demonstrated that targeting senescent cells pharmacologically with senolytic drugs can reduce symptomology of the disease. Here, we demonstrate the efficacy of senolytic drugs (dasatinib, quercetin, and fisetin) to improve age-associated degeneration in bone using the Zmpste24−/− (Z24−/−) progeria murine system for Hutchinson–Gilford progeria syndrome (HGPS). We found that the combination of dasatinib plus quercetin could not significantly mitigate trabecular bone loss although fisetin administration could reduce bone density loss in the accelerated aging Z24−/− model. Furthermore, the overt bone density loss observed in the Z24−/− model reported herein highlights the Z24 model as a translational model to recapitulate alterations in bone density associated with advanced age. Consistent with the “geroscience hypothesis,” these data demonstrate the utility of targeting a fundamental driver of systemic aging (senescent cell accumulation) to alleviate a common condition with age, bone deterioration.

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“…mRNA expression levels were normalized to those of mouse β-actin (forward, 5'-TGT TAC CAA CTG GGA CGA CA-3' and reverse, 5'-GGG GTG TTG AAG GTC TCA AA-3'). The relative mRNA levels of target genes were calculated using the 2 -∆∆Cq method (27,28).…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

4‑Hexylresorcinol inhibits osteoclastogenesis by suppressing the NF‑κB signaling pathway and reverses bone loss in ovariectomized mice

Liu

Gao

et al. 2021

Exp Ther Med

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4-Hexylresorcinol (4HR) is a small organic compound that is widely used as an antiseptic and antioxidant. In the present study, its role in osteoclastogenesis was investigated. Bone marrow-derived macrophages from mice were used to examine the role of 4HR in osteogenesis. An ovariectomy (OVX) mouse model was constructed to examine the effect of 4HR in vivo, followed by hematoxylin and eosin and tartrate resistant acid phosphatase staining. In the present study, 4HR effectively suppressed receptor activator of NF-κB ligand-induced osteoclastogenesis in a dose-dependent manner. 4HR was also found to significantly suppress the expression of osteoclast (OC)-specific markers, including tartrate-resistant acid phosphatase, cathepsin K, nuclear factor of activated T-cell cytoplasmic 1 and c-Fos in the presence of RANKL in BMMs. Furthermore, 4HR inhibited osteoclastogenesis by inhibiting the activation of the NF-κB signaling pathway in BMMs. Consistent with the in vitro results, 4HR effectively ameliorated OVX-induced bone loss and markedly reduced OC number in the proximal tibia in vivo. In conclusion, the present results suggested that 4HR inhibited osteoclastogenesis in vitro and rescued bone loss in vivo, suggesting that 4HR may serve as a novel therapeutic agent for osteoporosis treatment.

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High bone microarchitecture, strength, and resistance to bone loss in MRL/MpJ mice correlates with activation of different signaling pathways and systemic factors

Cited by 7 publications

References 67 publications

Notopterol Attenuates Estrogen Deficiency-Induced Osteoporosis via Repressing RANKL Signaling and Reactive Oxygen Species

Notopterol Attenuates Estrogen Deficiency-Induced Osteoporosis via Repressing RANKL Signaling and Reactive Oxygen Species

The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24−/− Progeria Mouse Model

4‑Hexylresorcinol inhibits osteoclastogenesis by suppressing the NF‑κB signaling pathway and reverses bone loss in ovariectomized mice

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