Celastrol, an NF-κB inhibitor, ameliorates hypercalciuria and articular cartilage lesions in a mouse model of secondary osteoporosis

Liu, Xiaodong; Cai, Feng; Zhang, Yan; Yang, Anli; Liu, Liang

doi:10.1016/j.jphs.2016.02.001

Cited by 14 publications

(9 citation statements)

References 43 publications

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“…33 TRAP-5b, primarily secreted by osteoclasts, accelerates the degradation of calcium and phosphorus mineralization substrates in the bone matrix. 35 In the present study, after bilateral removal of the ovaries, the estrogen levels, uterine weight, plasma BALP and OPG levels, and bone metabolic parameters were substantially downregulated. The U-Ca and U-P levels increased.…”

Section: Discussionsupporting

confidence: 45%

Protective effect of resveratrol on estrogen deficiency-induced osteoporosis though attenuating NADPH oxidase 4/nuclear factor kappa B pathway by increasing miR-92b-3p expression

Zhang

Liu

et al. 2020

Int J Immunopathol Pharmacol

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Introduction: Resveratrol (RES) exhibits estrogen-like effects and has potential applications to treatment of osteoporosis caused by estrogen deficiency; however, the specific mechanism of action of RES remains unclear. Here, we examined the therapeutic effects of RES on ovariectomized (OVX) rats with osteoporosis and determined the underlying mechanism. Methods: We established an OVX rat model to study osteoporosis caused by estrogen deficiency. The treatment groups were given orally with RES (50, 100, and 200 mg/day), the estrogen group received 0.8 mg/kg E2 daily via oral route, and the sham-operated and control groups received an equivalent dose of sodium carboxymethylcellulose orally. After 12 weeks of treatment, we used real-time quantitative polymerase chain reaction (PCR) and Western blot analysis to measure the gene and protein expression of miR-92b-3p, Nox4, NF-κBp65, IκB, BMP2, Smad7, and RUNX-2 in bone tissues. Right femur structural parameters were evaluated by micro-CT. Dual-energy X-ray 4500 W was used to determine systemic bone mineral density (BMD). Enzyme-linked immunosorbent assay (ELISA) kits were used to determine the serum levels of bone alkaline phosphatase (BALP), osteoprotegerin (OPG), anti-tartrate acid phosphatase-5b (PTRA5b), and carboxylated terminal peptide (CTX-I). The rat femoral bone specimens were stained using hematoxylin and eosin for pathological examination Results: We observed increased levels of serum estrogen in both ovaries, elevated miR-92b-3p levels in bone tissues, reduced levels of Nox4, NF-κBp65, p-IκB-a, and cathepsin K, and elevated gene and protein expression of BMP2, Smad7, and RUNX-2 in the OVX rat model of osteoporosis after treatment with RES. Elevated levels of BALP, OPG, ALP, and BMD along with reduced levels of TRAP-5b and CTX-I were also observed. The structural model index (SMI) and the trabecular space (Tb. Sp) decreased, while the trabecular thickness (Tb. Th), bone volume fraction (BV/TV), trabecular number (Tb.N), and tissue bone density (Conn.D) increased, thereby improving osteoporosis induced by estrogen deficiency in both ovaries. Conclusion: Cathepsin K expression and Nox4/NF-κB signaling pathway were suppressed by the elevated expression of miR-92b-3p. This inhibition was pivotal in the protective effect of RES against osteoporosis induced by estrogen deficiency in both ovaries. Thus, RES efficiently alleviated osteoporosis induced by estrogen deficiency in rats.

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Section: Discussionsupporting

confidence: 45%

Protective effect of resveratrol on estrogen deficiency-induced osteoporosis though attenuating NADPH oxidase 4/nuclear factor kappa B pathway by increasing miR-92b-3p expression

Zhang

Liu

et al. 2020

Int J Immunopathol Pharmacol

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“…In accordance, Liu and colleagues have observed in a mouse model of dexamethasone-induced secondary osteoporosis that celastrol not only improves lipid metabolism and reduces hypercalciuria, but also mitigates articular cartilage lesions, decreases NF-kB, MMP-1, and MMP-9 expression, and reduces serum PTH, tartrate-resistant acid phosphatase (TRACP)5b, CTX-I, as well as deoxypyridinoline (DPD), suggesting that it ameliorates abnormal bone metabolism (50). …”

Section: Anti-inflammatory Properties Of Celastrolmentioning

confidence: 88%

Celastrol: A Spectrum of Treatment Opportunities in Chronic Diseases

2017

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The identification of new bioactive compounds derived from medicinal plants with significant therapeutic properties has attracted considerable interest in recent years. Such is the case of the Tripterygium wilfordii (TW), an herb used in Chinese medicine. Clinical trials performed so far using its root extracts have shown impressive therapeutic properties but also revealed substantial gastrointestinal side effects. The most promising bioactive compound obtained from TW is celastrol. During the last decade, an increasing number of studies were published highlighting the medicinal usefulness of celastrol in diverse clinical areas. Here we systematically review the mechanism of action and the therapeutic properties of celastrol in inflammatory diseases, namely, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel diseases, osteoarthritis and allergy, as well as in cancer, neurodegenerative disorders and other diseases, such as diabetes, obesity, atherosclerosis, and hearing loss. We will also focus in the toxicological profile and limitations of celastrol formulation, namely, solubility, bioavailability, and dosage issues that still limit its further clinical application and usefulness.

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“…In addition, in an experimental mice model of secondary osteoporosis, celastrol treatment ameliorated abnormal bone metabolism also via NF-kB and MMPs inhibition. 56 …”

Section: Discussionmentioning

confidence: 99%

Effect of celastrol on bone structure and mechanics in arthritic rats

Cascão

Vidal

Finnilä³

et al. 2017

RMD Open

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ObjectiveRheumatoid arthritis (RA) is characterised by chronic inflammation leading to articular bone and cartilage damage. Despite recent progress in RA management, adverse effects, lack of efficacy and economic barriers to treatment access still limit therapeutic success. Therefore, safer and less expensive treatments that control inflammation and bone resorption are needed. We have previously shown that celastrol is a candidate for RA treatment. We have observed that it inhibits both interleukin (IL)-1β and tumor necrosis factor (TNF) in vitro, and that it has anti-inflammatory properties and ability to decrease synovial CD68+ macrophages in vivo. Herein our goal was to evaluate the effect of celastrol in local and systemic bone loss.MethodsCelastrol was administrated intraperitoneally at a dose of 1 µg/g/day to female Wistar adjuvant-induced arthritic rats. Rats were sacrificed after 22 days of disease progression, and blood, femurs, tibiae and paw samples were collected for bone remodelling markers quantification, 3-point bending test, micro-CT analysis, nanoindentation and Fourier transform infrared spectroscopy measurements, and immunohistochemical evaluation.ResultsWe have observed that celastrol preserved articular structures and decreased the number of osteoclasts and osteoblasts present in arthritic joints. Moreover, celastrol reduced tartrate-resistant acid phosphatase 5b, procollagen type 1 amino-terminal propeptide and C terminal crosslinked telopeptide of type II collagen serum levels. Importantly, celastrol prevented bone loss and bone microarchitecture degradation. Celastrol also preserved bone nanoproperties and mineral content. Additionally, animals treated with celastrol had less fragile bones, as depicted by an increase in maximum load and yield displacement.ConclusionsThese results suggest that celastrol reduces both bone resorption and cartilage degradation, and preserves bone structural properties.

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Celastrol, an NF-κB inhibitor, ameliorates hypercalciuria and articular cartilage lesions in a mouse model of secondary osteoporosis

Cited by 14 publications

References 43 publications

Protective effect of resveratrol on estrogen deficiency-induced osteoporosis though attenuating NADPH oxidase 4/nuclear factor kappa B pathway by increasing miR-92b-3p expression

Protective effect of resveratrol on estrogen deficiency-induced osteoporosis though attenuating NADPH oxidase 4/nuclear factor kappa B pathway by increasing miR-92b-3p expression

Celastrol: A Spectrum of Treatment Opportunities in Chronic Diseases

Effect of celastrol on bone structure and mechanics in arthritic rats

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