Anacardic acid inhibits RANKL‐induced osteoclastogenesis in vitro and prevents ovariectomy‐induced bone loss in vivo

Abstract

Postmenopausal osteoporosis is the most common form of primary osteoporosis, and the incidence of the condition is rapidly increasing. In consideration of the limitations of current therapeutic options for the treatment of postmenopausal osteoporosis, there is an urgent need to develop safer alternatives. Anacardic acid, a natural phenolic acid compound extracted from cashew nut shell, possesses potent antitumor and anti‐inflammatory effects and inhibits NF‐κB signaling. However, its effect on osteoclasts remains unknown. This study reports the first evidence for the antiosteoclastogenic and antiresorptive effects of anacardic acid on bone marrow–derived macrophage–derived osteoclasts. Mechanistically, anacardic acid disrupts the phosphorylation of TGF‐β activated kinase 1 and subsequently suppresses multiple receptor activator of NF‐κB ligand–induced signaling cascades, ultimately inhibiting the induction and activation of the crucial osteoclast transcriptional factor nuclear factor of activated T‐cell cytoplasmic 1. Consistent with cellular results in vitro, anacardic acid treatment improves bone density in the murine model of ovariectomy‐induced bone loss. Taken together, our study provides promising evidence for the therapeutic application of anacardic acid as a new potential pharmacological treatment for osteoporosis.—Zhao, K., Jia, Y., Peng, J., Pang, C., Zhang, T., Han, W., Jiang, J., Lu, X., Zhu, J., Qian, Y. Anacardic acid inhibits RANKL‐induced osteoclastogenesis in vitro and prevents ovariectomy‐induced bone loss in vivo. FASEB J. 33, 9100–9115 (2019). http://www.fasebj.org

TAZ inhibits osteoclastogenesis by attenuating TAK1/NF-κB signaling

“…3D reconstructions of tibias and calvarias were completed as previously described. 41 The bone morphometric parameters analyzed included BV/TV, Tb.N, Tb.Th and Tb. For femurs, Sp.…”

Protective Effects of Punicalagin on Osteoporosis by Inhibiting Osteoclastogenesis and Inflammation via the NF-κB and MAPK Pathways

“…Postmenopausal osteoporosis is a systemic metabolic bone disease that affects more than 200 million women worldwide (Zhao K. et al, 2019). Postmenopausal osteoporosis caused by dysfunctions in bone remodeling causes low bone mineral density and microstructural changes, which decrease bone strength and increase bone fragility, leading to increased fracture risk (Chen et al, 2018;Zhao X. et al, 2019).…”

“…Estrogens, estrogen receptor modulators, calcitonin, and bis-phosphonates are the current medications for bone loss. Anti-osteoporotic drugs are efficacious, but unfortunately, they increase the potential risk of breast cancer, myocardial ischemia, thromboembolic disease, and atypical femur facture (Eriksen et al, 2014;Black and Rosen, 2016;Compston et al, 2019;Zhao K. et al, 2019). Denosumab, a monoclonal antibody, can inhibit bone absorption by inhibiting the differentiation and activation of osteoclasts, but skin rash and infection occur more frequently, as well as the effect on bone turnover is rapidly reversible after drug discontinuation (Compston et al, 2019).…”

“…Estrogen deficiency induces the activation of receptor activator of nuclear factor kB (NF-kB) ligand (RANKL), the key molecule required for osteoclast differentiation, which can bind with receptor activator of NF-kB (RANK) on preosteoclast membranes and stimulate the NF-kB and mitogen-activated protein kinase (MAPK) pathways for osteoclast differentiation and formation (Chen et al, 2018;Jiang et al, 2019;Shang and Wu, 2019). Then, nuclear factor of activated T cells cytoplasmic 1 (NFATc1), the main transcription factor that regulates osteoclast differentiation, will be triggered to stimulate preosteoclast maturation (Jiang et al, 2019;Zhao K. et al, 2019). Maturational osteoclasts, which are characterized by tartrate-resistant acid phosphatase (TRAP) expression, can generate actin-bound sealing zones for attaching to the surface of bone, and osteoclasts then release proteolytic enzymes, such as cathepsin K (CTSK), which promote resorption pit formation (Lee et al, 2019;Zhao X. et al, 2019).…”

Synthesis, Characterization and Cytotoxic Studies of Benzamide Derivatives of Anacardic Acid using Human Liver Cancer Cells

“…Besides, it has also showed anticancer activity by inhibition of the histone acetyltransferase in human liver cancer cells, phosphodiesterase-5 inhibition, cytotoxic activity, RANKL-induced osteoclastogenesis inhibitors, fibroblast-like synoriocycle proliferation suppressor and ameliorates collagen-induced arthritis, induces cell apoptosis of prostate cancer through autophagy by ER stess/DAPK3/Akt signalling pathway, attenuates phenylephrineinduced cardiac hypertrophy, polyketide biosynthetic pathway modulator in endopytic fungus-Anteaglonium Sp. FL0768, antidepressant, regulates Wnt4 expression in chicken, VEGF-induced angiogenesis inhibitor, excellent paclitaxel transporter in breast cancer therapy, and anti-convulsant activities [5][6][7][8][9][10][11][12][13][14][15][16][17]. Thus, in continuation of our work on developing new anacardic acid based benzamides, we designed and synthesized new compounds, which contains alkoxy benzamides as additive groups that acted as cytotoxic agents in the previous reports [18][19][20][21][22][23][24][25][26].…”