Nicorandil Inhibits Osteoclast Formation Base on NF-κB and p-38 MAPK Signaling Pathways and Relieves Ovariectomy-Induced Bone Loss

Abstract

Osteolytic bone disorders are characterized by an overall reduction in bone mineral density which enhances bone ductility and vulnerability to fractures. This disorder is primarily associated with superabundant osteoclast formation and bone resorption activity. Nicorandil (NIC) is a vasodilatory anti-anginal drug with ATP-dependent potassium (KATP) channel openings. However, NIC is adopted to manage adverse cardiovascular and coronary events. Recent research has demonstrated that NIC also possesses anti-inflammatory peculiarity through the regulation of p38 MAPK and NF-κB signaling pathways. Both MAPK and NF-κB signaling pathways play pivotal roles in RANKL-induced osteoclast formation and bone resorption function. Herein, we hypothesized that NIC may exert potential biological effects against osteoclasts, and revealed that NIC dose-dependently suppressed bone marrow macrophage (BMM) precursors to differentiate into TRAP + multinucleated osteoclasts in vitro. Furthermore, osteoclast resorption assays demonstrated anti-resorptive effects exhibited by NIC. NIC had no impact on osteoblast differentiation or mineralization function. Based on Biochemical analyses, NIC relieved RANKL-induced ERK, NF-κB and p38 MAPK signaling without noticeable effects on JNK MAPK activation. However, the attenuation of NF-κB and p38 MAPK activation was sufficient to hamper the downstream induction of c-Fos and NFATc1 expression. Meanwhile, NIC administration markedly protected mice from ovariectomy (OVX)-induced bone loss through in vivo inhibition of osteoclast formation and bone resorption activity. Collectively, this work demonstrated the potential of NIC in the management of osteolytic bone disorders mediated by osteoclasts.

Azilsartan Suppresses Osteoclastogenesis and Ameliorates Ovariectomy-Induced Osteoporosis by Inhibiting Reactive Oxygen Species Production and Activating Nrf2 Signaling

“…Mice with a uniform heartbeat and respiration, relaxed muscles, no movement of limbs and, no touching reaction of whiskers were considered to have reached the state of complete anesthesia. The surgical procedure was performed as previously described (Xu et al, 2021). Azilsartan was administered by oral gavage twice a week for 6 weeks beginning on the seventh postoperative day.…”

miR-134-5p inhibits osteoclastogenesis through a novel miR-134-5p/Itgb1/MAPK pathway

“…The homeostasis of a healthy bone microenvironment is mainly maintained by osteoclastic bone resorption and osteoblastic bone formation (3)(4)(5)(6). However, the pathogenetic process of osteoporosis may be accompanied by excessive osteoclast activation and osteoblast reduction, which attenuates both bone mass and the normal structure of trabecular and cortical bone (7)(8)(9)(10). Therefore, it is vital to determine the underlying mechanism of abnormally activated bone resorption and identify effective methods to cure aggravating osteoporotic disease.…”

Deciphering Fracture Risk: A Comprehensive Analysis of Blood Metabolites via Mendelian Randomization.

“…SAGPC is a key regulator of p38 MAPK activity, which is vital for bone health [43] . This pathway contributes to osteoporotic lesions by regulating the bone marrow microenvironment, promoting osteoclast differentiation, and inhibiting osteoblast maturation [44] .…”

“…In myeloma cells, p38 MAPK regulates the expression of Dickkopf-1 (DKK-1), which inhibits osteoblast differentiation and bone formation [45] . Nicorandil, by inhibiting osteoclast formation based on NF-κB and p38 MAPK signaling pathways, alleviates bone loss induced by ovariectomy [43] . Nicorandil inhibits the differentiation of bone marrow macrophages into osteoclasts and reduces osteoclast resorptive activity, without affecting osteoblast differentiation or mineralization functions [43] .…”

“…Nicorandil, by inhibiting osteoclast formation based on NF-κB and p38 MAPK signaling pathways, alleviates bone loss induced by ovariectomy [43] . Nicorandil inhibits the differentiation of bone marrow macrophages into osteoclasts and reduces osteoclast resorptive activity, without affecting osteoblast differentiation or mineralization functions [43] . From these studies, it can be inferred that the levels of SAGPC may be a contributing factor in in uencing fracture risk.…”