Schisandrin A restrains osteoclastogenesis by inhibiting reactive oxygen species and activating Nrf2 signalling

Ni, Shuo; Qian, Zhi; Yin, Yuan; Li, Dejian; Zhong, Zeyuan; Ghorbani, Farnaz; Zhang, Xu; Zhang, Fangxue; Zhang, Zhenhua; Liu, Zichen; Yu, Baoqing

doi:10.1111/cpr.12882

Cited by 56 publications

(30 citation statements)

References 37 publications

(157 reference statements)

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“…Increased ROS production acts as a second messenger and oxidizes tyrosine phosphatases, thus activating the subsequent MAPK pathway ( Davis, 2000 ; Lee et al, 2005 ; Kanzaki et al, 2017 ). ROS and MAPK serve as two crucial mediators in RANKL-induced osteoclast differentiation progression, and inhibition of ROS production and MAPK signaling restrain osteoclastogenesis ( Lee et al, 2005 ; Yip et al, 2005 ; Agidigbi and Kim, 2019 ; Chen et al, 2019 ; Ni et al, 2020 ). Betaine has been reported to inhibit ROS and MAPK in previous studies ( Kim et al, 2014 ; Park et al, 2017 ; Jiang et al, 2019 ; Veskovic et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Betaine Attenuates Osteoarthritis by Inhibiting Osteoclastogenesis and Angiogenesis in Subchondral Bone

Wang

Cui

Gu³

et al. 2021

Front. Pharmacol.

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Osteoarthritis (OA) is the most common type of arthritis with no effective therapy. Subchondral bone and overlying articular cartilage are closely associated and function as “osteo-chondral unit” in the joint. Abnormal mechanical load leads to activated osteoclast activity and increased bone resorption in the subchondral bone, which is implicated in the onset of OA pathogenesis. Thus, inhibiting subchondral bone osteoclast activation could prevent OA onset. Betaine, isolated from the Lycii Radicis Cortex (LRC), has been demonstrated to exert anti-inflammatory, antifibrotic and antiangiogenic properties. Here, we evaluated the effects of betaine on anterior cruciate ligament transection (ACLT)-induced OA mice. We observed that betaine decreased the number of matrix metalloproteinase 13 (MMP-13)-positive and collagen X (Col X)-positive cells, prevented articular cartilage proteoglycan loss and lowered the OARSI score. Betaine decreased the thickness of calcified cartilage and increased the expression level of lubricin. Moreover, betaine normalized uncoupled subchondral bone remodeling as defined by lowered trabecular pattern factor (Tb.pf) and increased subchondral bone plate thickness (SBP). Additionally, aberrant angiogenesis in subchondral bone was blunted by betaine treatment. Mechanistically, we demonstrated that betaine suppressed osteoclastogenesis in vitro by inhibiting reactive oxygen species (ROS) production and subsequent mitogen-activated protein kinase (MAPK) signaling. These data demonstrated that betaine attenuated OA progression by inhibiting hyperactivated osteoclastogenesis and maintaining microarchitecture in subchondral bone.

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Section: Discussionmentioning

confidence: 99%

Betaine Attenuates Osteoarthritis by Inhibiting Osteoclastogenesis and Angiogenesis in Subchondral Bone

Wang

Cui

Gu³

et al. 2021

Front. Pharmacol.

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“…Intracellular ROS are the net effect of the balance between ROS generation and Nrf2-mediated clearance of ROS by the intracellular antioxidant system. Some antioxidants, such as pristimerin, chitosan, octyl itaconate, were reported to reduce ROS levels and inhibit osteoclast differentiation by activating Nrf2/HO-1 signaling (Chen et al, 2020;Ni et al, 2020;Qi et al, 2020). Nrf2 activation inhibits osteoclastogenesis, while inactivation of Nrf2 suppresses antioxidant enzyme expression and increases intracellular ROS levels in osteoclasts, subsequently promoting osteoclastogenesis (Kanzaki et al, 2013;Sun et al, 2020;Sánchez-de-Diego et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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Osteoporosis is characterized by a decrease in bone mass and destruction of the bone microarchitecture, and it commonly occurs in postmenopausal women and the elderly. Overactivation of osteoclasts caused by the inflammatory response or oxidative stress leads to osteoporosis. An increasing number of studies have suggested that intracellular reactive oxygen species (ROS) are strongly associated with osteoclastogenesis. As a novel angiotensin (Ang) II receptor blocker (ARB), azilsartan was reported to be associated with the inhibition of intracellular oxidative stress processes. However, the relationship between azilsartan and osteoclastogenesis is still unknown. In this study, we explored the effect of azilsartan on ovariectomy-induced osteoporosis in mice. Azilsartan significantly inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and downregulated the expression of osteoclast-associated markers (Nfatc1, c-Fos, and Ctsk) in vitro. Furthermore, azilsartan reduced RANKL-induced ROS production by increasing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2). Mechanistically, azilsartan inhibited the activation of MAPK/NF-κB signaling pathways, while Nrf2 silencing reversed the inhibitory effect of azilsartan on MAPK/NF-κB signaling pathways. Consistent with the in vitro data, azilsartan administration ameliorated ovariectomy (OVX)-induced osteoporosis, and decreased ROS levels in vivo. In conclusion, azilsartan inhibited oxidative stress and may be a novel treatment strategy for osteoporosis caused by osteoclast overactivation.

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“…However, long-term preventive and curative medical care is not currently available. Emerging studies have suggested that ROS play a critical role in bone homeostasis ( Chen et al, 2019 ; Xu et al, 2019 ; Ni et al, 2020 ). However, excessive ROS generation and oxidative status contribute to the progression of bone destruction ( Tao et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…In vivo ROS production was assessed by injection of dihydroethidium (DHE) into the calvaria 24 h prior to killing, according to a protocol previously reported ( Ni et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

The Novel Antioxidant Compound JSH-23 Prevents Osteolysis by Scavenging ROS During Both Osteoclastogenesis and Osteoblastogenesis

Mei

Zheng

et al. 2021

Front. Pharmacol.

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Inflammatory osteolysis is a pathological skeletal disease associated with not only the production of inflammatory cytokines but also local oxidative status. Excessive reactive oxygen species (ROS) promote bone resorption by osteoclasts and induce the apoptosis of osteoblasts. In consideration of the lack of effective preventive or treatments options against osteolysis, the exploitation of novel pharmacological compounds/agents is critically required. In our study, we found that a novel antioxidant compound, JSH-23, plays a role in restoring bone homeostasis by scavenging intracellular ROS during both osteoclastogenesis and osteoblastogenesis. Mechanically, JSH-23 suppressed RANKL-induced osteoclastogenesis, bone resorption and the expression of specific genes (including NFATc1, c-Fos, TRAP, CTSK and DC-STAMP) via inhibition of the NF-κB signaling pathway. Meanwhile, JSH-23 suppressed RANKL-induced ROS generation via the TRAF6/Rac1/NOX1 pathway and the enhanced expression of Nrf2/HO-1. In addition, JSH-23 attenuated H2O2-induced apoptosis and mineralization reduction in osteoblasts by reducing ROS production and enhancing Nrf2/HO-1 expression. Our in vivo results further revealed that JSH-23 exerts its protective effects on bone mass through its antioxidant activity. In conclusion, our results show that the application of JSH-23 might be a novel and plausible strategy for the treatment of osteolysis-related disease.

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Schisandrin A restrains osteoclastogenesis by inhibiting reactive oxygen species and activating Nrf2 signalling

Cited by 56 publications

References 37 publications

Betaine Attenuates Osteoarthritis by Inhibiting Osteoclastogenesis and Angiogenesis in Subchondral Bone

Betaine Attenuates Osteoarthritis by Inhibiting Osteoclastogenesis and Angiogenesis in Subchondral Bone

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

The Novel Antioxidant Compound JSH-23 Prevents Osteolysis by Scavenging ROS During Both Osteoclastogenesis and Osteoblastogenesis

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