Catharanthine tartrate ameliorates osteoclastogenesis by destabilizing HIF-1α

AUTHORS

Luqiong Cai, Chenxin Yu, Binli Zhao, Qihang Wu, Haibo Liang, Meng Zhou, Jiansen Miao, Jiangtao Luo, Jiake Xu, Haiming Jin, Youjin Pan

ABSTRACT

With the aging population, postmenopausal osteoporosis (PMOP), clinically manifested by reduced bone density, weakened skeletal strength, and compromised skeletal microstructure, has become the most prevalent type. The decline in estrogen levels fosters oxidative stress and osteoclastogenesis, which significantly enhance the activity of osteoclasts. Current treatments prefer to adopt relevant strategies to inactivate osteoclasts but come with unavoidable side effects. In our study, Catharanthine Tartrate (CAT), a derivative of the alkaloid catharanthine found in Catharanthus roseus, promised to be an effective therapy for PMOP. CAT inhibited RANKL-induced osteoclast differentiation and bone resorption in vitro. Moreover, CAT inhibited osteoclast activity by enhancing the ubiquitination-mediated proteasomal degradation of HIF-1α, which reduced oxidative stress and subsequently suppressed osteoclast activity. The inhibitory effects of CAT on osteoclast function and oxidative stress were reversed by DMOG, a known inhibitor of HIF-1α degradation. Next, an in vivo mouse experiment using the Ovariectomized (OVX) model to induce osteoporosis indicated that CAT enhanced bone mass density, bone structure, and bone remodeling. Our findings revealed that CAT inhibits PMOP through facilitating HIF-1α ubiquitination and degradation, suggesting a promising therapeutic approach for this disorder.

NLRP3 blockade by MCC950 suppressed osteoclastogenesis via NF-κB/c-Fos/NFATc1 signal pathway and alleviated bone loss in diabetes mellitus

AUTHORS

Guoping Cai, Xiaoting Song, Hua Luo, Gaoyuan Dai, Honghao Zhang, Dengteng Jiang, Xinhuan Lei, Haixiao Chen, Liwei Zhang

ABSTRACT

Obesity and type 2 diabetes mellitus (T2DM) are linked to osteoporosis development, with obesity being a significant risk factor for T2DM. T2DM patients with obesity exhibit a higher fracture rate and often have a poor prognosis post-fracture. To address the urgent need for understanding the mechanisms of diabetic osteoporosis (DOP), research is ongoing to explore how obesity and T2DM impact bone metabolism. The NLRP3 inflammasome has been implicated in the pathogenesis of osteoporosis, and MCC950, an NLRP3 inflammasome inhibitor, has shown promise in various diseases but its role in osteoporosis remains unexplored. In this study, BMMs and BMSCs were isolated and cultured to investigate the effects of MCC950 on bone metabolism, and DOP model was used to evaluate the efficacy of MCC950 in vivo. The study demonstrated that MCC950 treatment inhibited osteoclast differentiation, reduced bone resorption capacity in BMMs without suppression for osteoblast differentiation from BMSCs. Additionally, MCC950 suppressed the activation of the NF-κB signaling pathway and downregulated key factors associated with osteoclast differentiation. Additionally, MCC950 alleviated bone loss in DOP mouse. These findings suggest that MCC950, by targeting the NLRP3 inflammasome, may have a protective role in preventing osteoporosis induced by T2DM with obesity. The study highlights the potential therapeutic implications of MCC950 in managing diabetic osteoporosis and calls for further research to explore its clinical application in high-risk patient populations.

Piperlongumine, a Piper longum-derived amide alkaloid, protects mice from ovariectomy-induced osteoporosis by inhibiting osteoclastogenesis via suppression of p38 and JNK signaling†

AUTHORS

Na Luo, Lei Zhang, Chunmei Xiu, Xi Luo, Siyuan Hu, Kaizhong Ji, Qingbai Li, Jianquan Chen

ABSTRACT

Postmenopausal osteoporosis (PMOP) is a metabolic bone disease that results from overproduction and hyperactivation of osteoclasts caused by insufficient estrogen in women after menopause. Current therapeutic strategies are mainly focused on treating PMOP patients who have already developed severe bone loss or even osteoporotic fractures. Obviously, a better strategy is to prevent PMOP from occurring in the first place. However, such reagents are largely lacking. Piperlongumine (PLM), an amide alkaloid extracted from long pepper Piper longum, exhibits the anti-osteoclastogenic effect in normal bone marrow macrophages (BMMs) and the protective effect against osteolysis induced by titanium particles in mice. This study examined the preventive effect of PLM on PMOP and explored the potential mechanism of this effect using both ovariectomized mice and their primary cells. The result showed that PLM (5 and 10 mg kg−1) administered daily for 6 weeks ameliorated ovariectomy-induced bone loss and osteoclast formation in mice. Further cell experiments showed that PLM directly suppressed osteoclast formation, F-actin ring formation, and osteoclastic resorption pit formation in BMMs derived from osteoporotic mice, but did not obviously affect osteogenic differentiation of bone marrow stromal cells (BMSCs) from these mice. Western blot analysis revealed that PLM attenuated maximal activation of p38 and JNK pathways by RANKL stimulation without affecting acute activation of NF-κB, AKT, and ERK signaling. Furthermore, PLM inhibited expression of key osteoclastogenic transcription factors NFATc1/c-Fos and their target genes (Dcstamp, Atp6v0d2, Acp5, and Oscar). Taken together, our findings suggest that PLM inhibits osteoclast formation and function by suppressing RANKL-induced activation of the p38/JNK-cFos/NFATc1 signaling cascade, thereby preventing ovariectomy-induced osteoporosis in mice. Thus, PLM can potentially be used as an anti-resorption drug or dietary supplement for the prevention of PMOP.

VSIG4 inhibits RANKL-induced osteoclastogenesis by enhancing Nrf2-dependent antioxidant response against reactive oxygen species production

AUTHORS

Jiansen Miao, Yiting Tu, Junchen Jiang, Rufeng Ren, Qihang Wu, Haibo Liang, Tengjie Wang, Binghao Lin, Jingtao Wu, Youjin Pan, Xiangyang Wang, Haiming Jin

ABSTRACT

Osteoporosis is a prevalent systemic skeletal disorder, particularly affecting postmenopausal women, primarily due to excessive production and activation of osteoclasts. However, the current anti-osteoporotic drugs utilized in clinical practice may lead to certain side effects. Therefore, it is necessary to further unravel the potential mechanisms regulating the osteoclast differentiation and to identify novel targets for osteoporosis treatment. This study revealed the most significant decline in VSIG4 expression among the VSIG family members. VSIG4 overexpression significantly inhibited RANKL-induced osteoclastogenesis and bone resorption function. Mechanistically, both western blot and immunofluorescence assay results demonstrated that VSIG4 overexpression attenuated the expression of osteoclast marker genes and dampened the activation of MAPK and NF-κB signaling pathways. Furthermore, VSIG4 overexpression could inhibit the generation of reactive oxygen species (ROS) and stimulate the expression of Nrf2 along with its downstream antioxidant enzymes via interaction with Keap1. Notably, a potent Nrf2 inhibitor, ML385, could reverse the inhibitory effect of VSIG4 on osteoclast differentiation. In line with these findings, VSIG4 overexpression also mitigated bone loss induced by OVX and attenuated the activation of osteoclasts in vivo. In conclusion, our results suggest that VSIG4 holds promise as a novel target for addressing postmenopausal osteoporosis. This is achieved by suppressing osteoclast formation via enhancing Nrf2-dependent antioxidant response against reactive oxygen species production.

Praeruptorin B inhibits osteoclastogenesis by targeting GSTP1 and impacting on the S-glutathionylation of IKKβ

AUTHORS

Kebin Xu, Ziyi Chen, Jialong Hou, Chenlin Dong, Chengge Shi, Linglin Gao, Zhixian Huang, Ge Shen, Te Wang, Yan Zhou

ABSTRACT

Osteoporosis a common disease in postmenopausal women which contains significant impact on the living quality of women. With the aging of the population, the number of patients suffer from osteoporosis has shown a significant increase. Given the limitations of clinical drugs for the treatment of osteoporosis, natural extracts with small side effects have a great application prospect in the treatment of osteoporosis. Praeruptorin B (Pra-B), is one of the main components found in the roots of Peucedanum praeruptorum Dunn and exhibits anti-inflammatory effects. However, there is no research on the influence of Pra-B on osteoporosis. Here, we showed that Pra-B can dose-dependently suppress osteoclastogenesis without cytotoxicity. Receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL)-induced the nuclear import of P65 was inhibited by Pra-B, which indicated the suppressive effect of Pra-B on NF-κB signaling. Further, Pra-B enhanced the expression of Glutathione S-transferase Pi 1 (GSTP1) and promoted the S-glutathionylation of IKKβ to inhibit the nuclear translocation of P65. Moreover, in vivo experiments showed that Pra-B considerably attenuated the bone loss in ovariectomy (OVX)-induced mice. Collectively, our studies revealed that Pra-B suppress the NF-κB signaling targeting GSTP1 to rescued RANKL-induced osteoclastogenesis in vitro and OVX-induced bone loss in vivo, supporting the potential of Pra-B for treating osteoporosis in the future.