FKBP5 drives bone marrow stem cells senescence and suppresses osteogenic differentiation via canonical WNT/β-catenin signaling pathway

AUTHORS

Bin Zhu, Bowen Cai, Kaixiao Xue, Guoyong Yin, Shumin Zhou, Jiahu Fang

ABSTRACT

Senile osteoporosis and associated fractures significantly increase the morbidity and mortality of older people, thus increasing the cost of public health. Further investigations are required to explore the molecular causes of senile osteoporosis. In this study, FKBP5 expression in bone marrow mesenchymal stem cells (BMSCs) increased with age, and the degree of expression was inversely related to the patient's bone mineral density or CT values. Functional studies have validated the regulatory function of FKBP5 in BMSCs osteogenesis differentiation through the canonical WNT/β-catenin signaling pathway by binding to β-catenin and promoting its ubiquitination and degradation. Administration of SAFit2, a selective inhibitor of FKBP5, enhanced bone density in an animal model of senile osteoporosis. These findings suggest that FKBP5 may be a novel target and offer a new perspective on osteoporosis treatment.

BAP1 promotes osteoclast function by metabolic reprogramming

AUTHORS

Nidhi Rohatgi, Wei Zou, Yongjia Li, Kevin Cho, Patrick L. Collins, Eric Tycksen, Gaurav Pandey, Carl J. DeSelm, Gary J. Patti, Anwesha Dey & Steven L. Teitelbaum

ABSTRACT

Treatment of osteoporosis commonly diminishes osteoclast number which suppresses bone formation thus compromising fracture prevention. Bone formation is not suppressed, however, when bone degradation is reduced by retarding osteoclast functional resorptive capacity, rather than differentiation. We find deletion of deubiquitinase, BRCA1-associated protein 1 (Bap1), in myeloid cells (Bap1∆LysM), arrests osteoclast function but not formation. Bap1∆LysM osteoclasts fail to organize their cytoskeleton which is essential for bone degradation consequently increasing bone mass in both male and female mice. The deubiquitinase activity of BAP1 modifies osteoclast function by metabolic reprogramming. Bap1 deficient osteoclast upregulate the cystine transporter, Slc7a11, by enhanced H2Aub occupancy of its promoter. SLC7A11 controls cellular reactive oxygen species levels and redirects the mitochondrial metabolites away from the tricarboxylic acid cycle, both being necessary for osteoclast function. Thus, in osteoclasts BAP1 appears to regulate the epigenetic-metabolic axis and is a potential target to reduce bone degradation while maintaining osteogenesis in osteoporotic patients.

Inhibition of KIF11 ameliorates osteoclastogenesis via regulating mTORC1-mediated NF-κB signaling

AUTHORS

Jiansen Miao, Hanbing Yao, Jian Liu, Zhixian Huang, Chengge Shi, Xinyu Lu, Junchen Jiang, Rufeng Ren, Chenyu Wang, Youjin Pan, Te Wang, Haiming Jin

ABSTRACT

Osteoporosis, characterized by over-production and activation of osteoclasts, has become a major health problem especially in elderly women. In our study, we first tested the effect of Caudatin (Cau) in osteoclastogenesis, which is separated from Cynanchum auriculatum as a species of C-21 steroidal glyosides. The results indicated that Cau suppressed osteoclastogenesis in a time- and dose-dependent manner in vitro. Mechanistically, Cau was identified to inhibit NF-κB signaling pathway via modulation of KIF11-mediated mTORC1 activity. In vivo, by establishing an ovariectomized (OVX) mouse model to mimic osteoporosis, we confirmed that Cau treatment prevented OVX-induced bone loss in mice. In conclusion, we demonstrated that Cau inhibited NF-κB signaling pathway via modulation of KIF11-mediated mTORC1 activity to suppress osteoclast differentiation in vitro as well as OVX-induced bone loss in vivo. This provides the possibility of a novel prospective drug for osteoporosis remedies.

Metal-polyDNA nanoparticles reconstruct osteoporotic microenvironment for enhanced osteoporosis treatment

AUTHORS

XUELIANG LIU, FAN LI, ZILIANG DONG, CHAO GU, DONGSHENG MAO, JINGQI CHEN, LEI LUO, YUTING HUANG, JIE XIAO, ZHANCHUN LI, ZHUANG LIU, AND YU YANG

ABSTRACT

Current clinical approaches to osteoporosis primarily target osteoclast biology, overlooking the synergistic role of bone cells, immune cells, cytokines, and inorganic components in creating an abnormal osteoporotic microenvironment. Here, metal-polyDNA nanoparticles (Ca-polyCpG MDNs) composed of Ca2+ and ultralong single-stranded CpG sequences were developed to reconstruct the osteoporotic microenvironment and suppress osteoporosis. Ca-polyCpG MDNs can neutralize osteoclast-secreted hydrogen ions, provide calcium repletion, promote remineralization, and repair bone defects. Besides, the immune-adjuvant polyCpG in MDNs could induce the secretion of osteoclastogenesis inhibitor interleukin-12 and reduce the expression of osteoclast function effector protein to inhibit osteoclast differentiation, further reducing osteoclast-mediated bone resorption. PPi4− generated during the rolling circle amplification reaction acts as bisphosphonate analog and enhances bone targeting of Ca-polyCpG MDNs. In ovariectomized mouse and rabbit models, Ca-polyCpG MDNs prevented bone resorption and promoted bone repair by restoring the osteoporotic microenvironment, providing valuable insights into osteoporosis therapy.

Isosinensetin alleviates estrogen deficiency-induced osteoporosis via suppressing ROS-mediated NF-κB/MAPK signaling pathways

AUTHORS

Yiwu Qin, Dezhi Song, Shijie Liao, Junchun Chen, Minglian Xu, Yuangang Su, Haoyu Lian, Hui Peng, Linhua Wei, Kai Chen, Jiake Xu, Jinmin Zhao, Qian Liu

ABSTRACT

The formation of osteoclasts and their hyperactive bone resorption are related to the aggregation of intracellular reactive oxygen species (ROS). Flavonoids, derived from plant active ingredients, can alleviate the symptoms of osteoporosis (OP). Isosinensetin (Iss) is a flavonoid with antioxidant effects obtained mainly from citrus fruits, and its effect on osteoclastogenesis has not been reported. In this study, we investigated the antioxidant activity of Iss on osteoclast differentiation and function, as well as the therapeutic impact of Iss on OP. We found that Iss inhibited osteoclastogenesis and suppressed the bone resorption function of osteoclasts. Additionally, Iss reduced receptor activator of nuclear factor-κB ligand (RANKL)-induced intracellular ROS. Using quantitative real-time polymerase chain reaction and western blot, we further found that Iss inhibited osteoclast-specific genes and related proteins, while promoting the expression of antioxidant enzyme-related genes and proteins. Mechanistically, Iss reduces intracellular ROS by activating nuclear factor-erythroid 2-related factor 2 (Nrf2) and its related antioxidant enzymes and inhibits the downstream nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways of ROS, which in turn inhibits nuclear factor of activated T cells 1 (NFATc1), and ultimately inhibits osteoclastogenesis. In vivo, by micro-computed tomography (Micro-CT) assay and histological analyses, we found that Iss could reduce bone loss in ovariectomized (OVX) mice. Therefore, Iss has the potential as an OP preventative and therapeutic drug option.

Cedrol, a Ginger-derived sesquiterpineol, suppresses estrogen-deficient osteoporosis by intervening NFATc1 and reactive oxygen species

AUTHORS

Cong Xu, Shu-Qing Jin, Chen Jin, Zi-Han Dai, Yu-Hao Wu, Gao-Lu He, Hai-Wei Ma, Chao-Yi Xu, Wen-Lai Fang

ABSTRACT

Osteoporosis is a prevalent bone metabolic disease in menopause, and long-term medication is accompanied by serious side effects. Ginger, a food spice and traditional medicine with ancient history, exhibits the potential to alleviate osteoporosis in preclinical experiments, whereas its complex composition leads to ambiguous pharmacological mechanisms. The purpose of this study was to investigate the effect and mechanism of Ced in estrogen-deficient osteoporosis, a sesquiterpene alcohol recently discovered from Ginger with multiple pharmacological properties. RANKL was stimulated BMM (bone marrow macrophages) differentiation into osteoclasts in vitro. And the osteoclast activity and number were assessed by TRAcP and SEM. We found that Ced mitigated RANKL-induced osteoclastogenesis by descending the ROS content and obstructing NFATc1, NF-κB, and MAPK signaling. Also, Ced-mediated anti-osteolytic property was found in ovariectomized mice by Micro-CT scanning and histological staining. Summarily, our works demonstrated the anti-osteoporotic potential of Cedrol in Ginger for the first time, which also offered more pharmacological evidence for Ginger as food or medicine used for bone metabolic disease.