TET2 regulates osteoclastogenesis by modulating autophagy in OVX-induced bone loss

AUTHORS

Chen Yang, Huaqiang Tao, Haifeng Zhang, Yu Xia, Jiaxiang Bai, Gaoran Ge, Wenming Li, Wei Zhang, Long Xiao, Yaozeng Xu, Zhirong Wang, Ye Gu,H uilin Yang, Yu Liu & Dechun Geng

ABSTRACT

Increased bone resorption by osteoclasts after estrogen deficiency is the main cause of postmenopausal osteoporosis. TET2 (tet methylcytosine dioxygenase 2) is a DNA demethylase that regulates cellular function and differentiation potential. Macroautophagy/autophagy maintains cellular homeostasis by recycling unnecessary and damaged organelles. This study revealed that TET2 promoted bone loss in oophorectomized (OVX) mice and that TET2 promoted osteoclast differentiation by regulating autophagy. Tet2 knockdown inhibited autophagy and osteoclast differentiation in vitro. Mechanistically, Tet2 knockdown increased BCL2 (B cell leukemia/lymphoma 2) expression and BCL2 exhibited increased binding to BECN1 and negatively regulated autophagy. Small interfering RNA specific to Bcl2 interfered with BCL2 expression in Tet2-knockdown bone marrow cells/precursors, partially reversing autophagy dysregulation and promoting osteoclast differentiation. Moreover, the LV-shTet2 lentivirus prevented bone loss in OVX mice. In summary, our findings provide evidence that TET2 promotes osteoclast differentiation by inhibiting BCL2 expression and positively regulating BECN1-dependent autophagy.

Inhibition of myeloid PD-L1 suppresses osteoclastogenesis and cancer bone metastasis

AUTHORS

Hao Zuo & Yihong Wan

ABSTRACT

Programmed death-ligand 1 (PD-L1) is predominantly expressed in the antigen-presenting cells (APCs) that are originated and are abundant in the bone marrow. The roles of PD-L1 in bone cell differentiation and cancer bone metastasis remain unclear. Here we show that PD-L1 antibody or PD-L1 conditional knockout in the hematopoietic or myeloid lineage suppresses osteoclast differentiation in vitro and in vivo. Bone metastases of breast cancer and melanoma are diminished by PD-L1 antibody or PD-L1 deletion in the myeloid lineage. Transcriptional profiling of bone marrow cells reveals that PD-L1 deletion in the myeloid cells upregulates immune-stimulatory genes, leading to increased macrophage M1 polarization, decreased M2 polarization, enhanced IFNγ signaling, and elevated T cell recruitment and activation. All these alterations result in heightened anti-tumor immunity in the cancer microenvironment. Our findings support PD-L1 antibody as a potent therapy for bone metastasis of breast cancer and melanoma by simultaneously suppressing osteoclast and enhancing immunity.

3D gel-printed porous magnesium scaffold coated with dibasic calcium phosphate dihydrate for bone repair in vivo

AUTHORS

Yuxuan Zhang, Tao Lin, Haoye Meng, Xueting Wang, Hong Peng, Guangbo Liu, Shuai Wei, Qiang Lu, Yu Wang, Aiyuan Wang, Wenjing Xu, Huiping Shao, Jiang Peng

ABSTRACT

Background

Objective: The treatment of bone defect has always been a difficult problem in orthopedic clinic. The search for alternative biodegradable implants is a hot topic. The development of biodegradable magnesium scaffolds for the treatment of bone defects has long been a goal of the public.

Methods

In this study, we proposed a porous magnesium scaffold prepared by 3D gel printing and surface modification with an additional calcium phosphate coating and use of its strength, degradability and slow degradation rate in a bone graft substitute material. The porous magnesium granular scaffold was prepared by 3D gel printing technology and modified by DCPD (Dibasic Calcium Phosphate Dihydrate) coating. The biocompatibility, degradation rate, and osteogenic ability of the scaffold were evaluated in vitro and in vivo.

Results

The biocompatibility, in vivo degradation and bone defect healing response of the implants were investigated. Porous magnesium scaffolds were successfully prepared, and the strength of sintered scaffolds reached 5.38 ​MPa. The degradation rates of scaffolds were significantly reduced after coating with DCPD. The cell compatibility evaluation showed that DCPD-coated Mg scaffold was suitable for cell proliferation. In vivo biosafety monitoring showed that scaffold implantation did not cause an increase in Mg ion concentration in vivo, and no toxic damage was detected in the liver or kidney. Micro-CT and pathological results showed that a large amount of new bone was formed at 6 weeks. At 12 weeks, approximately 52% of the scaffold volume remained. At 24 weeks, osteogenesis, which was stimulated by some residual scaffold, still can be observed. In summary, this study suggests that 3D gel-printed DCPD-coated porous magnesium scaffolds have great potential as bone graft alternatives.

Conclusion

In summary, this study suggests that 3D gel-printed DCPD-coated porous magnesium scaffolds have great potential as bone graft alternatives.

The Translational potential of this article

The translational potential of this article is to make use of the advantages of 3D gel printing technology with higher efficiency and lower cost compared with SLM and SLS technologies, and use pure magnesium powder as raw material to prepare degradable porous magnesium metal scaffolds, opening up a new technical route for the preparation of degradable porous magnesium scaffolds which are made for bone defect regeneration in the future.

Fibrinogen Mediates Cadmium-induced Macrophage Activation and Serves as a Predictor of Cadmium Exposure in Chronic Obstructive Pulmonary Disease

AUTHORS

Fu Jun Li, Ranu Surolia, Pooja Singh, Kevin G Dsouza, Crystal T Stephens, Zheng Wang

ABSTRACT

The etiologies of chronic obstructive pulmonary disease (COPD) remain unclear. Cadmium (Cd) causes both pulmonary fibrosis and emphysema, however the predictors for Cd exposure and the mechanisms by which Cd causes COPD remain unknown. We demonstrated that Cd burden was increased in lung tissue from subjects with COPD and this was associated with cigarette smoking. Fibrinogen levels increased markedly in lung tissue of smoked COPD patients, compared to never-smokers and control subjects. Fibrinogen concentration also correlated positively with lung Cd load, but inversely with the predicted % of FEV1 and FEV1/FVC. Cd enhanced the secretion of fibrinogen in a cdc2-dependent manner whereas fibrinogen further mediated Cd-induced peptidylarginine deiminase 2 (PAD2)-dependent macrophage activation. Using lung fibroblasts from CdCl2-treated toll-like receptor 4 (TLR4) wild type and mutant mice, we demonstrated that fibrinogen enhanced Cd-induced TLR4-dependent collagen synthesis and cytokine/chemokine production. We further showed that fibrinogen complexed with connective tissue growth factor (CTGF), which in turn promoted the synthesis of plasminogen activator inhibitor-2 (PAI-2) and fibrinogen, and inhibited fibrinolysis in Cd-treated mice. The amounts of fibrinogen were increased in the bronchoalveolar lavage fluid (BALF) of Cd-exposed mice. Positive correlations were observed between fibrinogen with hydroxyproline. Our data suggests that fibrinogen is involved in Cd-induced macrophage activation and increases in fibrinogen in patients with COPD may be used as a marker of Cd exposure and predict disease progression.

The Role of Bone Muscle Ring Finger-1 (MuRF1), MuRF2, MuRF3, and Atrogin-1 on Microarchitecture In Vivo

AUTHORS

Vidyani Suryadevara, Connor J. Krehbial, Danielle Halsey & Monte S. Willis

ABSTRACT

Ubiquitin proteasome system was found to contribute to bone loss by regulating bone turnover and metabolism, by modulating osteoblast differentiation and bone formation as well as formation of osteoclasts that contribute to bone resorption. Muscle Ring Finger (MuRF) are novel ubiquitin ligases, which are muscle specific and have not been much implicated in the bone but have been implicated in several human diseases including heart failure and skeletal muscle atrophy. This study is aimed at understanding the role of MuRF1, MuRF2, MuRF3 and Atrogin which are distinct MuRF family proteins in bone homeostasis. Wildtype, heterozygous and homozygous mice of each of the isoforms were used and the bone microarchitecture and mechanical properties were assessed using microCT and biomechanics. MuRF1 depletion was found to alter cortical properties in both males and females, but only trabecular spacing in the females. MuRF2 depletion let to no changes in the cortical and trabecular properties but change in the strain to yield in the females. Depletion of MuRF3 led to decrease in the cortical properties in the females and increase in the trabecular properties in the males. Atrogin depletion was found to reduce cortical properties in both males and females, whereas some trabecular properties were found to be reduced in the females. Each muscle-specific ligase was found to alter the bone structure and mechanical properties in a distinct a sex-dependent manner.

Decaffeinated green tea extract as a nature-derived antibiotic alternative: An application in antibacterial nano-thin coating on medical implants

AUTHORS

Jihyo Park, Lianhua Chi, Hee-Young Kwon, Jisoo Lee, Seunghwi Kim, Seonki Hong

ABSTRACT

Plant-derived polyphenols have emerged as molecular building blocks for biomedical architectures. However, the isolation of polyphenols from other components requires labor-intensive procedures, which increases costs and often raises environmental concerns. Here, we suggest that decaffeination can be a convenient and cost-effective method for enhancing the antibacterial performance of polyphenol-rich tea extracts. As a demonstration, we compared the properties of a nano-thin coating made of decaffeinated (dGT coating) and raw green tea extract (GT coating). The dGT coating exhibited enhanced antibacterial performance with regard to bacterial killing and prevention of bacterial attachment compared with the GT coating. Moreover, the chemical reactivity of the dGT coating was further utilized for secondary modifications, which enhanced the overall antibacterial performance of the modified surface. Given its intrinsic low toxicity, we envision that the developed antibacterial coating is ready for the next steps toward application in real clinical settings.