Lycopene Improves Bone Quality in SAMP6 Mice by Inhibiting Oxidative Stress, Cellular Senescence, and the SASP.

SCOPE: Cellular senescence (CS) is closely related to tissue ageing including bone ageing. CS and the senescence-associated secretory phenotype (SASP) have emerged as critical pathogenesis elements of senile osteoporosis. This study aims to investigate the effect of lycopene on senile osteoporosis. METHODS AND RESULTS: The senescence-accelerated mouse prone 6 (SAMP6) strain of mice is used as the senile osteoporosis model. Daily ingestion of lycopene for 8 weeks preserves the bone mass, density, strength, and microarchitecture in the SAMP6 mice. Moreover, these alterations are associated with a decrease in oxidative stress in the senile osteoporosis model. In addition, there is a reduction in osteoblast and osteocyte senescence and the SASP in the bone tissues of the SAMP6 mice. Lycopene improves bone health likely due to its antioxidant properties that may be linked with the regulation of CS and SASP in the SAMP6 mice. CONCLUSION: These results suggest that lycopene may be beneficial for the management of senile osteoporosis by inhibiting oxidative stress, CS, and the SASP.

Astaxanthin attenuates irradiation-induced osteoporosis in mice by inhibiting oxidative stress, osteocyte senescence, and SASP.

Radiation therapy (RT) is a crucial part of many treatment plans for cancer patients. However, major undesired side effects are associated with this treatment, including impaired bone remodeling and bone loss. Irradiation induces bone loss due to promoted osteoclastic bone resorption and reduced osteoblastic bone formation. Astaxanthin (AST) is a natural antioxidant with anti-oxidative and anti-aging properties. However, it is unclear whether AST is also protective against osteoporosis induced by ionizing radiation (IR). Here, we evaluate the efficacy of AST in mitigating IR-induced bone loss in a mouse model where both hindlimbs received radiation. Reduced BMD, bone biomechanical strength, bone formation, elevated oxidative stress, and osteoclast activity with microarchitectural deterioration of trabecular and cortical bones were observed in IR mice. Supplementation with AST corrected these osteoporotic phenotypes, caused by IR, by inhibiting oxidative stress, DNA damage, osteocyte senescence, and senescence-associated secretory phenotype (SASP), subsequently promoting osteoblastic bone formation and inhibiting osteoclastic bone resorption. The results from our study provide experimental evidence for the clinical use of AST to prevent IR-induced osteoporosis in cancer patients.

Treatment with soluble bone morphogenetic protein type 1A receptor fusion protein alleviates irradiation-induced bone loss in mice through increased bone formation and reduced bone resorption.

An increased fracture risk is often observed in cancer patients undergoing radiotherapy (RT), particularly at sites within the field of radiation. Therefore, the development of appropriate therapeutic options to prevent RT-induced bone loss is urgently needed. A soluble form of the BMP receptor type 1A fusion protein (mBMPR1A-mFc) serves as an antagonist to endogenous BMPR1A. Previous studies have shown that mBMPR1A-mFc treatment increases bone mass in both ovary-intact and ovariectomized via promoting osteoblastic bone formation and inhibiting osteoclastic bone resorption. The present study was designed to investigate whether mBMPR1A-mFc administration prevents radiation-induced bone deterioration in mice. We constructed an animal model of radiation-induced osteoporosis by exposure to a 2-Gy dose of X-rays. Micro-CT, histomorphometric, bone-turnover, and mechanical analyses showed that mBMPR1A-mFc administration prevented trabecular microarchitecture deterioration after RT because of a marked increase in bone formation and a decrease in bone resorption. Mechanistic studies indicated that mBMPR1A-mFc administration promoted osteoblastogenesis by activating Wnt/Lrp5/ß-catenin signaling while decreasing osteoclastogenesis by inhibiting the RANKL/RANK/OPG pathway. Our novel findings provide solid evidence for the application of mBMPR1A-mFc as a therapeutic treatment for radiation-induced osteoporosis.

Deletion of p16 prevents estrogen deficiency-induced osteoporosis by inhibiting oxidative stress and osteocyte senescence.

To investigate whether p16 deletion can prevent osteoporosis caused by estrogen deficiency, we first confirmed that p16 protein expression levels were significantly up-regulated in bony tissue of ovariectomized (OVX) wild-type mice. Eight-week-old wild-type and p16-/- mice were then sham-operated or bilateral OVX. After 12 weeks, the bone phenotypes of all models were analyzed by radiography, micro-computed tomography, histology, immunohistochemistry, and molecular biology. The results showed that p16 deficiency could rescue OVX-induced osteoporosis by significantly increased bone mineral density, trabecular bone volume, total collagen positive area, osteoblast number, type I collagen positive area, fibroblast colony-forming unit (CFU-f) and alkaline phosphatase-positive CFU-f with up-regulation of the mRNA expression levels of Alp, Runx2, type I collagen and osteocalcin, and significantly reduced osteoclast surface and the ratio of RANKL/OPG mRNA expression level. Furthermore, we also demonstrated that p16 deletion inhibited OVX-induced oxidative stress and bone cell senescence, such as a significant decrease in reactive oxygen species levels, up-regulation of superoxide dismutase 1 and 2 protein expression levels, and reduction of the percentage of ß-galactosidase-positive osteocytes and p21 protein expression levels in bony tissue. Our results indicate that p16 deletion can prevent estrogen deficiency-induced osteoporosis by inhibiting oxidative stress, osteocyte senescence and osteoclastic bone resorption, stimulating osteogenesis and osteoblastic bone formation. Therefore, this study provides new insights into the potential of p16 as a novel therapeutic target for estrogen deficiency-induced osteoporosis.

Protein methylome analysis in Arabidopsis reveals regulation in RNA-related processes.

Protein methylation has been proposed as an important post-translational modification, which occurs predominantly on lysine and arginine residues. Recent discoveries have revealed that protein methylation is also present on non-histones besides histones, and plays critical roles in regulating protein stability and function. However, proteome-wide identification of methylated proteins in plants remains unexplored. Here, we present the first global survey of monomethyl arginine, symmetric and asymmetric dimethyl arginine, and monomethyl, dimethyl, trimethyl lysine modifications in the proteomes of 10-day-old Arabidopsis seedlings through a combination of immunoaffinity purification and mass spectrometry analysis. In total, we identified 617 methylation sites which mapped to 412 proteins, with 263 proteins harboring 381 lysine methylation sites and 149 proteins harboring 236 arginine methylation sites. Among them, 607 methylation sites on 408 proteins were novel findings. Motif analysis revealed that glycine preferentially flanked methylated arginine residues, whereas aspartate and glutamate enriched around mono- and dimethylated lysine sites. Methylated proteins were involved in a variety of metabolic processes, showing significant enrichment in RNA-related metabolic pathways including spliceosome, RNA transport, and ribosome. Our data provide a global view of methylated non-histone proteins in Arabidopsis, laying foundations for elucidating the biological function of protein methylation in plants. SIGNIFICANCE: Protein methylation has emerged as a common and important modification both in eukaryotes and prokaryotes. The identification of methylated sites/peptides is fundamental for further functional analysis of protein methylation. This study was the first proteome-scale identification of lysine and arginine methylation in plants. We found that methylation occurred widely on non-histone proteins in Arabidopsis and was involved in diverse biological functions. The results provide foundations for the investigation of the protein methylome in Arabidopsis and provide powerful resources for the functional analysis of protein methylation in plants.

Resequencing of 683 common bean genotypes identifies yield component trait associations across a north-south cline.

We conducted a large-scale genome-wide association study evaluation of 683 common bean accessions, including landraces and breeding lines, grown over 3 years and in four environments across China, ranging in latitude from 18.23° to 45.75° N, with different planting dates and abiotic or biotic stresses. A total of 505 loci were associated with yield components, of which seed size, flowering time and harvest maturity traits were stable across years and environments. Some loci aligned with candidate genes controlling these traits. Yield components were observed to have strong associations with a gene-rich region on the long arm of chromosome 1. Manipulation of seed size, through selection of seed length versus seed width and height, was deemed possible, providing a genome-based means to select for important yield components. This study shows that evaluation of large germplasm collections across north-south geographic clines is useful in the detection of marker associations that determine grain yield in pulses.

lncRNA UCA1 Predicts a Poor Prognosis and Regulates Cell Proliferation and Migration by Repressing p21 and SPRY1 Expression in GC.

Dysregulated expression of long non-coding RNAs (lncRNAs) has been reported in many types of cancers, indicating that it has important regulatory roles in human cancer biology. Recently, lncRNA urothelial cancer-associated 1 (UCA1) was shown to be dysregulated in many cancer types, but the detailed mechanisms remain largely unknown. In our study, we found that upregulated UCA1 is associated with poor prognosis in gastric cancer patients. Further experiments revealed that UCA1 knockdown significantly repressed the proliferation and migration both in vitro and in vivo. Moreover, RNA sequencing (RNA-seq) analysis revealed that UCA1 knockdown preferentially affected genes that are linked to cell proliferation, cell cycle, and cell migration. Mechanistically, UCA1 promotes cell proliferation progression through repressing p21 and Sprouty RTK signaling antagonist 1 (SPRY1) expression by binding to EZH2. We found that UCA1 could mediate the trimethylation of H3K27 in promoters of p21 and SPRY1. To our knowledge, this is the first report showing the global gene profile of downstream targets of UCA1 in the progression of gastric cancer. Collectively, our data reveal the important roles of UCA1 in gastric cancer (GC) oncogenesis.

A soluble bone morphogenetic protein type 1A receptor fusion protein treatment prevents glucocorticoid-Induced bone loss in mice.

Glucocorticoid-induced osteoporosis (GIOP) is a frequent complication of systemic glucocorticoid (GC) therapy, is the most common form of secondary osteoporosis, and is associated with skeletal fragility and increased fracture risk. A soluble form of BMP receptor type 1A fusion protein (mBMPR1A-mFc) acts as an antagonist to endogenous BMPR1A and could increase bone mass in both ovariectomized and ovary-intact mice, but its effects in GIOP mice remained unclear. The aim of this study was to evaluate the effects of mBMPR1A-mFc on the skeleton in experimental models of GIOP. mBMPR1A-mFc treatment could increase the bone mineral density (BMD), trabecular bone volume, thickness, and number, and cortical thickness, and reduce the structure model index and trabecular separation in GIOP mice. mBMPR1A-mFc treatment could also prevent bone loss and enhance biomechanical strength in GIOP mice by promoting osteoblastic bone formation and inhibiting osteoclastic bone resorption. Mechanistic studies revealed that mBMPR1A-mFc treatment increased murine osteoblastogenesis by activating the Wnt/ß-catenin signaling pathway while decreasing osteoclastogenesis by inhibiting the RANK/RANKL/osteoprotegerin (OPG) signaling pathway. These findings demonstrate that mBMPR1A-mFc treatment in GIOP mice improves bone mass, microarchitecture, and strength by enhancing osteoblastic bone formation and inhibiting osteoclastic bone resorption in GIOP mice and offers a promising novel alternative for the treatment of GIOP.

Pyrroloquinoline Quinone Prevents Estrogen Deficiency-Induced Osteoporosis by Inhibiting Oxidative Stress and Osteocyte Senescence.

Accumulating studies have shown that oxidative stress increases with aging, which is related to the pathophysiology of postmenopausal osteoporosis. Pyrroloquinoline quinone (PQQ) is a natural anti-oxidant with anti-oxidative and anti-aging effects. However, it is unclear whether PQQ has a protective role against estrogen deficiency-induced osteoporosis. Here, we evaluated the efficacy of PQQ on bone mineral density, bone microarchitecture, bone turnover and biomechanical strength in ovariectomy (OVX)-induced osteoporosis mouse model. Although dietary PQQ supplement did not affect serum E2 levels and uterine weight in OVX mice, it could prevent OVX-induced bone loss and improve bone strength by inhibiting oxidative stress, osteocyte senescence and senescence-associated secretory phenotype (SASP), subsequently promoting osteoblastic bone formation and inhibiting osteoclastic bone resorption, which was comparable to treatment with exogenous estrogen. The results from our study provide experimental evidence for the clinical use of PQQ to prevent estrogen deficiency-induced osteoporosis.

Nano-sized titanium alloy particles inhibit the proliferation and promote the apoptosis of bone marrow mesenchymal stem cells in vitro.

Aseptic loosening of artificial joints is the leading cause of failure for patients who receive total joint arthroplasty. Prior reports indicate that bone marrow mesenchymal stem cells (BSMC) are critical in the stabilization of implanted artificial joints, and that deregulated interaction between BMSCs and artificial joint derived particles is a risk factor for aseptic loosening with an unknown mechanism. In the present study, the pathomechanisms whereby titanium and its alloy derived particles facilitate aseptic loosing were investigated in vitro. It was demonstrated that nano­sized titanium alloy particles significantly inhibited the proliferation of BMSCs in a time and concentration dependent manner. Furthermore, it was demonstrated that the particles promoted the apoptosis of BMSCs in the same manner. Bax and Caspase­3 expression of BMSCs were elevated when cultured with the particles. As BMSCs exhibit a critical role in the stabilization of artificial joints, the results of the present study may provide a novel direction for the management of aseptic loosening in clinics.