BONE
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2024
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IF 3.5
Xueting Wang,Hui Zhang,Ling Hu,Jin He,Qifeng Jiang,Lingfei Ren,Ke Yu,Mengdie Fu,Zhikun Li,Zhixu He,Junhao Zhu,Ying Wang,Zhiwei Jiang,Guoli Yang
Gain-of-function mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) can cause high-bone-mass (HBM) phenotype, with 19 identified mutations so far. The A242T mutation in LRP5 has been found in 9 families, making it one of the most prevalent mutations. However, the correlation between the A242T mutation and HBM phenotype remains unverified in animal models. This study aimed to investigate the bone properties in a new transgenic mouse model carrying the LRP5 A241T missense mutation, equivalent to A242T in humans. Heterozygous Lrp5 A241T mice were generated using CRISPR/Cas9 genome editing. Body weight increased with age from 4 to 16 weeks, higher in males than females, with no difference between Lrp5 A241T mice and wild-type control. Micro-CT showed slightly longer femur and notably elevated trabecular bone mass of the femur and fifth lumbar spine with higher bone mineral density, bone volume fraction, and trabecular thickness in Lrp5 A241T mice compared to wild-type mice. Additionally, increased cortical bone thickness and volume of the femur shaft and skull were observed in Lrp5 A241T mice. Three-point bending tests of the tibia demonstrated enhanced bone strength properties in Lrp5 A241T mice. Histomorphometry confirmed that the A241T mutation increased bone formation without affecting osteoblast number and reduced resorption activities in vivo . In vitro experiments indicated that the LRP5 A241T mutation enhanced osteogenic capacity of osteoblasts with upregulation of the Wnt signaling pathway, with no significant impact on the resorptive activity of osteoclasts . In summary, mice carrying the LRP5 A241T mutation displayed high bone mass and quality due to enhanced bone formation and reduced bone resorption in vivo , potentially mediated by the augmented osteogenic potential of osteoblasts. Continued investigation into the regulatory mechanisms of its bone metabolism and homeostasis may contribute to the advancement of novel therapeutic strategies for bone disorders.
研究领域:
遗传学
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分子生物学
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骨生物学
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产品关联
DOI
PubMed
高影响因子
ORAL DISEASES
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2025
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IF 2.9
Danhong Zhou,Xueting Wang,Hui Zhang,Qifeng Jiang,Qinmeng Zhang,Xiaoyan Miao,Ying Wang,Guoli Yang,Zhiwei Jiang
Objectives This study aimed to assess the effect of the low-density lipoprotein receptor-related protein 5 (Lrp5) A241T gain-of-function mutation, which induces a high-bone-mass phenotype, on implant osseointegration in a murine model. Methods Heterozygous Lrp5 A241T mutant ( Lrp5 A/+ ) and wild-type (WT) littermate male mice on a C57BL/6J background were used. Micro-computed tomography (micro-CT) was performed to assess tibial trabecular bone architecture. Sandblasted and acid-etched (SLA) titanium implants were surgically inserted into the proximal tibiae, and samples were harvested after 4 weeks for micro-CT and histological analysis. Primary osteoblasts were seeded onto SLA titanium sheets and induced for osteogenesis for 7 days. Osteogenic marker expression was assessed by quantitative real-time polymerase chain reaction and western blotting. Results The Lrp5 A/+ group exhibited significantly improved trabecular bone architecture compared to WT controls. At 4 weeks post-implantation, micro-CT revealed greater peri-implant bone formation in the Lrp5 A/+ group, while hard tissue sections showed increased bone area and bone-implant contact. HE and Masson staining further confirmed greater new bone formation. After 7 days of in vitro osteogenic induction, Lrp5, Runx2, and Sp7 were significantly upregulated in the Lrp5 A/+ group. Conclusions The Lrp5 A241T mutation significantly enhanced implant osseointegration in a transgenic murine model.
研究领域:
骨生物学
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分子骨病学
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生物材料学
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口腔种植学
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转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
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2022
·Vol. 20
·期 1
·1-15
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IF 8.44
Guan Huanshuai,Kong Ning,Tian Run,Cao Ruomu,Liu Guanzhi,Li Yiyang,Wei Qilu,Jiao Ming,Lei Yutian,Xing Fangze,Tian Peng,Wang Kunzheng,Yang Pei
Background Osteoporosis is a disease threatening the health of millions of individuals. Melatonin is found to be a potential anti-osteoporosis drug. However, whether melatonin plays a role against osteoporosis at different stages of the menopause and the underlying mechanisms are unknown. Methods Ovariectomy was utilized as a model of perimenopausal and postmenopausal osteoporosis. A total of 100 mg/kg melatonin, or solvent alone, was added to the drinking water of the rats over 8 weeks. Perimenopausal rats immediately received intervention following ovariectomy while postmenopausal rats received intervention 8 weeks after ovariectomy. All rats underwent overdose anesthesia following intervention after which blood samples and femurs were collected for further analysis. Rat femurs were scanned using micro-CT and examined histologically. The serum levels of melatonin and osteogenic biochemical markers were measured and the expression of osteogenesis-associated genes ( Runx2 , Sp7 ) were quantified by real-time quantitative PCR. Alkaline phosphatase (ALP) activity and the gene expression ( Col1a1 , Runx2 , Alpl , and Bglap ) were measured after bone marrow mesenchymal stem cells (BMSCs) were osteogenically induced, both with and without melatonin in vitro. ALP staining and Alizarin Red S staining were used to identify osteogenesis. Results Analysis by micro-CT and histological staining demonstrated that bone mass decreased and bone microarchitecture deteriorated over time after ovariectomy. Intervention with melatonin increased bone mass in normal, perimenopausal, and postmenopausal osteoporotic rats. Serum levels of ALP continuously increased after ovariectomy while osteocalcin levels initially rose, then decreased. Melatonin increased the serum levels of ALP and osteocalcin and mRNA expression levels of Runx2 and Sp7 in normal and postmenopausal rats, the opposite of the markers in perimenopausal rats. In vitro study demonstrated that 100 μmol/L melatonin increased the mRNA expression of Col1a1 , Runx2 , and Alpl three and/or seven days after intervention, and Alpl and Bglap 14 d after intervention. Melatonin increased ALP activity and the extent of ALP and matrix mineralization in the late stage of osteogenesis. Conclusions Bone mass continuously decreased after ovariectomy, while melatonin increased bone mass and ameliorated bone metabolism in normal, perimenopausal, and postmenopausal osteoporotic rats due to the induction of osteogenic differentiation in BMSCs.
研究领域:
内分泌学
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骨科
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
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IF 3.322
Ye Gao,He Xin,Bolei Cai,Le Wang,Qianxin Lv,Yan Hou,Fuwei Liu,Taiqiang Dai,Liang Kong
RNA interference (RNAi)-based gene therapy that promotes anabolic bone formation is an effective approach for addressing osteoporosis. However, the selection of target gene and tissue-specific delivery systems has hindered the progression of this strategy. In this study, we identified casein kinase-2 interacting protein-1 encoding gene ( Ckip-1 ), a negative regulator of bone formation, as an effective target of small interfering RNAs (siRNAs) for improving bone mass. Moreover, an impressive (DSS) 6 -Liposome (Lipos) nanoparticle system that could target the bone formation surface was synthesized to enhance the delivery of Ckip-1 siRNA to osteogenic lineage cells. The in vitro results confirmed that the (DSS) 6 -Lipos system could efficaciously improve the intracellular delivery of Ckip-1 siRNA without obvious cell toxicity. The in vivo application of the delivery system showed specific accumulation of siRNA in osteogenic cells located around the bone formation surface. Bone-related analysis indicated increased bone mass and improved bone microarchitecture in mice with ovariectomy-induced osteoporosis. Moreover, the biomechanical characteristics of the tibia were enhanced significantly, indicating increased resistance to fragile fracture induced by osteoporosis. Thus, (DSS) 6 -Lipos- Ckip-1 siRNA-based osteoanabolic therapy may be a promising option for the treatment of osteoporosis.
研究领域:
药理学
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基因治疗
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骨生物学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
Bioactive Materials
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2024
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IF 18
Guoyang Zhang,Yuhao Kang,Jizhao Dong,Dingyi Shi,Yu Xiang,Haihan Gao,Zhiqi Lin,Xiaojuan Wei,Ren Ding,Beibei Fan,Hongmei Zhang,Tonghe Zhu,Liren Wang,Xiaoyu Yan
Osteoporosis is majorly caused by an imbalance between osteoclastic and osteogenic niches. Despite the development of nationally recognized first-line anti-osteoporosis drugs, including alendronate (AL), their low bioavailability, poor uptake rate, and dose-related side effects present significant challenges in treatment. This calls for an urgent need for more effective bone-affinity drug delivery systems. In this study, we produced hybrid structures with bioactive components and stable fluffy topological morphology by cross-linking calcium and phosphorus precursors based on mesoporous silica to fabricate nanoadjuvants for AL delivery. The subsequent grafting of -PEG-DAsp 8 ensured superior biocompatibility and bone targeting capacity. RNA sequencing revealed that these fluffy nanoadjuvants effectively activated adhesion pathways through CARD11 and CD34 molecular mechanisms, hence promoting cellular uptake and intracellular delivery of AL. Experiments showed that small-dose AL nanoadjuvants effectively suppress osteoclast formation and potentially promote osteogenesis. In vivo results restored the balance between osteogenic and osteoclastic niches against osteoporosis as well as the consequent significant recovery of bone mass. Therefore, this study constructed a drug nanoadjuvant with peculiar topological structures and high bone targeting capacities, efficient intracellular drug delivery as well as bone bioactivity. This provides a novel perspective on drug delivery for osteoporosis and treatment strategies for other bone diseases.
研究领域:
药理学
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纳米技术
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骨骼生物学
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
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2023
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IF 15.1
Bingyang Dai,Yuwei Zhu,Xu Li,Zuru Liang,Shunxiang Xu,Shian Zhang,Zhe Zhang,Shanshan Bai,Wenxue Tong,Mingde Cao,Ye Li,Xiaobo Zhu,Wei Liu,Yuantao Zhang,Liang Chang,Patrick Shu-hang Yung,Kevin Ki-wai Ho,Jiankun Xu,To Ngai,Ling Qin
The knowledge of osteoarthritis (OA) has nowadays been extended from a focalized cartilage disorder to a multifactorial disease. Although recent investigations have reported that infrapatellar fat pad (IPFP) can trigger inflammation in the knee joint, the mechanisms behind the role of IPFP on knee OA progression remain to be defined. Here, dysregulated osteopontin (OPN) and integrin β 3 signaling are found in the OA specimens of both human and mice. It is further demonstrated that IPFP-derived OPN participates in OA progression, including activated matrix metallopeptidase 9 in chondrocyte hypertrophy and integrin β 3 in IPFP fibrosis. Motivated by these findings, an injectable nanogel is fabricated to provide sustained release of siRNA Cd61 ( RGD− Nanogel/siRNA Cd61 ) that targets integrins. The RGD− Nanogel possesses excellent biocompatibility and desired targeting abilities both in vitro and in vivo. Local injection of RGD− Nanogel/siRNA Cd61 robustly alleviates the cartilage degeneration, suppresses the advancement of tidemark, and reduces the subchondral trabecular bone mass in OA mice. Taken together, this study provides an avenue for developing RGD− Nanogel/siRNA Cd61 therapy to mitigate OA progression via blocking OPN-integrin β 3 signaling in IPFP.
研究领域:
骨科
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分子生物学
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纳米技术
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风湿病学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Yuna Shang,Qingrun Zhu,Jiaming Ding,Liang Zhao,Fan Zhang,Jiayi Lu,Yinyin Feng,Jiayu Wang,Zhixue Liu,Mingjie Kuang,Chunju Li
Bioactive peptides play a crucial role in the field of regenerative medicine and tissue engineering. However, their application in vivo and clinic is hindered by their poor stability, short half-life, and low retention rate. Herein, we propose a novel strategy for encapsulating bioactive peptides using giant macrocycles. Platelet-derived growth factor (PDGF) bioactive mimicking peptide Nap-FFGVRKKP ( P ) was selected as the representative of a bioactive peptide. Quaterphen[4]arene ( 4 ) exhibited extensive host-guest complexation with P , and the binding constant was (1.16 ± 0.10) × 10 7 M −1 . In vitro cell experiments confirmed that P + 4 could promote the proliferation of BMSCs by 2.27 times. Even with the addition of the inhibitor dexamethasone (Dex), P + 4 was still able to save 76.94% of the cells in the control group. Compared to the Dex group, the bone mass of the mice with osteoporosis in the P + 4 group was significantly increased. The mean trabecular thickness (Tb.Th) increased by 17.03%, and the trabecular bone volume fraction (BV/TV) values increased by 40.55%. This supramolecular bioactive peptide delivery strategy provides a general approach for delivering bioactive peptides and opens up new opportunities for the development of peptide-based drugs.
研究领域:
再生医学
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组织工程
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药学
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骨骼生物学
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）