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Yamamoto K, Sawada SI, Shindo S, Nakamura S, Kwon YM, Kianinejad N, Vardar S, Hernandez M, Akiyoshi K, Kawai T. Cationic Glucan Dendrimer Gel-Mediated Local Delivery of Anti-OC-STAMP-siRNA for Treatment of Pathogenic Bone Resorption. Gels 2024; 10:377. [PMID: 38920924 PMCID: PMC11202495 DOI: 10.3390/gels10060377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/17/2024] [Accepted: 05/28/2024] [Indexed: 06/27/2024] Open
Abstract
Osteoclast stimulatory transmembrane protein (OC-STAMP) plays a pivotal role in the promotion of cell fusion during osteoclast differentiation (osteoclastogenesis) in the context of pathogenic bone resorption. Thus, it is plausible that the suppression of OC-STAMP through a bioengineering approach could lead to the development of an effective treatment for inflammatory bone resorptive diseases with minimum side effects. Here, we synthesized two types of spermine-bearing (Spe) cationic glucan dendrimer (GD) gels (with or without C12) as carriers of short interfering RNA (siRNA) to silence OC-STAMP. The results showed that amphiphilic C12-GD-Spe gel was more efficient in silencing OC-STAMP than GD-Spe gel and that the mixture of anti-OC-STAMP siRNA/C12-GD-Spe significantly downregulated RANKL-induced osteoclastogenesis. Also, local injection of anti-OC-STAMP-siRNA/C12-GD-Spe could attenuate bone resorption induced in a mouse model of periodontitis. These results suggest that OC-STAMP is a promising target for the development of a novel bone regenerative therapy and that C12-GD-Spe gel provides a new nanocarrier platform of gene therapies for osteolytic disease.
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Affiliation(s)
- Kenta Yamamoto
- Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
- Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (S.S.); (S.N.); (T.K.)
| | - Shin-Ichi Sawada
- Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 605-0981, Japan; (S.-I.S.); (K.A.)
- Synergy Institute for Futuristic Mucosal Vaccine Research and Development, Chiba University, Chiba 260-8670, Japan
| | - Satoru Shindo
- Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (S.S.); (S.N.); (T.K.)
| | - Shin Nakamura
- Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (S.S.); (S.N.); (T.K.)
| | - Young M. Kwon
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA (N.K.)
| | - Nazanin Kianinejad
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA (N.K.)
| | - Saynur Vardar
- Department of Periodontology, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (S.V.); (M.H.)
| | - Maria Hernandez
- Department of Periodontology, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (S.V.); (M.H.)
| | - Kazunari Akiyoshi
- Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 605-0981, Japan; (S.-I.S.); (K.A.)
| | - Toshihisa Kawai
- Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (S.S.); (S.N.); (T.K.)
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Xu H, Xu J, Chen F, Liu T, Li J, Jiang L, Jia Y, Hu C, Gao Z, Gan C, Hu L, Wang X, Sheng J. Acanthopanax senticosus aqueous extract ameliorates ovariectomy-induced bone loss in middle-aged mice by inhibiting the receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis. Food Funct 2021; 11:9696-9709. [PMID: 33057520 DOI: 10.1039/d0fo02251a] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Acanthopanax senticosus (Ciwujia) has broad-spectrum pharmacological activities, including osteoprotective effects. However, the mechanisms underlying these effects remain unclear. We investigated whether Acanthopanax senticosus aqueous extract (ASAE) ameliorates ovariectomy-induced bone loss in middle-aged mice through inhibition of osteoclastogenesis. In vitro, ASAE significantly suppressed the receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclast differentiation and formation of F-actin rings by downregulating the expression of the nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), c-Fos, and osteoclastogenesis-related marker genes and proteins, including c-Src, tartrate-resistant acid phosphatase (TRAP), cathepsin K, β3-integrin, and matrix metallopeptidase-9 (MMP-9). This was achieved by inhibiting RANK signaling pathways, including p65, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 in osteoclast precursors. In vivo, ASAE markedly ameliorated bone loss in ovariectomized (OVX) middle-aged mice. ASAE significantly inhibited the serum levels of tartrate-resistant acid phosphatase 5b (TRACP-5b) and RANKL, whereas it increased those of osteocalcin, procollagen 1 N-terminal peptide (P1NP), and osteoprotegerin in OVX mice. ASAE significantly inhibited the OVX-induced expression of osteoclast-specific proteins and genes in the femur. In conclusion, ASAE prevents ovariectomy-induced bone loss in middle-aged mice by inhibiting RANKL-induced osteoclastogenesis through suppression of RANK signaling pathways and could be potentially used in mediated treatment of osteoclast-related diseases (e.g., osteoporosis).
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Affiliation(s)
- Huanhuan Xu
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650201, China.
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Wang N, Li J, Song H, Liu C, Hu H, Liao H, Cong W. Synthesis and anti-osteoporosis activity of novel Teriparatide glycosylation derivatives. RSC Adv 2020; 10:25730-25735. [PMID: 35518599 PMCID: PMC9055339 DOI: 10.1039/d0ra05136e] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 07/01/2020] [Indexed: 12/13/2022] Open
Abstract
Osteoporosis is a metabolic bone disease that is characterized by low bone mass and micro-architectural deterioration of bones. The mechanism underlying this disease implicates an imbalance between bone resorption and bone remodeling. In 2002, the US Food and Drug Administration (FDA) approved Teriparatide for the treatment of osteoporosis, and so far, this compound is the only permitted osteoanabolic. However, as a structurally flexible linear peptide, this drug may be further optimized. In this study, we develop a series of novel N-acetyl glucosamine glycosylation derivatives of Teriparatide and examine their characteristics. Of the analyzed compounds, PTHG-9 exhibits enhanced helicity, greater protease stability, and increased osteoblast differentiation promoting ability compared with the original Teriparatide. Accordingly, PTHG-9 is suggested as a therapeutic candidate for postmenopausal osteoporosis (PMOP) and other related diseases. The successful development of an enhanced osteoporosis drug proves that the method proposed herein can be used to effectively enhance the chemical and biological properties of linear peptides with various biological functions.
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Affiliation(s)
- Nan Wang
- Institute of Translational Medicine, Shanghai University Shanghai China
| | - Jingyang Li
- Department of Pediatric Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Hui Song
- Institute of Translational Medicine, Shanghai University Shanghai China
| | - Chao Liu
- Institute of Translational Medicine, Shanghai University Shanghai China
| | - Honggang Hu
- Institute of Translational Medicine, Shanghai University Shanghai China
| | - Hongli Liao
- School of Pharmacy, Chengdu Medical College Chengdu China
| | - Wei Cong
- Institute of Translational Medicine, Shanghai University Shanghai China
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Yan G, Yuan Y, He M, Gong R, Lei H, Zhou H, Wang W, Du W, Ma T, Liu S, Xu Z, Gao M, Yu M, Bian Y, Pang P, Li X, Yu S, Yang F, Cai B, Yang L. m 6A Methylation of Precursor-miR-320/RUNX2 Controls Osteogenic Potential of Bone Marrow-Derived Mesenchymal Stem Cells. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 19:421-436. [PMID: 31896070 PMCID: PMC6940653 DOI: 10.1016/j.omtn.2019.12.001] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 12/03/2019] [Accepted: 12/03/2019] [Indexed: 01/13/2023]
Abstract
Methyltransferase-like 3 (METTL3) is the main enzyme for N6-methyladenosine (m6A)-based methylation of RNAs and it has been implicated in many biological and pathophysiological processes. In this study, we aimed to explore the potential involvement of METTL3 in osteoblast differentiation and decipher the underlying cellular and molecular mechanisms. We demonstrated that METTL3 is downregulated in human osteoporosis and the ovariectomized (OVX) mouse model, as well as during the osteogenic differentiation. Silence of METTL3 by short interfering RNA (siRNA) decreased m6A methylation levels and inhibited osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) and reduced bone mass, and similar effects were observed in METTL3+/- knockout mice. In contrast, adenovirus-mediated overexpression of METTL3 produced the opposite effects. In addition, METTL3 enhanced, whereas METTL3 silence or knockout suppressed, the m6A methylations of runt-related transcription factor 2 (RUNX2; a key transcription factor for osteoblast differentiation and bone formation) and precursor (pre-)miR-320. Moreover, downregulation of mature miR-320 rescued the decreased bone mass caused by METTL3 silence or METTL3+/- knockout. Therefore, METTL3-based m6A modification favors osteogenic differentiation of BMSCs through m6A-based direct and indirect regulation of RUNX2, and abnormal downregulation of METTL3 is likely one of the mechanisms underlying osteoporosis in patients and mice. Thus, METTL3 overexpression might be considered a new approach of replacement therapy for the treatment of human osteoporosis.
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Affiliation(s)
- Gege Yan
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Ye Yuan
- Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China.
| | - Mingyu He
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Rui Gong
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Hong Lei
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Hongbao Zhou
- Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Wenbo Wang
- Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Weijie Du
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Tianshuai Ma
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Shenzhen Liu
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Zihang Xu
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Manqi Gao
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Meixi Yu
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Yu Bian
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Ping Pang
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Xin Li
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Shuting Yu
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Fan Yang
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Benzhi Cai
- Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China.
| | - Lei Yang
- Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
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Qi XY, Liu H, Bi DD, Wang XT, Guo YF, Hao T, Zhang BX, Wang XG, Han MH. Combined administration on You-Gui Yin and low-dose Raloxifene partially attenuates the bone loss in ovariectomized mice through the proliferation and osteogenic differentiation of bone marrow stromal cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 53:286-293. [PMID: 30668409 DOI: 10.1016/j.phymed.2018.09.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 07/16/2018] [Accepted: 09/03/2018] [Indexed: 06/09/2023]
Abstract
BACKGROUND Osteoporosis is a systemic skeletal disease of fragility fractures due to the loss of mass and deterioration of the microarchitecture of bone. PURPOSE The aim of the study was to assess the osteogenic effects and the underlying mechanisms of the combined administration of You-Gui Yin (YGY) and Raloxifene hydrochloride (RLX) in ovariectomized (OVX) mice. METHODS First, a classic animal model was used to mimic postmenopausal osteoporosis through the removal of the ovary of mice. Second, the OVX mice were administered YGY, RLX, and YGY + RLX for 12 weeks. Next, the bone microtomographic histomorphometry and bone mineral density (BMD) were assessed by micro-CT, and the biochemical markers of procollagen type I N-terminal propeptide (P1NP) and beta-isomerized C-telopeptide (β-CTX) in serum were assessed. Finally, primary bone marrow stromal cells (BMSCs) were isolated from the tibia and cultured to evaluate cell proliferation and osteogenic differentiation. RESULTS The results showed that BMD on the YGY + RLX group was higher than that on the RLX group (p < 0.05) and did not have a significant difference when compared with the sham group. Notably, the YGY + RLX group had a dramatically increased trabecular number (Tb.N) compared with that of the YGY group (p < 0.05). Moreover, the BV/TV (bone volume/total volume) and Tb.N in the YGY + RLX group were higher than that in the RLX group (p < 0.05), and the Tb.Sp (trabecular separation) was lower than that in the RLX group (p < 0.05). Moreover, the serum level of P1NP from the YGY + RLX group dramatically increased when compared with that from the YGY and RLX groups (YGY group: p < 0.05; RLX groups: p < 0.01). Notably, there was no significant difference between the YGY and YGY + RLX groups. In addition, cell proliferation from the co-administration of YGY and RLX was clearly higher than a single use of YGY and RLX (p < 0.01, respectively). The ALP/BCA (alkaline phosphatase/bicinchoninic acid) in the YGY + RLX group was higher than that in the RLX group (p < 0.01). CONCLUSION Overall, co-administered YGY and RLX could partially attenuate bone loss and were more effective than individually using either one; this outcome might be associated with the proliferation and osteogenic differentiation of BMSCs.
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Affiliation(s)
- Xiao-Yu Qi
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Room 109, Chemistry Building, 151 Malianwa North Road, Haidian District, Beijing 100193, China; College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin 150040, China
| | - Hao Liu
- The Core Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Dong-Dong Bi
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Room 109, Chemistry Building, 151 Malianwa North Road, Haidian District, Beijing 100193, China
| | - Xiang-Tao Wang
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Room 109, Chemistry Building, 151 Malianwa North Road, Haidian District, Beijing 100193, China
| | - Yi-Fei Guo
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Room 109, Chemistry Building, 151 Malianwa North Road, Haidian District, Beijing 100193, China
| | - Ting Hao
- Department of Trauma, the Second Affiliated Hospital of Inner Mongolia Medical University, 1 Cultural Palace Street, Huimin District, Hohhot 010030, China
| | - Bao-Xin Zhang
- Department of Trauma, the Second Affiliated Hospital of Inner Mongolia Medical University, 1 Cultural Palace Street, Huimin District, Hohhot 010030, China
| | - Xing-Guo Wang
- Department of Trauma, the Second Affiliated Hospital of Inner Mongolia Medical University, 1 Cultural Palace Street, Huimin District, Hohhot 010030, China.
| | - Mei-Hua Han
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Room 109, Chemistry Building, 151 Malianwa North Road, Haidian District, Beijing 100193, China.
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Yang K, Miron RJ, Bian Z, Zhang YF. A bone-targeting drug-delivery system based on Semaphorin 3A gene therapy ameliorates bone loss in osteoporotic ovariectomized mice. Bone 2018; 114:40-49. [PMID: 29883786 DOI: 10.1016/j.bone.2018.06.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Revised: 06/01/2018] [Accepted: 06/04/2018] [Indexed: 12/15/2022]
Abstract
Osteoporosis is a serious health problem worldwide. Semaphorins (Sema) have been described as key molecules involved in the cross-talk between bone cells (osteoblasts/osteoclasts). In this study, we investigated whether plasmid containing Sema3a could ameliorate bone loss in an ovariectomized (OVX) mouse model via (AspSerSer)6, a selectively bone-targeting moiety. Plasmid pcDNA3.1(+)-Sema3a-GFP was fabricated and transfected cells with the plasmid demonstrated statistically higher levels of Sema3A in vitro (p < 0.001). Mice were ovariectomized and injected twice weekly with (AspSerSer)6-(STR-R8)+pcDNA3.1(+)-Sema3a-GFP for four weeks. The aim of the study was twofold: firstly to design an effective bone-targeting drug-delivery system (AspSerSer)6. Secondly, the effects of Sem3A gene therapy on bone loss was investigated. Here, the targeting selectivity of pcDNA3.1(+)-Sema3a-GFP via (AspSerSer)6 to the trabecular bone surface was firstly verified by histological observation of frozen sections and immunofluorescence staining. Then, bone microstructure analysis by Micro-CT indicated significantly less bone loss in mice treated with (AspSerSer)6-(STR-R8)+pcDNA3.1(+)-Sema3a-GFP compared to the control group (p < 0.05). Furthermore,H&E staining and Safranin O staining of the decalcified sections demonstrated statistically significantly higher bone area/total area in the mice that were injected with (AspSerSer)6-(STR-R8)+pcDNA3.1(+)-Sema3a-GFP (p < 0.001, p < 0.01,respectively). TRAP staining and immunohistochemistry staining of COL I demonstrated lower numbers of osteoclasts and significantly increased numbers of osteoblasts in the bone-targeting moiety delivering pcDNA3.1(+)-Sema3a-GFP group, when compared to the control group (p < 0.01, p < 0.001,respectively). Together, our findings have identified that, (AspSerSer)6, a bone-targeting drug-delivery system based on semaphorin3A gene therapy, ameliorated bone loss in osteoporotic ovariectomized mice, by suppressing osteoclastic bone resorption and simultaneously increasing osteoblastic bone formation. Gene therapy by local site-specific Sema3A overexpression might be a potential new strategy for treating osteoporosis and bone defects.
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Affiliation(s)
- K Yang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - R J Miron
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Department of Periodontology, Cell Therapy Institute, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, Florida, USA
| | - Z Bian
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Department of Endodontics, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
| | - Y F Zhang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Department of Dental Implantology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
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Zheng JP, Miao HX, Zheng SW, Liu WL, Chen CQ, Zhong HB, Li SF, Fang YP, Sun CH. Risk factors for osteoporosis in liver cirrhosis patients measured by transient elastography. Medicine (Baltimore) 2018; 97:e10645. [PMID: 29768330 PMCID: PMC5976349 DOI: 10.1097/md.0000000000010645] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 04/11/2018] [Indexed: 12/15/2022] Open
Abstract
Osteoporosis or osteopenia is a common complication in patients with cirrhosis, but little is known about the risk factors for the occurrence of osteoporosis.Patients with liver cirrhosis due to chronic virus infection and alcoholic abuse were enrolled. Bone mineral density (BMD) was determined using dual-energy x-ray absorptiometry (DXA). Osteoporosis was diagnosed according to WHO criteria. The severity of liver stiffness was measured by Fibroscan. Demographic data, such as age, gender, weight, height, and body mass index (BMI), were collected. Logistic regression analysis was used to recognize the risk factors of osteoporosis in patients with cirrhosis.A total of 446 patients were included in this study: 217 had liver cirrhosis (male, 74.2%; mean age, 57.2 ± 10.27) and 229 were matched controls (male, 69%, mean age, 56.69 ± 9.37). Osteoporosis was found in 44 patients (44/217, 20.3%). The spine and hip BMD in cirrhotic patients were significantly lower than that in controls. When the cirrhotic and control subjects were stratified by age, gender, and BMI, the significant difference was also observed in women patients, patients older than 60, and patients with BMI < 18. Multivariate analysis showed that the older age [odds ratio (OR) = 1.78, P = .046], lower BMI (OR = 0.63, P = .049), greater fibroscan score (OR = 1.15, P = .009), and liver cirrhosis induced by alcohol liver disease (OR = 3.42, P < .001) were independently associated with osteoporosis in cirrhotic patients.Osteoporosis occurred in about one-fifth of patients with liver cirrhosis, which was associated with age, BMI, Fibroscan score, and alcohol liver disease related liver cirrhosis.
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Affiliation(s)
| | | | | | | | | | | | | | - Yong-ping Fang
- Department of Hepatobiliary Surgery, Huizhou Medical Research Center, Huizhou First People's Hospital, Huizhou, Guangdong, China
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Varshosaz J, Minaiyan M, Dayyani L. Poly(methyl vinyl ether-co-maleic acid) for enhancement of solubility, oral bioavailability and anti-osteoporotic effects of raloxifene hydrochloride. Eur J Pharm Sci 2017; 112:195-206. [PMID: 29196024 DOI: 10.1016/j.ejps.2017.11.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 11/25/2017] [Accepted: 11/28/2017] [Indexed: 11/25/2022]
Abstract
Raloxifene HCl (RH) has poor water solubility and due to its extensive first pass metabolism; its bioavailability is only 2%. The purpose of the present study was to enhance the aqueous solubility, oral bioavailability and anti-osteoporotic effects of RH by electro-sprayed nanoparticles (NPs) in ovariectomized rats. NPs containing RH and different ratio of poly(methyl vinyl ether-co-maleic acid) (PMVEMA) were electrosprayed. The voltage, distance of needle to the collector, flow rate of the solution and polymeric percentage were optimized according to the size of NPs and drug solubility. The optimized formulation was characterized by SEM, XRD, DSC, and FTIR. The pharmacokinetic parameters were studies by oral administration of a single dose of 15mg/kg in Wistar rats. The anti-osteoporotic effects were studied in female ovariectomized rats. Animals were treated with 6mg/kg/day for 2months then serum calcium, phosphorous and alkaline phosphatase levels were measured. RH loaded electrosprayed NPs showed 10-fold enhanced solubility compared to the free drug. Moreover, the XRD and SEM tests displayed an amorphous state of drug in the NPs. FTIR and DSC tests revealed no interaction between the polymer and the drug. Serum calcium, phosphorous and alkaline phosphatase levels were significantly decreased in ovariectomized rats receiving oral RH NPs (P<0.05). No significant difference was detected between RH NPs and estradiol groups (P>0.05). Oral bioavailability of NPs showed 7.5-fold increase compared to the pure drug. The electrosprayed PMVEMA nanoparticles can enhance solubility, bioavailability and antiosteoporotic effects of RH.
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Affiliation(s)
- Jaleh Varshosaz
- Department of Pharmaceutics, Faculty of Pharmacy and Novel Drug Delivery Systems Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Mohsen Minaiyan
- Department of Pharmacology, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Ladan Dayyani
- Department of Pharmaceutics, Faculty of Pharmacy and Novel Drug Delivery Systems Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran
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Transplantation of osteoporotic bone marrow stromal cells rejuvenated by the overexpression of SATB2 prevents alveolar bone loss in ovariectomized rats. Exp Gerontol 2016; 84:71-79. [PMID: 27599698 DOI: 10.1016/j.exger.2016.09.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 08/12/2016] [Accepted: 09/02/2016] [Indexed: 12/16/2022]
Abstract
Estrogen-deficient osteoporosis is an aging-related disease with high morbidity that not only significantly increases a woman's risk of fragility fracture but is also associated with tooth and bone loss in the supporting alveolar bone of the jaw. Emerging evidence suggests that the aging of bone marrow stromal cells (BMSCs) contributes to the development of osteoporosis. In this study, we aimed to investigate the role of the special AT-rich sequence-binding protein 2 (SATB2), a stemness and senescence regulator of craniofacial BMSCs, in rat ovariectomy-induced alveolar osteoporosis. We also sought to determine whether transplantation of SATB2-modified BMSCs could ameliorate estrogen deficient alveolar bone loss. Our data revealed that BMSCs from ovariectomy-induced alveolar bone exhibited typical senescence phenotypes such as diminished stemness and osteogenic capacity, increased expression of senescence or osteoclastic markers and enhanced adipogenic potential. These phenotypic changes are a result of SATB2-mediated senescence dysregulation as evidenced by nuclear γH2AX foci formation. Moreover, overexpression of SATB2 significantly alleviated the senescence of osteoporotic BMSCs in vitro. Importantly, transplantation of SATB2-modified BMSCs significantly attenuated ovariectomy-induced alveolar bone loss in vivo. Together, our results revealed that SATB2 is a critical regulator of alveolar BMSC senescence, and its overexpression decreases these senescent changes both in vitro and in vivo. SATB2-modified BMSC delivery could be a viable and promising therapeutic strategy for alveolar bone loss induced by estrogen-deficient osteoporosis.
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Liu H, Li W, Liu YS, Zhou YS. Bone micro-architectural analysis of mandible and tibia in ovariectomised rats: A quantitative structural comparison between undecalcified histological sections and micro-CT. Bone Joint Res 2016; 5:253-62. [PMID: 27354715 PMCID: PMC4957176 DOI: 10.1302/2046-3758.56.2000565] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 03/22/2016] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVES This study aims to evaluate if micro-CT can work as a method for the 3D assessment and analysis of cancellous bone by comparing micro-CT with undecalcified histological sections in OVX rats. METHODS The mandible and tibia of sham, ovariectomised (OVX) and zoledronate-injected ovariectomised (OVX-ZOL) rats were assessed morphometrically. Specimens were scanned by micro-CT. Undecalcified histological sections were manufactured from the specimen scanned by micro-CT and stained with haematoxylin and eosin. Bivariate linear regressions and one-way analysis of variance were undertaken for statistics using SPSS 16.0.1 software. RESULTS There were highly significant correlations between undecalcified histological sections and micro-CT for all parameters (bone volume density (BV/TV), bone surface density (BS/BV), trabecular thickness (Tb.Th), trabecular number (Tb.N), and trabecular separation (Tb.Sp))in the mandible and tibia. Bone histomorphometric parameters analysed by both methods exhibited significant differences among sham, OVX, and OVX-ZOL groups. There were significant correlations between mandible and tibia in BV/TV, BS/BV, and Tb.Sp. CONCLUSIONS Micro-CT is a complementary tool to histological sections in basic research that could improve our understanding of bone histomorphometry. The mandible can be used as an effective site to assess bone morphometry of OVX or metabolic bone disease rat models.Cite this article: H. Liu, W. Li, Y. S. Liu, Y. S. Zhou. Bone micro-architectural analysis of mandible and tibia in ovariectomised rats: A quantitative structural comparison between undecalcified histological sections and micro-CT. Bone Joint Res 2016;5:253-262.
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Affiliation(s)
- H Liu
- Department of Prosthodontics, The Core Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China
| | - W Li
- Department of Oral Pathology, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China
| | - Y S Liu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China
| | - Y S Zhou
- Department of Prosthodontics, National Engineering Lab for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China
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11
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Bone scaffolds loaded with siRNA-Semaphorin4d for the treatment of osteoporosis related bone defects. Sci Rep 2016; 6:26925. [PMID: 27254469 PMCID: PMC4890584 DOI: 10.1038/srep26925] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 05/03/2016] [Indexed: 12/25/2022] Open
Abstract
Osteoporosis is a prominent disorder affecting over 200 million people worldwide. Recently, semaphorins have been implicated in the cell-cell communication between osteoclasts and osteoblasts and have been associated with the progression of osteoporosis. Previously, we demonstrated that knockdown of semaphorin4d (Sema4d) using siRNA delivered with a bone-targeting system prevented bone loss in an osteoporotic animal model. Here, we used this bone-specific technology containing siRNA-Sema4d and fabricated a PLLA scaffold capable of enhancing bone repair following fracture. We investigated the ability of the implant to release siRNA-Sema4d into the surrounding tissues over time and to influence new bone formation in a 3 mm femur osteoporotic defect model in ovariectomized rats. Delivery of the bone-targeting system released from PLLA scaffolds began 2 hours post-implantation, peaked at 1 day, and was sustained over a 21 day period. μCT analysis demonstrated a significantly higher bone volume/total volume bone mineral density and number of osteoblasts in the rats that were transplanted with scaffolds loaded with siRNA-Sema4d. These results confirm the specific role of Sema4d in bone remodeling and demonstrate that significant increases in the speed and quality of new bone formation occur when siRNA-Sema4d is delivered via a PLLA scaffold.
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12
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MacNabb C, Patton D, Hayes JS. Sclerostin Antibody Therapy for the Treatment of Osteoporosis: Clinical Prospects and Challenges. J Osteoporos 2016; 2016:6217286. [PMID: 27313945 PMCID: PMC4899597 DOI: 10.1155/2016/6217286] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 04/21/2016] [Indexed: 01/22/2023] Open
Abstract
It is estimated that over 200 million adults worldwide have osteoporosis, a disease that has increasing socioeconomic impact reflected by unsustainable costs associated with disability, fracture management, hospital stays, and treatment. Existing therapeutic treatments for osteoporosis are associated with a variety of issues relating to use, clinical predictability, and health risks. Consequently, additional novel therapeutic targets are increasingly sought. A promising therapeutic candidate is sclerostin, a Wnt pathway antagonist and, as such, a negative regulator of bone formation. Sclerostin antibody treatment has demonstrated efficacy and superiority compared to other anabolic treatments for increasing bone formation in both preclinical and clinical settings. Accordingly, it has been suggested that sclerostin antibody treatment is set to achieve market approval by 2017 and aggressively compete as the gold standard for osteoporotic treatment by 2021. In anticipation of phase III trial results which may potentially signify a significant step in achieving market approval here, we review the preclinical and clinical emergence of sclerostin antibody therapies for both osteoporosis and alternative applications. Potential clinical challenges are also explored as well as ongoing developments that may impact on the eventual clinical application of sclerostin antibodies as an effective treatment of osteoporosis.
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Affiliation(s)
- Claire MacNabb
- Regenerative Medicine Institute, NUI Galway, Biosciences Research Building, Corrib Village, Dangan, Galway, Ireland
| | - D. Patton
- Regenerative Medicine Institute, NUI Galway, Biosciences Research Building, Corrib Village, Dangan, Galway, Ireland
| | - J. S. Hayes
- Regenerative Medicine Institute, NUI Galway, Biosciences Research Building, Corrib Village, Dangan, Galway, Ireland
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13
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Che CT, Wong MS, Lam CWK. Natural Products from Chinese Medicines with Potential Benefits to Bone Health. Molecules 2016; 21:239. [PMID: 26927052 PMCID: PMC6274145 DOI: 10.3390/molecules21030239] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 02/03/2016] [Accepted: 02/12/2016] [Indexed: 01/23/2023] Open
Abstract
Osteoporosis is a progressive, systemic bone disorder characterized by loss of bone mass and microstructure, leading to reduced bone strength and increased risk of fracture. It is often associated with reduced quality of life and other medical complications. The disease is common in the aging population, particularly among postmenopausal women and patients who receive long-term steroidal therapy. Given the rapid growth of the aging population, increasing life expectancy, the prevalence of bone loss, and financial burden to the healthcare system and individuals, demand for new therapeutic agents and nutritional supplements for the management and promotion of bone health is pressing. With the advent of global interest in complementary and alternative medicine and natural products, Chinese medicine serves as a viable source to offer benefits for the improvement and maintenance of bone health. This review summarizes the scientific information obtained from recent literatures on the chemical ingredients of Chinese medicinal plants that have been reported to possess osteoprotective and related properties in cell-based and/or animal models. Some of these natural products (or their derivatives) may become promising leads for development into dietary supplements or therapeutic drugs.
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Affiliation(s)
- Chun-Tao Che
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The University of Illinois at Chicago, Chicago, IL 60612, USA.
| | - Man Sau Wong
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China.
| | - Christopher Wai Kei Lam
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China.
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14
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Che CT, Wong MS. Ligustrum lucidum and its Constituents: A Mini-Review on the Anti-Osteoporosis Potential. Nat Prod Commun 2015. [DOI: 10.1177/1934578x1501001242] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Osteoporosis is a metabolic bone disorder commonly occurred in aging populations, particularly postmenopausal women and patients who undergo long-term steroid or anti-estrogen therapies. Given the rapid growth of the aging population, the prevalence of bone loss, and the huge medical and healthcare cost involved, demand for alternative approaches for the promotion of bone health is pressing. With the advent of global interest in complementary and alternative medicine and natural products, Chinese medicine serves as a viable source that offers benefits to improve and maintain bone health. This review summarizes the scientific information on the Chinese medicinal herb Ligustrum lucidum and its chemical components as potential therapy for osteoporosis.
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Affiliation(s)
- Chun-Tao Che
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, USA
| | - Man-Sau Wong
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
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15
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Liu H, Li W, Liu Y, Zhang X, Zhou Y. Co-administration of aspirin and allogeneic adipose-derived stromal cells attenuates bone loss in ovariectomized rats through the anti-inflammatory and chemotactic abilities of aspirin. Stem Cell Res Ther 2015; 6:200. [PMID: 26474767 PMCID: PMC4609080 DOI: 10.1186/s13287-015-0195-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 08/20/2015] [Accepted: 10/01/2015] [Indexed: 01/21/2023] Open
Abstract
Introduction Osteoporosis is a syndrome of excessive skeletal fragility characterized by the loss of mass and deterioration of microarchitecture in bone. Single use of aspirin or adipose-derived stromal cells (ASCs) has been recognized recently to be effective against osteoporosis. The goal of the study was to evaluate the osteogenic effects of the co-administration of aspirin and allogeneic rat adipose-derived stromal cells (rASCs) on ovariectomized (OVX)-induced bone loss in rats. The underlying mechanisms were investigated in vitro and in vivo. Methods Firstly, allogeneic rASCs were isolated and cultured, and the conditioned medium (CM) from the maintenance of rASCs was collected. Secondly, the OVX rats were administrated CM, rASCs, aspirin (ASP) or rASCs + ASP, respectively. Twelve weeks later, the anti-inflammatory and osteogenic effects were assessed by micro-CT, undecalcified histological sections, dynamic histomorphometric analyses and serologic assays for biochemical markers. Finally, a Transwell migration assay in vitro and cell-trafficking analyses in vivo were used to explore the effects of aspirin on rASC migration. Results Systemic administration of aspirin and rASCs attenuated OVX-induced bone loss better than single use of aspirin or ASCs (p < 0.05, respectively). Next, we analyzed the underlying mechanisms of the anti-inflammatory and chemotactic abilities of aspirin. Aspirin suppressed serum levels of the pro-inflammatory cytokines on tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), and the anti-inflammatory ability was positively associated with bone morphometry. Also, aspirin exhibited excellent chemotactic effects in vitro and accelerated the homing of allogeneic rASCs into bone marrow during early in vivo stages. Conclusions Co-administered aspirin and allogeneic ASCs can partially reverse OVX-induced bone loss in rats. This effect appears to be mediated by the anti-inflammatory and chemotactic abilities of aspirin.
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Affiliation(s)
- Hao Liu
- The Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
| | - Wei Li
- The Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
| | - Yunsong Liu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing, 100081, China.
| | - Xiao Zhang
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing, 100081, China.
| | - Yongsheng Zhou
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing, 100081, China. .,National Engineering Lab for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
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16
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Safety of 3-year raloxifene treatment in Japanese postmenopausal women aged 75 years or older with osteoporosis. Menopause 2015; 22:1134-7. [DOI: 10.1097/gme.0000000000000441] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Dai J, Ma Y, Shi M, Cao Z, Zhang Y, Miron RJ. Initial changes in alveolar bone volume for sham-operated and ovariectomized rats in ligature-induced experimental periodontitis. Clin Oral Investig 2015; 20:581-8. [DOI: 10.1007/s00784-015-1531-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 07/03/2015] [Indexed: 01/11/2023]
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Zhang Y, Wei L, Miron RJ, Shi B, Bian Z. Anabolic bone formation via a site-specific bone-targeting delivery system by interfering with semaphorin 4D expression. J Bone Miner Res 2015; 30:286-96. [PMID: 25088728 DOI: 10.1002/jbmr.2322] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 07/25/2014] [Accepted: 07/31/2014] [Indexed: 12/30/2022]
Abstract
Semaphorins have been recently targeted as new molecules directly implicated in the cell-cell communication that occurs between osteoclasts and osteoblasts. Overexpression of certain semaphorins, such as semaphorin4D (sema4D), is found in an osteoporotic phenotype and plays a key role in osteoclast activity by suppressing osteoblast maturation, thus significantly altering the bone modeling cycle. In the present study, we fabricate a site-specific bone-targeting drug-delivery system from polymeric nanoparticles with the incorporation of siRNA interference molecule for sema4D and demonstrate their cellular uptake and intracellular trafficking within osteoclasts, thus preventing the suppression of osteoblast activity. We then demonstrate in an osteoporotic animal model induced by ovariectomy that weekly intravenous injections led to a significantly greater number of active osteoblasts at the bone surface, resulting in higher bone volume in compromised animals. The findings from the present study demonstrate a novel and promising site-specific therapeutic option for the treatment of osteoporosis via interference of the sema4D-plexin cell communication pathway between osteoclasts and osteoblasts.
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Affiliation(s)
- Yufeng Zhang
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, People's Republic of China, China; Department of Dental Implantology, School and Hospital of Stomatology, Wuhan University, Wuhan, People's Republic of China, China
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Chen X, Zhao Y, Geng S, Miron RJ, Zhang Q, Wu C, Zhang Y. In vivo experimental study on bone regeneration in critical bone defects using PIB nanogels/boron-containing mesoporous bioactive glass composite scaffold. Int J Nanomedicine 2015; 10:839-46. [PMID: 25653525 PMCID: PMC4309792 DOI: 10.2147/ijn.s69001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
PURPOSE In the present study, the fabrication of novel p(N-isopropylacrylamide-co-butyl methylacrylate) (PIB) nanogels was combined with boron-containing mesoporous bioactive glass (B-MBG) scaffolds in order to improve the mechanical properties of PIB nanogels alone. Scaffolds were tested for mechanical strength and the ability to promote new bone formation in vivo. PATIENTS AND METHODS To evaluate the potential of each scaffold in bone regeneration, ovariectomized rats were chosen as a study model to determine the ability of PIB nanogels to stimulate bone formation in a complicated anatomical bone defect. PIB nanogels and PIB nanogels/B-MBG composites were respectively implanted into ovariectomized rats with critical-sized femur defects following treatment periods of 2, 4, and 8 weeks post-implantation. RESULTS Results from the present study demonstrate that PIB nanogels/B-MBG composites showed greater improvement in mechanical strength when compared to PIB nanogels alone. In vivo, hematoxylin and eosin staining revealed significantly more newly formed bone in defects containing PIB nanogels/B-MBG composite scaffolds when compared to PIB nanogels alone. Tartrate-resistant acid phosphatase-positive staining demonstrated that both scaffolds were degraded over time and bone remodeling occurred in the surrounding bone defect as early as 4 weeks post-implantation. CONCLUSION The results from the present study indicate that PIB nanogels are a potential bone tissue engineering biomaterial able to treat defects of irregular shapes and deformities as an injectable, thermoresponsive, biocompatible hydrogel which undergoes rapid thermal gelation once body temperature is reached. Furthermore, its combination with B-MBG scaffolds improves the mechanical properties and ability to promote new bone formation when compared to PIB nanogels alone.
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Affiliation(s)
- Xiaohui Chen
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, People's Republic of China ; Department of Dental Implantology, School and Hospital of Stomatology, Wuhan University, People's Republic of China
| | - Yanbing Zhao
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Shinan Geng
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Richard J Miron
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, People's Republic of China
| | - Qiao Zhang
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, People's Republic of China
| | - Chengtie Wu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, People's Republic of China
| | - Yufeng Zhang
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, People's Republic of China ; Department of Dental Implantology, School and Hospital of Stomatology, Wuhan University, People's Republic of China
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20
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Jang WS, Seo CR, Jang HH, Song NJ, Kim JK, Ahn JY, Han J, Seo WD, Lee YM, Park KW. Black rice (Oryza sativa L.) extracts induce osteoblast differentiation and protect against bone loss in ovariectomized rats. Food Funct 2014; 6:265-75. [PMID: 25428526 DOI: 10.1039/c4fo00836g] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Osteoporosis, an age associated skeletal disease, exhibits increased adipogenesis at the expense of osteogenesis from common osteoporotic bone marrow cells. In this study, black rice (Oryza sativa L.) extracts (BRE) were identified as osteogenic inducers. BRE stimulated the alkaline phosphatase (ALP) activity in both C3H10T1/2 and primary bone marrow cells. Similarly, BRE increased mRNA expression of ALP and osterix. Oral administration of BRE in OVX rats prevented decreases in bone density and strength. By contrast, BRE inhibited adipocyte differentiation of mesenchymal C3H10T1/2 cells and prevented increases in body weight and fat mass in high fat diet fed obese mice, further suggesting the dual effects of BRE on anti-adipogenesis and pro-osteogenesis. UPLC analysis identified cyanidin-3-O-glucoside and peonidin-3-O-glucoside as main anti-adipogenic effectors but not for pro-osteogenic induction. In mechanism studies, BRE selectively stimulated Wnt-driven luciferase activities. BRE treatment also induced Wnt-specific target genes such as Axin2, WISP2, and Cyclin D1. Taken together, these data suggest that BRE is a potentially useful ingredient to protect against age related osteoporosis and diet induced obesity.
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Affiliation(s)
- Woo-Seok Jang
- Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon 440-746, Korea.
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Zhang Y, Wei L, Miron RJ, Zhang Q, Bian Z. Prevention of alveolar bone loss in an osteoporotic animal model via interference of semaphorin 4d. J Dent Res 2014; 93:1095-100. [PMID: 25252878 DOI: 10.1177/0022034514552676] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Semaphorin 4d (Sema4d) has been proposed as a novel target gene for the treatment of osteoporosis. Recently, we fabricated a site-specific bone-targeting system from polymeric nanoparticles that demonstrates an ability to prevent bone loss in an osteoporotic model by interfering with Sema4d gene expression using small interference RNA (siRNA) molecules. The aim of the present investigation was to determine the effects of this targeting system on the periodontium, an area of high bone turnover. We demonstrated, by single photon emission computed tomography, that intravenous injection of this molecule in ovariectomized Balb/C mice is able to target alveolar bone peaking 4 hr post-injection. We then compared, by histological analysis, the bone volume/total volume (BV/TV), alveolar bone height loss, immunohistochemical expression of Sema4d, and total number of osteoclasts in mandibular alveolar bone. Four treatment modalities were compared as follows: (1) sham-operated, (2) OVX-operated, (3) OVX+estrogen replacement therapy, and (4) OVX+siRNA-Sema4d animals. The results from the present study demonstrate that an osteoporotic condition significantly increases alveolar bone height loss, and that the therapeutic effects via bone-targeting systems featuring interference of Sema4d are able to partly counteract alveolar bone loss caused by osteoporosis. While the future therapeutic demand for the large number of patients suffering from osteoporosis faces many challenges, we demonstrate within the present study an effective drug-delivery moiety with anabolic effects on the bone remodeling cycle able to locate and target alveolar bone regeneration.
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Affiliation(s)
- Y Zhang
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, People's Republic of China Department of Dental Implantology, School and Hospital of Stomatology, Wuhan University, People's Republic of China
| | - L Wei
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, People's Republic of China
| | - R J Miron
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, People's Republic of China
| | - Q Zhang
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, People's Republic of China
| | - Z Bian
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, People's Republic of China
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22
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Zhang Y, Wei L, Wu C, Miron RJ. Periodontal regeneration using strontium-loaded mesoporous bioactive glass scaffolds in osteoporotic rats. PLoS One 2014; 9:e104527. [PMID: 25116811 PMCID: PMC4130544 DOI: 10.1371/journal.pone.0104527] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 07/14/2014] [Indexed: 11/23/2022] Open
Abstract
Recent studies demonstrate that the rate of periodontal breakdown significantly increased in patients compromised from both periodontal disease and osteoporosis. One pharmacological agent used for their treatment is strontium renalate due to its simultaneous ability to increase bone formation and halt bone resorption. The aim of the present study was to achieve periodontal regeneration of strontium-incorporated mesoporous bioactive glass (Sr-MBG) scaffolds in an osteoporotic animal model carried out by bilateral ovariectomy (OVX). 15 female Wistar rats were randomly assigned to three groups: control unfilled periodontal defects, 2) MBG alone and 3) Sr-MBG scaffolds. 10 weeks after OVX, bilateral fenestration defects were created at the buccal aspect of the first mandibular molar and assessed by micro-CT and histomorphometric analysis after 28 days. Periodontal fenestration defects treated with Sr-MBG scaffolds showed greater new bone formation (46.67%) when compared to MBG scaffolds (39.33%) and control unfilled samples (17.50%). The number of TRAP-positive osteoclasts was also significantly reduced in defects receiving Sr-MBG scaffolds. The results from the present study suggest that Sr-MBG scaffolds may provide greater periondontal regeneration. Clinical studies are required to fully characterize the possible beneficial effect of Sr-releasing scaffolds for patients suffering from a combination of both periodontal disease and osteoporosis.
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Affiliation(s)
- Yufeng Zhang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, People's Republic of China
| | - Lingfei Wei
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, People's Republic of China
| | - Chengtie Wu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Shanghai, People's Republic of China
| | - Richard J. Miron
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, People's Republic of China
- Faculté de medecine dentaire, Université Laval, Québec, Canada
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Kim MJ, Jang WS, Lee IK, Kim JK, Seong KS, Seo CR, Song NJ, Bang MH, Lee YM, Kim HR, Park KM, Park KW. Reciprocal regulation of adipocyte and osteoblast differentiation of mesenchymal stem cells by Eupatorium japonicum prevents bone loss and adiposity increase in osteoporotic rats. J Med Food 2014; 17:772-81. [PMID: 24927400 DOI: 10.1089/jmf.2013.3056] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Pathological increases in adipogenic potential with decreases in osteogenic differentiation occur in osteoporotic bone marrow cells. Previous studies have shown that bioactive materials isolated from natural products can reciprocally regulate adipogenic and osteogenic fates of bone marrow cells. In this study, we showed that Eupatorium japonicum stem extracts (EJE) suppressed lipid accumulation and inhibited the expression of adipocyte markers in multipotent C3H10T1/2 and primary bone marrow cells. Conversely, EJE stimulated alkaline phosphatase activity and induced the expression of osteoblast markers in C3H10T1/2 and primary bone marrow cells. Daily oral administration of 50 mg/kg of EJE for 6 weeks to ovariectomized rats prevented body weight increase and bone mineral density decrease. Finally, activity-guided fractionation led to the identification of coumaric acid and coumaric acid methyl ester as bioactive anti-adipogenic and pro-osteogenic components in EJE. Taken together, our data indicate a promising possibility of E. japonicum as a functional food and as a therapeutic intervention for preventing osteoporosis and bone fractures.
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Affiliation(s)
- Min-Ji Kim
- 1 Department of Food Science and Biotechnology, Sungkyunkwan University , Suwon, Korea
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Kukita A, Kukita T. Multifunctional properties of RANKL/RANK in cell differentiation, proliferation and metastasis. Future Oncol 2013; 9:1609-22. [DOI: 10.2217/fon.13.115] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
It is known that there are close relationships between bone destruction and tumor growth in bone metastasis. RANKL is a central factor in bone metastasis, inducing osteoclastogenesis mediated by its receptor RANK. Recent reports demonstrate that RANKL has important roles in organogenesis stimulating proliferation and differentiation of epithelial and stroma cells. RANKL is induced not only by cytokines and hormones but also by UV-irradiation, inflammation and carcinogens. Expression of RANK and RANKL is found in several human cancer cell lines, and RANK signaling stimulates proliferation, migration and epithelial–mesenchymal transition of cancer cells, which may be involved in metastasis via an autocrine/paracrine mechanism. RANKL regulates the number of Tregs that produce RANKL, which may affect cancer metastasis. In this review we discuss the multifunctional roles of RANKL/RANK in osteoclastogenesis, organogenesis, and the metastasis and tumorigenesis of cancer cells.
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Affiliation(s)
- Akiko Kukita
- Department of Microbiology, Medicine, Saga University, 5-1-1, Nabeshima, Saga, 849-8501, Japan
| | - Toshio Kukita
- Molecular Cell Biology & Oral Anatomy, Kyushu University, Maidashi, Fukuoka, Japan
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Cheng N, Dai J, Cheng X, Li S, Miron RJ, Wu T, Chen W, Zhang Y, Shi B. Porous CaP/silk composite scaffolds to repair femur defects in an osteoporotic model. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2013; 24:1963-1975. [PMID: 23674058 PMCID: PMC5995474 DOI: 10.1007/s10856-013-4945-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Accepted: 04/29/2013] [Indexed: 06/02/2023]
Abstract
The most common complication for patients with postmenopausal osteoporosis is bone-related defects and fractures. While routine medication has a high probability of undesirable side effects, new approaches have aimed to develop regeneration procedures that stimulate new bone formation while reversing bone loss. Recently, we have synthesized a new hybrid CaP/silk scaffold with a CaP-phase distribution and pore architecture better suited to facilitate cell differentiation and bone formation. The aim of the present study was to compare the involved remodeling process and therapeutic effect of porous CaP/silk composite scaffolds upon local implantation into osteoporotic defects. Wistar rats were used to induce postmenopausal osteoporotic model by bilateral ovariectomy. The pure silk and hybrid CaP/silk scaffolds were implanted into critical sized defects created in distal femoral epiphysis. After 14 and 28 days, the in vivo osteogenetic efficiency was evaluated by μCT analysis, hematoxylin and eosin staining, Safranin O staining, tartrate-resistant acid phosphatase staining, and immunohistochemical assessment. Animals with or without critical-sized defects were used as drill or blank controls, respectively. The osteoporotic defect model was well established with significantly decreased μCT parameters of BV/TV, Tb.N and increased Tb.Sp, porosity, combined with changes in histological observations. During the healing process, the critical-sized drill control defects failed to regenerate appreciable bone tissue, while more significantly increased bone formation and mineralization with dynamic scaffold degradation and decreased osteoclastic bone resorption could be detected within defects with hybrid CaP/silk scaffolds compared to pure silk scaffolds.
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Affiliation(s)
- Ning Cheng
- State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, People's Republic of China
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Abstract
OBJECTIVE To review primary hyperparathyroidism and the key issues that are relevant to the practicing endocrinologist. METHODS The latest information on the presentation, diagnosis, and traditional and nontraditional aspects of primary hyperparathyroidism is reviewed. RESULTS The diagnosis of primary hyperparathyroidism is straightforward when the traditional hypercalcemic patient is documented to have an elevated parathyroid hormone (PTH) level. Commonly, patients are identified who have normal serum calcium levels but elevated PTH levels in whom no secondary causes for hyperparathyroidism can be confirmed. Traditional target organs of primary hyperparathyroidism-the skeleton and the kidneys-continue to be a focus in the patient evaluation. Bone mineral density shows a typical pattern of involvement with the distal one-third radius being selectively reduced compared with the lumbar spine in which bone mineral density is generally well maintained. Neurocognitive and cardiovascular aspects of primary hyperparathyroidism, while a focus of recent interest, have not been shown to definitively aid in the decision for or against surgery. The recommendation for surgery in primary hyperparathyroidism is based on guidelines that focus on the serum calcium level, renal function, bone mineral density, and age. In patients who do not meet guidelines, a nonsurgical management approach has merit. CONCLUSIONS Primary hyperparathyroidism is continuing to show changes in its clinical profile, with normocalcemic primary hyperparathyroidism being a topic of great interest. Skeletal and renal features of primary hyperparathyroidism drive, in most cases, the decision to recommend surgery. In patients who do not meet any criteria for surgery, a conservative approach with appropriate monitoring is acceptable.
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Affiliation(s)
- John P Bilezikian
- Metabolic Bone Diseases Unit, Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
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Decani S, Baruzzi E, Martini V, Ficarra G, Lodi G. Condizioni orali farmaco-indotte. DENTAL CADMOS 2013. [DOI: 10.1016/s0011-8524(13)70019-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Fei Y, Hurley MM. Role of fibroblast growth factor 2 and Wnt signaling in anabolic effects of parathyroid hormone on bone formation. J Cell Physiol 2012; 227:3539-45. [PMID: 22378151 DOI: 10.1002/jcp.24075] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Osteoporosis poses enormous health and economic burden worldwide. One of the very few anabolic agents for osteoporosis is parathyroid hormone (PTH). Although great progress has been made since the FDA approved PTH in 2002, the detailed mechanisms of the bone anabolic effects of intermittent PTH treatment is still not well understood. PTH bone anabolic effect is regulated by extracellular factors. Maximal bone anabolic effect of PTH requires fibroblast growth factor 2 (FGF2) signaling, which might be mediated by transcription factor activating transcription factor 4 (ATF4). Maximal bone anabolic effect of PTH also requires Wnt signaling. Particularly, Wnt antagonists such as sclerostin, dickkopf 1 (DKK1) and secreted frizzled related protein 1 (sFRP1) are promising targets to increase bone formation. Interestingly, FGF2 signaling modulates Wnt/β-Catenin signaling pathway in bone. Therefore, multiple signaling pathways utilized by PTH are cross talking and working together to promote bone formation. Extensive studies on the mechanisms of action of PTH will help to identify new pathways that regulate bone formation, to improve available agents to stimulate bone formation, and to identify potential new anabolic agents for osteoporosis.
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Affiliation(s)
- Yurong Fei
- Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA
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Zhang Y, Cheng N, Miron R, Shi B, Cheng X. Delivery of PDGF-B and BMP-7 by mesoporous bioglass/silk fibrin scaffolds for the repair of osteoporotic defects. Biomaterials 2012; 33:6698-708. [PMID: 22763224 DOI: 10.1016/j.biomaterials.2012.06.021] [Citation(s) in RCA: 135] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2012] [Accepted: 06/15/2012] [Indexed: 01/23/2023]
Abstract
Osteoporosis is a chronic disease affecting millions of people worldwide caused by an imbalance between bone-forming osteoblasts and bone-resorbing osteoclasts. Despite recent developments in pharmacological agents to prevent osteoporotic-related fractures, much less attention has been placed on the repair of bone defects following fracture. Critical to this process is the recruitment of mesenchymal stem cells (MSCs) to defect sites by growth factors. One method which has been effective for the sustained release of growth factors is that of gene therapy. The aim of the present study was to investigate newly developed mesoporous bioglass/silk fibrin scaffolds containing adPDGF-b and adBMP-7 into osteoporotic critical-sized femur defects in ovariectomised rats following treatment periods of 2 and 4 weeks. In vivo osteogenetic efficiency evaluated by μ-CT analysis, hematoxylin and eosin staining, and immunohistochemical (type I collagen, osteopontin and BSP) revealed significantly new bone formation in defects containing adenovirus for both PDGF-b and BMP-7 when compared to scaffolds alone and scaffolds containing BMP-7. TRAP-positive staining also demonstrated the ability for these scaffolds to be degraded over time and initiate bone turnover/remodeling. Although the use of gene therapy for clinical applications is still in its infancy, results from the present study demonstrate their potent ability to recruit mesenchymal progenitor cells through sustained release of PDGF-b and BMP-7 which may be beneficial for patients suffering from osteoporotic-related fractures.
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Affiliation(s)
- Yufeng Zhang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079, PR China.
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Abstract
Zoanthamine alkaloids, isolated from organisms in the Zoanthus genus, constitute a distinctive family of marine metabolites. These molecules exhibit a broad spectrum of unique biological properties. For example, norzoanthamine inhibits interleukin-6, the key mediator of bone resorption in osteoporosis, providing a promising drug candidate for a disease that affects more than 10 million people over age 50 in the United States. In addition, these natural products are characterized by a densely functionalized heptacyclic framework, as exemplified by the structures of zoanthamine, norzoanthamine, and zoanthenol, which makes them extremely attractive targets for chemical synthesis. Prior to our first total synthesis of norzoanthamine in 2004, the densely functionalized and complex stereostructures of the zoanthamine alkaloids had impeded synthetic studies of these molecules. In this Account, we describe our synthetic approach toward the total synthesis of zoanthamine alkaloids, focusing on how we overcame various synthetic challenges. At the beginning of our synthetic studies, we aimed to develop an efficient route that was flexible enough to provide access to several members of the family while allowing the synthesis of various analogues for biological testing. Our first project was the total synthesis of norzoanthamine, and we established an efficient synthetic route based on a novel strategy involving the following key features. First, we used a sequential three-component coupling reactions and subsequent photosensitized oxidation of a furan moiety to synthesize the precursor for the key intramolecular Diels-Alder reaction. Second, the key intramolecular Diels-Alder reaction constructed the ABC-ring carbon framework bearing two adjacent quaternary asymmetric carbon atoms at the C12 and C22 positions in a single stereoselective step. Third, we installed the third quaternary asymmetric carbon center at the C9 position by an intramolecular acylation of a keto alcohol followed by successive O-methylation and C-methylation reactions with complete stereoselectivity. Through the exploitation of a deuterium kinetic isoptope effect, we then efficiently synthesized the alkyne segment. Next, a coupling reaction between the alkyne segment and the amino alcohol segment and several subsequent synthetic transformations afforded the bis-aminoacetalization precursor. Finally, bis-aminoacetalization reactions carried out in one-pot constructed the DEFG-ring system and culminated in the total synthesis of norzoanthamine. Our synthetic route to norzoanthamine also allowed access to other zoanthamine alkaloids from a common synthetic intermediate, by way of stereoselective introduction of the C19 methyl group for zoanthamine, and isoaromatization for construction of the aromatic A-ring in zoanthenol. The chemistry described here not only allowed us to overcome formidable synthetic challenges but also opened a completely chemical avenue to naturally occurring zoanthamine alkaloids and their synthetic derivatives.
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Affiliation(s)
- Fumihiko Yoshimura
- Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
| | - Keiji Tanino
- Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
| | - Masaaki Miyashita
- Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
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Datta NS. Osteoporotic fracture and parathyroid hormone. World J Orthop 2011; 2:67-74. [PMID: 22474638 PMCID: PMC3302045 DOI: 10.5312/wjo.v2.i8.67] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Revised: 04/19/2011] [Accepted: 06/01/2011] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis and age-related bone loss is associated with changes in bone remodeling characterized by decreased bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Stimulating the function of bone-forming osteoblasts, is the preferred pharmacological intervention for osteoporosis. Recombinant parathyroid hormone (PTH), PTH(1-34), is an anabolic agent with proven benefits to bone strength and has been characterized as a potential therapy for skeletal repair. In spite of PTH's clinical use, safety is a major consideration for long-term treatment. Studies have demonstrated that intermittent PTH treatment enhances and accelerates the skeletal repair process via a number of mechanisms. Recent research into the molecular mechanism of PTH action on bone tissue has led to the development of PTH analogs to control osteoporotic fractures. This review summarizes a number of advances made in the field of PTH and bone fracture to combat these injuries in humans and in animal models. The ultimate goal of providing an alternative to PTH, currently the sole anabolic therapy in clinical use, to promote bone formation and improve bone strength in the aging population is yet to be achieved.
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