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Hoque K, Ali Z, Maliha A, Al-Ghouti MA, Cugno C, Rahman SM, Rahman MM. Enhancing Bone Health with Conjugated Linoleic Acid: Mechanisms, Challenges, and Innovative Strategies. Nutrients 2025; 17:1395. [PMID: 40284258 PMCID: PMC12030704 DOI: 10.3390/nu17081395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/18/2025] [Accepted: 04/19/2025] [Indexed: 04/29/2025] Open
Abstract
Conjugated linoleic acid (CLA) is a bioactive compound known for its anti-inflammatory, anti-carcinogenic, and metabolic effects, with growing interest in its role in supporting bone health. Preclinical studies, particularly those involving the t10c12 isomer, have shown that CLA can enhance bone mineral density (BMD) by enhancing bone formation and reducing bone resorption, indicating its potential as a therapeutic agent to improve bone health. However, clinical trials have yielded inconsistent results, underscoring the difficulty in translating animal model successes to human applications. A major challenge is CLA's low water solubility, poor absorption, and limited bioavailability, which restrict its therapeutic effectiveness. To address these issues, nanoparticle-based delivery systems have been proposed to improve its solubility, stability, and resistance to oxidative damage, thereby enhancing its bioactivity. Recent studies also suggest that electrical stimulation can stimulate bone regeneration by promoting bone cell proliferation, differentiation, and adherence to scaffolds. This review explores the combined use of CLA supplementation and electrical stimulation as a novel approach to improving bone health, particularly in osteoporosis management. By integrating CLA's biological effects with the regenerative potential of electrical stimulation, this multimodal strategy offers a promising method for enhancing bone restoration, with significant implications for clinical applications in bone health.
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Affiliation(s)
- Khandoker Hoque
- Department of Electrical and Electronics Engineering, San Francisco Bay University, Fremont, CA 94539, USA;
| | - Zayana Ali
- Biological Program, Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha P.O. Box 2713, Qatar;
| | - Asma Maliha
- Biomedical Sciences Department, College of Health Sciences, Qatar University, Doha P.O. Box 2713, Qatar;
| | - Mohammad A. Al-Ghouti
- Environmental Program, Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha P.O. Box 2713, Qatar;
| | - Chiara Cugno
- Advanced Cell Therapy Core, Research Department, Sidra Medicine, Doha P.O. Box 26999, Qatar;
| | | | - Md Mizanur Rahman
- Biological Program, Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha P.O. Box 2713, Qatar;
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Li S, Zhang Y, Ding S, Chang J, Liu G, Hu S. Curcumin Ameliorated Glucocorticoid-Induced Osteoporosis While Modulating the Gut Microbiota and Serum Metabolome. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:8254-8276. [PMID: 40139762 DOI: 10.1021/acs.jafc.4c06689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
Glucocorticoid-induced osteoporosis (GIOP) is the leading cause of secondary osteoporosis. Recently, the "bone-gut axis" theory has linked bone development with gut microbial diversity, community composition, and metabolites. Curcumin, a well-studied polyphenol, shows potential in mitigating bone loss and osteoporosis. Alendronate, a standard therapeutic agent for osteoporosis, serves as a positive control in this investigation. The study demonstrates the potency of curcumin in reducing bone loss and restoring bone mineral density, enhancing trabecular parameters notably through increased trabecular number, volume, and thickness and reduced bone marrow cavity size. Gut microbiome sequencing revealed that both curcumin and alendronate treatments similarly enhanced gut microbial diversity and altered microbiota composition, increasing beneficial bacteria (Akkermansia_muciniphila, Dubosiella_sp910585105, and Ruminococcus_sp910584195) while reducing harmful bacteria (Treponema_D_sp910584475 and Duncaniella_sp910584825). Furthermore, significant changes in serum levels of metabolites including raffinose, ursolic acid, spermidine, inosine, hypoxanthine, thiamine, and pantothenic acid were observed post-treatment with curcumin or alendronate. Importantly, these beneficial metabolites and microorganisms were negatively correlated with inflammatory cytokines. In conclusion, curcumin holds promise for use against GIOP by modulating the gut microbiome and serum metabolome as well as reducing systemic inflammation.
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Affiliation(s)
- Siying Li
- The Orthopaedic Center, The First People' s Hospital of Wenling, Wenling Hospital of Wenzhou Medical University, Wenling 317500, Zhejiang Province, China
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan 410128, China
| | - Yating Zhang
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan 410128, China
| | - Sujuan Ding
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan 410128, China
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Jiang Chang
- The Orthopaedic Center, The First People' s Hospital of Wenling, Wenling Hospital of Wenzhou Medical University, Wenling 317500, Zhejiang Province, China
| | - Gang Liu
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan 410128, China
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Siwang Hu
- The Orthopaedic Center, The First People' s Hospital of Wenling, Wenling Hospital of Wenzhou Medical University, Wenling 317500, Zhejiang Province, China
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Gu JH, Chae MY, Choi JJ, Duc TC, Son CG, Lee EJ. Deer antler velvet (Cervus elaphus sibiricus) promotes fracture healing via partial BMP2-Smad mediated osteoblast differentiation. J Orthop Surg Res 2025; 20:70. [PMID: 39833827 PMCID: PMC11744865 DOI: 10.1186/s13018-024-05426-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 12/26/2024] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND CERVUS ELAPHUS SIBIRICUS: (CES) has been traditionally used in Korean clinics to promote fracture healing based on its function of tonifying the kidneys and strengthening bones. However, experimental data supporting its efficacy are still insufficient. The aim of this study investigated the bone-union properties of CES in a femoral fracture animal model and its corresponding molecular mechanisms. METHODS Fifty-four C57BL/6 male mice underwent femoral shaft fracture by Bonnarens and Einhorn's method, subsequently receiving a water extract of CES (200 mg/kg/day, daily) for 7 and 14 days. Safranin O staining and immunohistochemistry of the fracture region were conducted against transforming growth factor-β (TGF-β), bone morphogenetic protein 2 (BMP2), and osterix. MG63 cells used to examine the underlying mechanisms of CES focused on BMP2-Smad pathway-related osteogenesis. RESULTS CES administration led to earlier union of the fractured bones, supported by Safranin O staining of the fracture region, demonstrating significantly increased cartilage formation day on 7 and a rapidly decreased cartilage area due to callus formation day on 14. CES administration also significantly upregulated the expression of TGF-β1 day 7, BMP 2, and osterix day 14 at the fracture site and also up-regulated alkaline phosphatase (ALP) activity, calcium deposition, and the phosphorylation of Smad in MG63 cells. CONCLUSIONS CES promotes fracture healing by promoting osteoblastogenesis via a partial BMP2-Smad pathway.
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Affiliation(s)
- Ji Hyang Gu
- Department of Korean Rehabilitation Medicine, Cheonan Korean Medicine Hospital of Daejeon University, Cheonan, 31099, South Korea
| | - Min-Young Chae
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Daejeon University, Daejeon, 35235, South Korea
| | - Jeong June Choi
- Laboratory of Molecular Medicine, College of Korean Medicine, Daejeon University, Daejeon, 34520, South Korea
| | - Thanh Chu Duc
- College of Pharmacy, Chungnam National University, Daejeon, 34134, South Korea
- Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, Ha Noi, Viet Nam
| | - Chang Gue Son
- Institute of Bioscience & Integrative Medicine, Dunsan Hospital of Daejeon University, Daejeon, South Korea
| | - Eun-Jung Lee
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Daejeon University, Daejeon, 35235, South Korea.
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Al‐Ibraheem AMT, Hameed AAZ, Marsool MDM, Jain H, Prajjwal P, Khazmi I, Nazzal RS, AL‐Najati HMH, Al‐Zuhairi BHYK, Razzaq M, Abd ZB, Marsool ADM, wahedaldin AI, Amir O. Exercise-Induced cytokines, diet, and inflammation and their role in adipose tissue metabolism. Health Sci Rep 2024; 7:e70034. [PMID: 39221051 PMCID: PMC11365580 DOI: 10.1002/hsr2.70034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 04/23/2024] [Accepted: 08/15/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Obesity poses a significant global health challenge, necessitating effective prevention and treatment strategies. Exercise and diet are recognized as pivotal interventions in combating obesity. This study reviews the literature concerning the impact of exercise-induced cytokines, dietary factors, and inflammation on adipose tissue metabolism, shedding light on potential pathways for therapeutic intervention. METHODOLOGY A comprehensive review of relevant literature was conducted to elucidate the role of exercise-induced cytokines, including interleukin-6 (IL-6), interleukin-15 (IL-15), brain-derived neurotrophic factor (BDNF), irisin, myostatin, fibroblast growth factor 21 (FGF21), follistatin (FST), and angiopoietin-like 4 (ANGPTL4), in adipose tissue metabolism. Various databases were systematically searched using predefined search terms to identify relevant studies. Articles selected for inclusion underwent thorough analysis to extract pertinent data on the mechanisms underlying the influence of these cytokines on adipose tissue metabolism. RESULTS AND DISCUSSION Exercise-induced cytokines exert profound effects on adipose tissue metabolism, influencing energy expenditure (EE), thermogenesis, fat loss, and adipogenesis. For instance, IL-6 activates AMP-activated protein kinase (AMPK), promoting fatty acid oxidation and reducing lipogenesis. IL-15 upregulates peroxisome proliferator-activated receptor delta (PPARδ), stimulating fatty acid catabolism and suppressing lipogenesis. BDNF enhances AMPK-dependent fat oxidation, while irisin induces the browning of white adipose tissue (WAT), augmenting thermogenesis. Moreover, myostatin, FGF21, FST, and ANGPTL4 each play distinct roles in modulating adipose tissue metabolism, impacting factors such as fatty acid oxidation, adipogenesis, and lipid uptake. The elucidation of these pathways offers valuable insights into the complex interplay between exercise, cytokines, and adipose tissue metabolism, thereby informing the development of targeted obesity management strategies. CONCLUSION Understanding the mechanisms by which exercise-induced cytokines regulate adipose tissue metabolism is critical for devising effective obesity prevention and treatment modalities. Harnessing the therapeutic potential of exercise-induced cytokines, in conjunction with dietary interventions, holds promise for mitigating the global burden of obesity. Further research is warranted to delineate the precise mechanisms underlying the interactions between exercise, cytokines, and adipose tissue metabolism.
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Affiliation(s)
| | | | | | - Hritvik Jain
- All India Institute of Medical SciencesJodhpurIndia
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Kazmi I, Afzal M, Al-Abbasi FA, AlGhamdi SA, Alghamdi AM, Alzarea SI, Almalki WH, AlGhamdi AS, Alkinani KB, Sayyed N. Review of the potential pharmacological role of erucic acid: a monounsaturated omega-9 fatty acid. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:3663-3674. [PMID: 38060041 DOI: 10.1007/s00210-023-02875-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 11/26/2023] [Indexed: 12/08/2023]
Abstract
This comprehensive review aims to provide an overview of the pharmacological properties of erucic acid (EA) and highlight areas that require further research. EA is an omega-9 fatty acid found in certain vegetable oil, such as rapeseed oil has demonstrated favourable effects in rodents, including ameliorating myocardial lipidosis (fat accumulation in the heart muscle), congestive heart disease, hepatic steatosis (fat accumulation in the liver), and memory impairments. These findings have prompted regulatory bodies to establish limits on EA content in food oils. The studies were performed on rodents and led to caution on ingesting the EA at high levels. Moreover, EA is frequently utilized as a nutritional supplement for the treatment of adrenoleukodystrophy, myocardial disease, and memory improvement. The review of the article indicated that EA improves cognitive function, has a part in Huntington's disease, interacts with peroxisome proliferator-activated receptors, inhibits elastase and thrombin, has anti-inflammatory, antioxidant, and anti-tumour properties, and inhibits influenza A virus. This article elucidates the pharmacological effects of EA, an omega-9 fatty acid.
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Affiliation(s)
- Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589, Jeddah, Saudi Arabia.
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, 21442, Jeddah, Saudi Arabia
| | - Fahad A Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | - Shareefa A AlGhamdi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
- Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | - Amira M Alghamdi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, 72341, Sakaka, Aljouf, Saudi Arabia
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, 21955, Makkah, Saudi Arabia
| | - Abeer S AlGhamdi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | - Khadijah B Alkinani
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
- Department of Public Health, Faculty of Health Sciences, Umm Al-Qura University, 21955, Makkah, Saudi Arabia
| | - Nadeem Sayyed
- School of Pharmacy, Glocal University, Saharanpur, 247121, India.
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Nie HY, Ge J, Liu KG, Yue Y, Li H, Lin HG, Yan HF, Zhang T, Sun HW, Yang JW, Zhou JL, Cui Y. The effects of microgravity on stem cells and the new insights it brings to tissue engineering and regenerative medicine. LIFE SCIENCES IN SPACE RESEARCH 2024; 41:1-17. [PMID: 38670635 DOI: 10.1016/j.lssr.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/13/2023] [Accepted: 01/06/2024] [Indexed: 04/28/2024]
Abstract
Conventional two-dimensional (2D) cell culture techniques may undergo modifications in the future, as life scientists have widely acknowledged the ability of three-dimensional (3D) in vitro culture systems to accurately simulate in vivo biology. In recent years, researchers have discovered that microgravity devices can address many challenges associated with 3D cell culture. Stem cells, being pluripotent cells, are regarded as a promising resource for regenerative medicine. Recent studies have demonstrated that 3D culture in microgravity devices can effectively guide stem cells towards differentiation and facilitate the formation of functional tissue, thereby exhibiting advantages within the field of tissue engineering and regenerative medicine. Furthermore, We delineate the impact of microgravity on the biological behavior of various types of stem cells, while elucidating the underlying mechanisms governing these alterations. These findings offer exciting prospects for diverse applications.
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Affiliation(s)
- Hong-Yun Nie
- Department of General Surgery, The 306th Hospital of PLA-Peking University Teaching Hospital, Beijing 100101, China; Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Jun Ge
- Department of General Surgery, The 306th Hospital of PLA-Peking University Teaching Hospital, Beijing 100101, China; Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Kai-Ge Liu
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Yuan Yue
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Hao Li
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China.
| | - Hai-Guan Lin
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Hong-Feng Yan
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Tao Zhang
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Hong-Wei Sun
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Jian-Wu Yang
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Jin-Lian Zhou
- Department of Pathology, Strategic Support Force Medical Center, Beijing 100101, China
| | - Yan Cui
- Department of General Surgery, The 306th Hospital of PLA-Peking University Teaching Hospital, Beijing 100101, China; Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China.
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Zhu W, Wang R, Yang Z, Luo X, Yu B, Zhang J, Fu M. GC-MS based comparative metabolomic analysis of human cancellous bone reveals the critical role of linoleic acid metabolism in femur head necrosis. Metabolomics 2023; 19:86. [PMID: 37776501 DOI: 10.1007/s11306-023-02053-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 09/20/2023] [Indexed: 10/02/2023]
Abstract
INTRODUCTION Femur head necrosis (FHN) is a challenging clinical disease with unclear underlying mechanism, which pathologically is associated with disordered metabolism. However, the disordered metabolism in cancellous bone of FHN was never analyzed by gas chromatography-mass spectrometry (GC-MS). OBJECTIVES To elucidate altered metabolism pathways in FHN and identify putative biomarkers for the detection of FHN. METHODS We recruited 26 patients with femur head necrosis and 22 patients with femur neck fracture in this study. Cancellous bone tissues from the femoral heads were collected after the surgery and were analyzed by GC-MS based untargeted metabolomics approach. The resulting data were analyzed via uni- and multivariate statistical approaches. The changed metabolites were used for the pathway analysis and potential biomarker identification. RESULTS Thirty-seven metabolites distinctly changed in FHN group were identified. Among them, 32 metabolites were upregulated and 5 were downregulated in FHN. The pathway analysis showed that linoleic acid metabolism were the most relevant to FHN pathology. On the basis of metabolites network, L-lysine, L-glutamine and L-serine were deemed as the junctions of the whole metabolites. Finally, 9,12-octadecadienoic acid, inosine, L-proline and octadecanoic acid were considered as the potential biomarkers of FHN. CONCLUSION This study provides a new insight into the pathogenesis of FHN and confirms linoleic acid metabolism as the core.
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Affiliation(s)
- Weiwen Zhu
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Rui Wang
- Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Zhijian Yang
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Xuming Luo
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Baoxi Yu
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Jian Zhang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| | - Ming Fu
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
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Jun JY, Kim JH, Kim M, Hong S, Kim M, Ryu GH, Park JH, Jung HS, Sohn Y. Persicae Semen Promotes Bone Union in Rat Fractures by Stimulating Osteoblastogenesis through BMP-2 and Wnt Signaling. Int J Mol Sci 2023; 24:ijms24087388. [PMID: 37108563 PMCID: PMC10138545 DOI: 10.3390/ijms24087388] [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: 02/21/2023] [Revised: 03/30/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
Fractures cause extreme pain to patients and impair movement, thereby significantly reducing their quality of life. However, in fracture patients, movement of the fracture site is restricted through application of a cast, and they are reliant on conservative treatment through calcium intake. Persicae semen (PS) is the dried mature seeds of Prunus persica (L.) Batsch, and in this study the effects of PS on osteoblast differentiation and bone union promotion were investigated. The osteoblast-differentiation-promoting effect of PS was investigated through alizarin red S and Von Kossa staining, and the regulatory role of PS on BMP-2 (Bmp2) and Wnt (Wnt10b) signaling, representing a key mechanism, was demonstrated at the protein and mRNA levels. In addition, the bone-union-promoting effect of PS was investigated in rats with fractured femurs. The results of the cell experiments showed that PS promotes mineralization and upregulates RUNX2 through BMP-2 and Wnt signaling. PS induced the expression of various osteoblast genes, including Alpl, Bglap, and Ibsp. The results of animal experiments show that the PS group had improved bone union and upregulated expression of osteogenic genes. Overall, the results of this study suggest that PS can promote fracture recovery by upregulating osteoblast differentiation and bone formation, and thus can be considered a new therapeutic alternative for fracture patients.
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Affiliation(s)
- Jae-Yun Jun
- Department of Anatomy, College of Korean Medicine, Seoul 02447, Republic of Korea
| | - Jae-Hyun Kim
- Department of Anatomy, College of Korean Medicine, Seoul 02447, Republic of Korea
| | - Minsun Kim
- Department of Anatomy, College of Korean Medicine, Seoul 02447, Republic of Korea
| | - Sooyeon Hong
- Department of Anatomy, College of Korean Medicine, Seoul 02447, Republic of Korea
| | - Myunghyun Kim
- Department of Anatomy, College of Korean Medicine, Seoul 02447, Republic of Korea
| | - Gwang-Hyun Ryu
- Department of Anatomy, College of Korean Medicine, Seoul 02447, Republic of Korea
| | - Jae Ho Park
- Department of Pharmaceutical Science, Jungwon University, Goesan-eup 28024, Republic of Korea
| | - Hyuk-Sang Jung
- Department of Anatomy, College of Korean Medicine, Seoul 02447, Republic of Korea
| | - Youngjoo Sohn
- Department of Anatomy, College of Korean Medicine, Seoul 02447, Republic of Korea
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Fuiten AM, Yoshimoto Y, Shukunami C, Stadler HS. Digits in a dish: An in vitro system to assess the molecular genetics of hand/foot development at single-cell resolution. Front Cell Dev Biol 2023; 11:1135025. [PMID: 36994104 PMCID: PMC10040768 DOI: 10.3389/fcell.2023.1135025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 02/21/2023] [Indexed: 03/16/2023] Open
Abstract
In vitro models allow for the study of developmental processes outside of the embryo. To gain access to the cells mediating digit and joint development, we identified a unique property of undifferentiated mesenchyme isolated from the distal early autopod to autonomously re-assemble forming multiple autopod structures including: digits, interdigital tissues, joints, muscles and tendons. Single-cell transcriptomic analysis of these developing structures revealed distinct cell clusters that express canonical markers of distal limb development including: Col2a1, Col10a1, and Sp7 (phalanx formation), Thbs2 and Col1a1 (perichondrium), Gdf5, Wnt5a, and Jun (joint interzone), Aldh1a2 and Msx1 (interdigital tissues), Myod1 (muscle progenitors), Prg4 (articular perichondrium/articular cartilage), and Scx and Tnmd (tenocytes/tendons). Analysis of the gene expression patterns for these signature genes indicates that developmental timing and tissue-specific localization were also recapitulated in a manner similar to the initiation and maturation of the developing murine autopod. Finally, the in vitro digit system also recapitulates congenital malformations associated with genetic mutations as in vitro cultures of Hoxa13 mutant mesenchyme produced defects present in Hoxa13 mutant autopods including digit fusions, reduced phalangeal segment numbers, and poor mesenchymal condensation. These findings demonstrate the robustness of the in vitro digit system to recapitulate digit and joint development. As an in vitro model of murine digit and joint development, this innovative system will provide access to the developing limb tissues facilitating studies to discern how digit and articular joint formation is initiated and how undifferentiated mesenchyme is patterned to establish individual digit morphologies. The in vitro digit system also provides a platform to rapidly evaluate treatments aimed at stimulating the repair or regeneration of mammalian digits impacted by congenital malformation, injury, or disease.
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Affiliation(s)
- Allison M. Fuiten
- Research Center, Shriners Children’s, Portland, OR, United States
- Department of Orthopaedics and Rehabilitation, Oregon Health and Science University, Portland, OR, United States
| | - Yuki Yoshimoto
- Department of Molecular Biology and Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Chisa Shukunami
- Department of Molecular Biology and Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - H. Scott Stadler
- Research Center, Shriners Children’s, Portland, OR, United States
- Department of Orthopaedics and Rehabilitation, Oregon Health and Science University, Portland, OR, United States
- *Correspondence: H. Scott Stadler,
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Chen J, You R, Lv Y, Liu H, Yang G. Conjugated linoleic acid regulates adipocyte fatty acid binding protein expression via peroxisome proliferator-activated receptor α signaling pathway and increases intramuscular fat content. Front Nutr 2022; 9:1029864. [PMID: 36523338 PMCID: PMC9745092 DOI: 10.3389/fnut.2022.1029864] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/19/2022] [Indexed: 06/22/2024] Open
Abstract
Intramuscular fat (IMF) is correlated positively with meat tenderness, juiciness and taste that affected sensory meat quality. Conjugated linoleic acid (CLA) has been extensively researched to increase IMF content in animals, however, the regulatory mechanism remains unclear. Adipocyte fatty acid binding protein (A-FABP) gene has been proposed as candidates for IMF accretion. The purpose of this study is to explore the molecular regulatory pathways of CLA on intramuscular fat deposition. Here, our results by cell lines indicated that CLA treatment promoted the expression of A-FABP through activated the transcription factor of peroxisome proliferator-activated receptor α (PPARα). Moreover, in an animal model, we discovered that dietary supplemental with CLA significantly enhanced IMF deposition by up-regulating the mRNA and protein expression of PPARα and A-FABP in the muscle tissues of mice. In addition, our current study also demonstrated that dietary CLA increased mRNA expression of genes and enzymes involved in fatty acid synthesis and lipid metabolism the muscle tissues of mice. These findings suggest that CLA mainly increases the expression of A-FABP through PPARα signaling pathway and regulates the expression of genes and enzymes related to IMF deposition, thus increasing IMF content. These results contribute to better understanding the molecular mechanism of IMF accretion in animals for the improvement of meat quality.
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Affiliation(s)
| | | | | | | | - Guoqing Yang
- Laboratory of Animal Gene Engineering, College of Life Sciences, Henan Agricultural University, Zhengzhou, China
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Li P, Wang Y, Li P, Liu YL, Liu WJ, Chen XY, Tang TT, Qi KM, Zhang Y. Maternal inappropriate calcium intake aggravates dietary-induced obesity in male offspring by affecting the differentiation potential of mesenchymal stem cells. World J Stem Cells 2022; 14:756-776. [PMID: 36337156 PMCID: PMC9630989 DOI: 10.4252/wjsc.v14.i10.756] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/24/2022] [Accepted: 08/07/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The effects of inappropriate dietary calcium intake in early life on later obesity have not been fully elucidated.
AIM To raise the mechanism of maternal calcium intake on the multi-differentiation potential of mesenchymal stem cells among their male offspring.
METHODS Four-week-old female C57BL/6N mice were fed by deficient, low, normal and excessive calcium reproductive diets throughout pregnancy and lactation. Bone MSCs (BMSCs) were obtained from 7-day-old male offspring to measure the adipogenic differentiation potential by the Wnt/β-catenin signaling pathway. The other weaning male pups were fed a high-fat diet for 16 wk, along with normal-fat diet as the control. Then the serum was collected for the measurement of biochemical indicators. Meanwhile, the adipose tissues were excised to analyze the adipocyte sizes and inflammatory infiltration. And the target gene expressions on the adipogenic differentiation and Wnt/β-catenin signaling pathway in the adipose tissues and BMSCs were determined by real-time reverse transcription polymerase chain reaction.
RESULTS Compared with the control group, maternal deficient, low and excessive calcium intake during pregnancy and lactation aggravated dietary-induced obesity, with larger adipocytes, more serious inflammatory infiltration and higher serum metabolism indicators by interfering with higher expressions of adipogenic differentiation (PPARγ, C/EBPα, Fabp4, LPL, Adiponectin, Resistin and/or Leptin) among their male offspring (P < 0.05). And there were significantly different expression of similar specific genes in the BMSCs to successfully polarize adipogenic differentiation and suppress osteogenic differentiation in vivo and in vitro, respectively (P < 0.05). Meanwhile, it was accompanied by more significant disorders on the expressions of Wnt/β-catenin signaling pathway both in BMSCs and adulthood adipose tissues among the offspring from maternal inappropriate dietary calcium intake groups.
CONCLUSION Early-life abnormal dietary calcium intake might program the adipogenic differentiation potential of BMSCs from male offspring, with significant expressions on the Wnt/β-catenin signaling pathway to aggravate high-fat-diet-induced obesity in adulthood.
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Affiliation(s)
- Ping Li
- Laboratory of Nutrition and Development, Key Laboratory of Major Diseases in Children's Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Yang Wang
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing 100085, China
| | - Pei Li
- Department of Pediatrics, General Hospital of Tianjin Medical University, Tianjin Medical University, Tianjin 300070, China
| | - Yuan-Lin Liu
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing 100085, China
| | - Wei-Jiang Liu
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing 100085, China
| | - Xiao-Yu Chen
- Laboratory of Nutrition and Development, Key Laboratory of Major Diseases in Children's Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Tian-Tian Tang
- Laboratory of Nutrition and Development, Key Laboratory of Major Diseases in Children's Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Ke-Min Qi
- Laboratory of Nutrition and Development, Key Laboratory of Major Diseases in Children's Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Yi Zhang
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing 100085, China
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12
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Aleidi SM, Al-Ansari MM, Alnehmi EA, Malkawi AK, Alodaib A, Alshaker M, Benabdelkamel H, Abdel Rahman AM. Lipidomics Profiling of Patients with Low Bone Mineral Density (LBMD). Int J Mol Sci 2022; 23:ijms231912017. [PMID: 36233318 PMCID: PMC9570421 DOI: 10.3390/ijms231912017] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 09/28/2022] [Accepted: 10/01/2022] [Indexed: 11/20/2022] Open
Abstract
The relationship between lipid metabolism and bone mineral density (BMD) is still not fully elucidated. Despite the presence of investigations using osteoporotic animal models, clinical studies in humans are limited. In this work, untargeted lipidomics profiling using liquid chromatography-mass spectrometry (LC-MS) analysis of human serum samples was performed to identify the lipidomics profile associated with low bone mineral density (LBMD), with a subsequent examination of potential biomarkers related to OP risk prediction or progression. A total of 69 participants were recruited for this cohort study, including the osteoporotic group (OP, n = 25), osteopenia group (ON, n = 22), and control (Ctrl, n = 22). The LBMD group included OP and ON patients. The lipidomics effect of confounding factors such as age, gender, lipid profile, body mass index (BMD), chronic diseases, and medications was excluded from the dataset. The results showed a clear group separation and clustering between LBMD and Ctrl (Q2 = 0.944, R2 = 0.991), indicating a significant difference in the lipids profile. In addition, 322 putatively identified lipid molecules were dysregulated, with 163 up- and 159 down-regulated in LBMD, compared with the Ctrl. The most significantly dysregulated subclasses were phosphatidylcholines (PC) (n = 81, 25.16% of all dysregulated lipids 322), followed by triacylglycerol (TG) (n = 65, 20.19%), and then phosphatidylethanolamine (PE) (n = 40, 12.42%). In addition, groups of glycerophospholipids, including LPC (7.45%), LPE (5.59%), and PI (2.48%) were also dysregulated as of LBMD. These findings provide insights into the lipidomics alteration involved in bone remodeling and LBMD. and may drive the development of therapeutic targets and nutritional strategies for OP management.
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Affiliation(s)
- Shereen M. Aleidi
- Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, The University of Jordan, Amman 11942, Jordan
| | - Mysoon M. Al-Ansari
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Eman A. Alnehmi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
- Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital & Research Center (KFSHRC), Zahrawi Street, Al Maather, Riyadh 11211, Saudi Arabia
| | - Abeer K. Malkawi
- Department of Chemistry and Biochemistry, The University of Quebec at Montreal, Montreal, QC H3C 3P8, Canada
| | - Ahmad Alodaib
- Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital & Research Center (KFSHRC), Zahrawi Street, Al Maather, Riyadh 11211, Saudi Arabia
| | - Mohamed Alshaker
- Department of Family Medicine and Polyclinic, King Faisal Specialist Hospital & Research Center (KFSHRC), Zahrawi Street, Al Maather, Riyadh 11211, Saudi Arabia
| | - Hicham Benabdelkamel
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925 (98), Riyadh 11461, Saudi Arabia
| | - Anas M. Abdel Rahman
- Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital & Research Center (KFSHRC), Zahrawi Street, Al Maather, Riyadh 11211, Saudi Arabia
- Department of Biochemistry and Molecular Medicine, College of Medicine, Al Faisal University, Riyadh 11533, Saudi Arabia
- Correspondence:
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13
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Shan Z, Zhao Y, Qiu Z, Angxiu S, Gu Y, Luo J, Bi H, Luo W, Xiong R, Ma S, He Z, Chen L. Conjugated linoleic acid prompts bone formation in ovariectomized osteoporotic rats and weakens osteoclast formation after treatment with ultraviolet B. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:503. [PMID: 33850900 PMCID: PMC8039685 DOI: 10.21037/atm-21-934] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Background Ultraviolet B (UVB) has been reported to prevent bone loss by promoting the synthesis of vitamin D. However, UVB can also enhance osteoclastic differentiation, inhibit osteogenic differentiation, and cause oxidative damage. The present study aimed to analyze the osteoprotective effects of UVB and conjugated linoleic acid (CLA) in rats with ovariectomy-induced osteoporosis, and to determine the interactions between UVB and CLA and their effects on bone mesenchymal stem cells (BMSCs) and bone marrow mononuclear cells (BMMCs). Methods In vitro, the distance of UVB irradiation and the dose of CLA were selected by immunofluorescence assays and Cytotoxicity assay. BMSCs and BMMCs were detected by immunohistochemical and immunofluorescence assays. In vivo, three-month-old female Sprague-Dawley rats that had undergone ovariectomy were treated with UVB and CLA. After 8 weeks of therapy, the femurs of the rats were examined by micro-computed tomography (CT) and immunohistochemical detection to assess the therapeutic efficacy. Results The least inhibitive UVB distance and dosage of CLA were selected for the in vivo experiments. CLA effectively weakened the osteogenic inhibitory effect of UVB (72 cm), significantly improved the activity of alkaline phosphatase (ALP), promoted the formation of mineralized nodules, and alleviated the oxidative damage induced by UVB. CLA also effectively weakened the osteoclast-promoting effect of UVB (72 cm), inhibited osteoclast formation, and inhibited the inflammatory damage to BMMCs caused by UVB (72 cm) irradiation. Micro-CT results showed that UVB irradiation could promote bone formation in ovariectomized Sprague-Dawley rats, while CLA could significantly promote bone regeneration. Immunofluorescence assays results showed that CLA alleviated UVB-induced oxidative damage to osteoblasts. The ROS detection results demonstrated that CLA effectively alleviated UVB-induced oxidative damage to BMSCs. Furthermore, Immunohistochemical assays showed that UVB and CLA treatment increased bone density, inhibited osteolytic osteolysis, and enhanced osteogenic activity. Conclusions CLA can effectively weaken osteoclast promotion, osteogenic inhibition, and oxidative damage caused by UVB. Combination treatment of UVB and CLA exerts an osteoprotective effect on ovariectomized osteoporotic rats and stimulates osteogenesis. The molecular mechanism of this interaction requires further investigation.
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Affiliation(s)
- Zhongshu Shan
- Department of Orthopedic Surgery, the 1st Affiliated Hospital of Soochow University, Suzhou, China.,Department of Orthopedic Surgery, People's Hospital of Qinghai Province, Xining, China
| | - Yanyan Zhao
- Department of Orthopedic Surgery, People's Hospital of Qinghai Province, Xining, China
| | - Zhixue Qiu
- Department of Orthopedic Surgery, People's Hospital of Qinghai Province, Xining, China
| | - Suonan Angxiu
- Department of Orthopedic Surgery, People's Hospital of Qinghai Province, Xining, China
| | - Yong Gu
- Department of Orthopedic Surgery, the 1st Affiliated Hospital of Soochow University, Suzhou, China
| | - Junming Luo
- Department of Pathology, People's Hospital of Qinghai Province, Xining, China
| | - Hongtao Bi
- Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences; Xining, China
| | - Wei Luo
- Department of Endocrinology, People's Hospital of Qinghai Province, Xining, China
| | - Rui Xiong
- Nutrition Department, People's Hospital of Qinghai Province, Xining, China
| | - Siqing Ma
- Department of Critical Care Medicine, People's Hospital of Qinghai Province, Xining, China
| | - Zhao He
- Department of Orthopedic Surgery, People's Hospital of Qinghai Province, Xining, China
| | - Liang Chen
- Department of Orthopedic Surgery, the 1st Affiliated Hospital of Soochow University, Suzhou, China
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14
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Whitney DG, Alford AI, Devlin MJ, Li Y, Caird MS. Intersite reliability of vertebral bone marrow lipidomics-derived lipid composition among children with varying degrees of bone fragility undergoing routine orthopedic surgery. Bone 2021; 143:115633. [PMID: 32927104 PMCID: PMC7770023 DOI: 10.1016/j.bone.2020.115633] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/30/2020] [Accepted: 09/09/2020] [Indexed: 01/18/2023]
Abstract
BACKGROUND Lipidomics, a branch of metabolomics, is an attractive technique to characterize bone marrow lipid composition, which may be associated with skeletal acquisition and homeostasis. However, the reliability of lipidomics-derived lipid composition of the bone marrow is unknown, especially for pediatric populations with bone fragility. The purpose of this study was to evaluate the intersite reliability and standard error of measurement (SEM) of vertebral bone marrow lipid composition at the thoracic (T11/T12) and lumbar (L1/L2) spine determined by targeted lipidomics among children with varying degrees of bone fragility undergoing routine orthopedic surgery. METHODS Children aged between 12 and 19 years of age, with a confirmed diagnosis of adolescent idiopathic scoliosis or neuromuscular scoliosis and cerebral palsy, and undergoing routine posterior spinal fusion surgery at our institution were initially included in this study. Transpedicular vertebral body bone marrow samples were taken from thoracic (T) or lumbar (L) vertebrae. Further inclusion criteria involved having bone marrow extracted from both T11 and T12 (n = 24) or L1 and L2 (n = 19). Lipid composition was measured using a targeted lipidomics technique and examined as the saturated, monounsaturated, and polyunsaturated index and as individual fatty acids. Relative and absolute test-retest reliability was assessed using the intraclass correlation coefficient (ICC) and SEM. RESULTS For the T11/T12 analysis: the ICC and SEM were 0.59 and 1.7% for the saturated index, 0.31 and 6.2% for the monounsaturated index, and 0.44 and 6.1% for the polyunsaturated index; the ICC showed a considerable range for individual fatty acids from 0.07 (fatty acid 20:2) to 0.82 (15:0) with 62.1% of the fatty acids having poor reliability (i.e., ICC < 0.50). For the L1/L2 analysis: the ICC and SEM were 0.50 and 2.4% for the saturated index, -0.12 and 6.0% for the monounsaturated index, and 0.00 and 4.9% for the polyunsaturated index; the ICC showed a considerable range for individual fatty acids from -0.34 (18:1_n-9) to 0.88 (15:0 and 18:3_n-3) with 79.3% of the fatty acids having poor reliability. CONCLUSIONS The intersite test-retest reliability was poor-to-moderate for index measures and generally poor for individual fatty acids for the thoracic and lumbar spine. At this time, it is not recommended to pool bone marrow adipose tissue across vertebral sites for bone marrow adiposity research or clinical monitoring for pediatric populations with bone fragility.
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Affiliation(s)
- Daniel G Whitney
- Department of Physical Medicine and Rehabilitation, University of Michigan, 325 E. Eisenhower, Ann Arbor, MI 48108, United States of America; Institute for Healthcare Policy and Innovation, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, United States of America.
| | - Andrea I Alford
- Department of Orthopaedic Surgery, University of Michigan, A. Alfred Taubman Biomedical Sciences Research Building, Room 2009, Ann Arbor, MI 48109, United States of America
| | - Maureen J Devlin
- Department of Anthropology, University of Michigan, 1085 S. University Ave., Ann Arbor, MI 48109, United States of America
| | - Ying Li
- Department of Orthopaedic Surgery, University of Michigan, A. Alfred Taubman Biomedical Sciences Research Building, Room 2009, Ann Arbor, MI 48109, United States of America
| | - Michelle S Caird
- Department of Orthopaedic Surgery, University of Michigan, A. Alfred Taubman Biomedical Sciences Research Building, Room 2009, Ann Arbor, MI 48109, United States of America
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15
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Erucic Acid-Rich Yellow Mustard Oil Improves Insulin Resistance in KK-A y Mice. Molecules 2021; 26:molecules26030546. [PMID: 33494317 PMCID: PMC7864507 DOI: 10.3390/molecules26030546] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/07/2021] [Accepted: 01/16/2021] [Indexed: 12/24/2022] Open
Abstract
Obesity is a major risk factor for some metabolic disorders including type 2 diabetes. Enhancement of peroxisome proliferator-activated receptor (PPAR) γ, a master regulator of adipocyte differentiation, is known to increase insulin-sensitive small adipocytes. In contrast, decreased PPARγ activity is also reported to improve insulin resistance. We have previously identified erucic acid as a novel natural component suppressing PPARγ transcriptional activity. In this study, we investigated the effect of erucic acid-rich yellow mustard oil (YMO) on obese/diabetic KK-Ay mice. An in vitro luciferase reporter assay and mesenchymal stem cell (MSC) differentiation assay revealed that 25 µg/mL YMO significantly inhibited PPARγ transcriptional activity and differentiation of MSCs into adipocytes but promoted their differentiation into osteoblasts. In KK-Ay mice, dietary intake of 7.0% (w/w) YMO significantly decreased the surrogate indexes for insulin resistance and the infiltration of macrophages into adipose tissue. Furthermore, 7.0% YMO increased bone mineral density. These results suggest that YMO can ameliorate obesity-induced metabolic disorders.
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16
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Merlotti D, Cosso R, Eller-Vainicher C, Vescini F, Chiodini I, Gennari L, Falchetti A. Energy Metabolism and Ketogenic Diets: What about the Skeletal Health? A Narrative Review and a Prospective Vision for Planning Clinical Trials on this Issue. Int J Mol Sci 2021; 22:ijms22010435. [PMID: 33406758 PMCID: PMC7796307 DOI: 10.3390/ijms22010435] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/27/2020] [Accepted: 12/30/2020] [Indexed: 12/15/2022] Open
Abstract
The existence of a common mesenchymal cell progenitor shared by bone, skeletal muscle, and adipocytes cell progenitors, makes the role of the skeleton in energy metabolism no longer surprising. Thus, bone fragility could also be seen as a consequence of a “poor” quality in nutrition. Ketogenic diet was originally proven to be effective in epilepsy, and long-term follow-up studies on epileptic children undergoing a ketogenic diet reported an increased incidence of bone fractures and decreased bone mineral density. However, the causes of such negative impacts on bone health have to be better defined. In these subjects, the concomitant use of antiepileptic drugs and the reduced mobilization may partly explain the negative effects on bone health, but little is known about the effects of diet itself, and/or generic alterations in vitamin D and/or impaired growth factor production. Despite these remarks, clinical studies were adequately designed to investigate bone health are scarce and bone health related aspects are not included among the various metabolic pathologies positively influenced by ketogenic diets. Here, we provide not only a narrative review on this issue, but also practical advice to design and implement clinical studies on ketogenic nutritional regimens and bone health outcomes. Perspectives on ketogenic regimens, microbiota, microRNAs, and bone health are also included.
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Affiliation(s)
- Daniela Merlotti
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (D.M.); (L.G.)
| | - Roberta Cosso
- Istituto Auxologico Italiano “Scientific Institute for Hospitalisation and Care”, 20100 Milano, Italy; (R.C.); (I.C.)
| | - Cristina Eller-Vainicher
- Unit of Endocrinology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico Milano, 20122 Milano, Italy;
| | - Fabio Vescini
- Endocrinology and Metabolism Unit, University-Hospital S. Maria della Misericordia of Udine, 33100 Udine, Italy;
| | - Iacopo Chiodini
- Istituto Auxologico Italiano “Scientific Institute for Hospitalisation and Care”, 20100 Milano, Italy; (R.C.); (I.C.)
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milano, Italy
| | - Luigi Gennari
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (D.M.); (L.G.)
| | - Alberto Falchetti
- Istituto Auxologico Italiano “Scientific Institute for Hospitalisation and Care”, 20100 Milano, Italy; (R.C.); (I.C.)
- Correspondence:
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17
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Whitney DG, Devlin MJ, Alford AI, Caird MS. Pattern of bone marrow lipid composition measures along the vertebral column: A descriptive study of adolescents with idiopathic scoliosis. Bone 2021; 142:115702. [PMID: 33099030 PMCID: PMC9426858 DOI: 10.1016/j.bone.2020.115702] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 10/03/2020] [Accepted: 10/18/2020] [Indexed: 11/21/2022]
Abstract
BACKGROUND There is evidence that the extent of vertebral bone marrow adiposity increases caudally along the vertebral column in children and adolescents. However, no studies have examined the lipid composition of bone marrow along the vertebral column, which may uniquely influence bone acquisition and metabolism during growth independent of the amount of bone marrow adipose tissue. The goal of this study was to characterize the pattern of lipid composition index measures from the thoracic to lumbar spine (T11-L4) among a sample of adolescents with idiopathic scoliosis (AIS) undergoing routine orthopedic surgical care for scoliosis correction. METHODS Adolescents between 14 and 18 years of age, with a confirmed diagnosis of AIS, and undergoing routine posterior spinal fusion surgery at our institution were initially included for this descriptive study. The surgery yielded transpedicular vertebral body marrow samples from T11 through L4; 11 participants had bone marrow samples from T11 through L2 and 4 of the 11 participants had marrow samples from T11 through L4. Lipid composition index measures, including the saturated, monounsaturated, and polyunsaturated index, were measured using a targeted lipidomics technique. Linear regression equation for the slope (m) and Pearson correlation coefficient (r) was computed to assess the pattern of lipid composition index measures along the vertebral column from T11 to L2 (n = 11) and extended analysis to L4. Exploratory analyses were performed to examine the association between the pattern of lipid composition measures (individual slopes) and physical characteristics for T11-L2. RESULTS For T11-L2, the slope of the saturated index was near 0 (r = 0.08; P = 0.92), whereas the slopes of the unsaturated indices were approximately opposite of one another: the monounsaturated index exhibited a -0.55 change (r = 0.58; P = 0.42) per vertebra and the polyunsaturated index exhibited a 0.52 change (r = 0.72; P = 0.28) per vertebra in the caudal direction from T11-L2. For T11-L4, there were modest changes in slope for the saturated (m = 0.12; r = 0.30; P = 0.57) and monounsaturated (m = -0.68; r = 0.74; P = 0.09) indices, while the polyunsaturated index slope remained similar (m = 0.56; r = 0.89; P = 0.02). Age, sex, height, body mass, and BMI were not associated with the pattern of any of the lipid composition index measures. CONCLUSIONS Study findings in this small sample of individuals with AIS suggest that the bone marrow saturated index may be relatively stable across T11-L4, while the monounsaturated index may decrease by 0.55-0.68% per vertebra and the polyunsaturated index may increase by 0.52-0.56% per vertebra in the caudal direction.
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Affiliation(s)
- Daniel G Whitney
- Department of Physical Medicine and Rehabilitation, University of Michigan, 325 E. Eisenhower, Ann Arbor, MI 48108, United States of America; Institute for Healthcare Policy and Innovation, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, United States of America.
| | - Maureen J Devlin
- Department of Anthropology, University of Michigan, 1085 S. University Ave., Ann Arbor, MI 48109, United States of America
| | - Andrea I Alford
- Department of Orthopaedic Surgery, University of Michigan, A. Alfred Taubman Biomedical Sciences Research Building, Room 2009, Ann Arbor, MI 48109, United States of America
| | - Michelle S Caird
- Department of Orthopaedic Surgery, University of Michigan, A. Alfred Taubman Biomedical Sciences Research Building, Room 2009, Ann Arbor, MI 48109, United States of America
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18
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Whitney DG, Devlin MJ, Alford AI, Modlesky CM, Peterson MD, Li Y, Caird MS. Test-Retest Reliability and Correlates of Vertebral Bone Marrow Lipid Composition by Lipidomics Among Children With Varying Degrees of Bone Fragility. JBMR Plus 2020; 4:e10400. [PMID: 33103029 PMCID: PMC7574707 DOI: 10.1002/jbm4.10400] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/01/2020] [Accepted: 07/20/2020] [Indexed: 12/22/2022] Open
Abstract
The reliability of lipidomics, an approach to identify the presence and interactions of lipids, to analyze the bone marrow lipid composition among pediatric populations with bone fragility is unknown. The objective of this study was to assess the test–retest reliability, standard error of measurement (SEM), and the minimal detectable change (MDC) of vertebral bone marrow lipid composition determined by targeted lipidomics among children with varying degrees of bone fragility undergoing routine orthopedic surgery. Children aged 10 to 19 years, with a confirmed diagnosis of adolescent idiopathic scoliosis (n = 13) or neuromuscular scoliosis and cerebral palsy (n = 3), undergoing posterior spinal fusion surgery at our institution were included in this study. Transpedicular vertebral body bone marrow samples were taken from thoracic vertebrae (T11, 12) or lumbar vertebrae (L1 to L4). Lipid composition was assessed via targeted lipidomics and all samples were analyzed in the same batch. Lipid composition measures were examined as the saturated, monounsaturated, and polyunsaturated index and as individual fatty acids. Relative and absolute test–retest reliability was assessed using the intraclass correlation coefficient (ICC), SEM, and MDC. Associations between demographics and index measures were explored. The ICC, SEM, and MDC were 0.81 (95% CI, 0.55–0.93), 1.6%, and 4.3%, respectively, for the saturated index, 0.66 (95% CI, 0.25–0.87), 3.5%, and 9.7%, respectively, for the monounsaturated index, and 0.60 (95% CI, 0.17–0.84), 3.6%, and 9.9%, respectively, for the polyunsaturated index. For the individual fatty acids, the ICC showed a considerable range from 0.04 (22:2n‐6) to 0.97 (18:3n‐3). Age was positively correlated with the saturated index (r2 = 0.36; p = 0.014) and negatively correlated with the polyunsaturated index (r2 = 0.26; p = 0.043); there was no difference in index measures by sex (p > 0.58). The test–retest reliability was moderate‐to‐good for index measures and poor to excellent for individual fatty acids; this information can be used to power research studies and identify measures for clinical or research monitoring. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Daniel G Whitney
- Department of Physical Medicine and Rehabilitation University of Michigan Ann Arbor MI USA.,Institute for Healthcare Policy and Innovation University of Michigan Ann Arbor MI USA
| | - Maureen J Devlin
- Department of Anthropology University of Michigan Ann Arbor MI USA
| | - Andrea I Alford
- Department of Orthopaedic Surgery University of Michigan Ann Arbor MI USA
| | | | - Mark D Peterson
- Department of Physical Medicine and Rehabilitation University of Michigan Ann Arbor MI USA.,Institute for Healthcare Policy and Innovation University of Michigan Ann Arbor MI USA
| | - Ying Li
- Department of Orthopaedic Surgery University of Michigan Ann Arbor MI USA
| | - Michelle S Caird
- Department of Orthopaedic Surgery University of Michigan Ann Arbor MI USA
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19
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Takahashi A, Dohi H, Egashira Y, Hirai S. Erucic acid derived from rosemary regulates differentiation of mesenchymal stem cells into osteoblasts/adipocytes via suppression of peroxisome proliferator-activated receptor γ transcriptional activity. Phytother Res 2020; 34:1358-1366. [PMID: 31989712 DOI: 10.1002/ptr.6607] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 12/14/2019] [Accepted: 12/16/2019] [Indexed: 12/27/2022]
Abstract
Osteoporosis is associated with increase in fat tissue in bone marrow in humans. Mesenchymal stem cells in bone marrow are induced to differentiate into osteoblasts rather than adipocytes by the stimulation of peroxisome proliferator-activated receptor (PPAR) γ antagonists. PPARγ antagonists are expected to be useful to prevent osteoporosis by regulating the lineages of mesenchymal stem cells in bone marrow, as well as the prevention of obesity. In this study, we explored natural components suppressing PPARγ transcriptional activity in rosemary. Separation of active fraction of rosemary extract by repeated high performance liquid chromatograph and PPARγ luciferase reporter assay identified erucic acid, one of the monounsaturated fatty acids, as an active component. Twenty-five-micrometer erucic acid significantly decreased PPARγ luciferase activity and enhanced the differentiation of mouse-delivered C3H10T1/2 cells into osteoblasts rather than adipocytes. Furthermore, 25-μM erucic acid significantly decreased the expression of adipocyte marker genes, while accelerating osteoblast marker genes. In conclusion, erucic acid is a novel natural component derived from rosemary regulating mesenchymal stem cell differentiation via suppression of PPARγ transcriptional activity.
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Affiliation(s)
- Asako Takahashi
- Laboratory of Food Nutrition, Division of Applied Biochemistry, Graduate School of Horticulture, Chiba University, Matsudo, Chiba, Japan
| | - Hirofumi Dohi
- Laboratory of Bioorganic Chemistry, Division of Applied Biochemistry, Graduate School of Horticulture & Molecular Chirality Research Center, Chiba University, Inage-ku, Chiba, Japan
| | - Yukari Egashira
- Laboratory of Food Nutrition, Division of Applied Biochemistry, Graduate School of Horticulture, Chiba University, Matsudo, Chiba, Japan
| | - Shizuka Hirai
- Laboratory of Food Nutrition, Division of Applied Biochemistry, Graduate School of Horticulture, Chiba University, Matsudo, Chiba, Japan
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Bone Marrow Fat Physiology in Relation to Skeletal Metabolism and Cardiometabolic Disease Risk in Children With Cerebral Palsy. Am J Phys Med Rehabil 2019; 97:911-919. [PMID: 29894311 DOI: 10.1097/phm.0000000000000981] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Individuals with cerebral palsy exhibit neuromuscular complications and low physical activity levels. Adults with cerebral palsy exhibit a high prevalence of chronic diseases, which is associated with musculoskeletal deficits. Children with cerebral palsy have poor musculoskeletal accretion accompanied by excess bone marrow fat, which may lead to weaker bones. Mechanistic studies to determine the role of bone marrow fat on skeletal growth and maintenance and how it relates to systemic energy metabolism among individuals with cerebral palsy are lacking. In this review, we highlight the skeletal status in children with cerebral palsy and analyze the existing literature on the interactions among bone marrow fat, skeletal health, and cardiometabolic disease risk in the general population. Clinically vital questions are proposed, including the following: (1) Is the bone marrow fat in children with cerebral palsy metabolically distinct from typically developing children in terms of its lipid and inflammatory composition? (2) Does the bone marrow fat suppress skeletal acquisition? (3) Or, does it accelerate chronic disease development in children with cerebral palsy? (4) If so, what are the mechanisms? In conclusion, although inadequate mechanical loading may initiate poor skeletal development, subsequent expansion of bone marrow fat may further impede skeletal acquisition and increase cardiometabolic disease risk in those with cerebral palsy.
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Novel Neohesperidin Dihydrochalcone Analogue Inhibits Adipogenic Differentiation of Human Adipose-Derived Stem Cells through the Nrf2 Pathway. Int J Mol Sci 2018; 19:ijms19082215. [PMID: 30060630 PMCID: PMC6121477 DOI: 10.3390/ijms19082215] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 07/12/2018] [Accepted: 07/24/2018] [Indexed: 12/12/2022] Open
Abstract
Obesity, characterized by excess lipid accumulation, has emerged as a leading public health problem. Excessive, adipocyte-induced lipid accumulation raises the risk of metabolic disorders. Adipose-derived stem cells (ASCs) are mesenchymal stem cells (MSCs) that can be obtained from abundant adipose tissue. High fat mass could be caused by an increase in the size (hypertrophy) and number (hyperplasia) of adipocytes. Reactive oxygen species (ROS) are involved in the adipogenic differentiation of human adipose-derived stem cells (hASCs). Lowering the level of ROS is important to blocking or retarding the adipogenic differentiation of hASCs. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a transcription factor that mediates various antioxidant enzymes and regulates cellular ROS levels. Neohesperidin dihydrochalcone (NHDC), widely used as artificial sweetener, has been shown to have significant free radical scavenging activity. In the present study, (E)-3-(4-chlorophenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one (CTP), a novel NHDC analogue, was synthesized and examined to determine whether it could inhibit adipogenic differentiation. The inhibition of adipogenic differentiation in hASCs was tested using NHDC and CTP. In the CTP group, reduced Oil Red O staining was observed compared with the differentiation group. CTP treatment also downregulated the expression of PPAR-γ and C/EBP-α, adipogenic differentiation markers in hASCs, compared to the adipogenic differentiation group. The expression of FAS and SREBP-1 decreased in the CTP group, along with the fluorescent intensity (amount) of ROS. Expression of the Nrf2 protein was slightly decreased in the differentiation group. Meanwhile, in both the NHDC and CTP groups, Nrf2 expression was restored to the level of the control group. Moreover, the expression of HO-1 and NQO-1 increased significantly in the CTP group. Taken together, these results suggest that CTP treatment suppresses the adipogenic differentiation of hASCs by decreasing intracellular ROS, possibly through activation of the Nrf2 cytoprotective pathway. Thus, the use of bioactive substances such as CTP, which activates Nrf2 to reduce the cellular level of ROS and inhibit the adipogenic differentiation of hASCs, could be a new strategy for overcoming obesity.
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Chen L, Jiang F, Qiao Y, Li H, Wei Z, Huang T, Lan J, Xia Y, Li J. Nucleoskeletal stiffness regulates stem cell migration and differentiation through lamin A/C. J Cell Physiol 2018; 233:5112-5118. [PMID: 29215717 DOI: 10.1002/jcp.26336] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 11/27/2017] [Indexed: 02/05/2023]
Abstract
Stem cell-based tissue engineering provides a prospective strategy to bone tissue repair. Bone tissue repair begins at the recruitment and directional movement of stem cells, and ultimately achieved on the directional differentiation of stem cells. The migration and differentiation of stem cells are regulated by nucleoskeletal stiffness. Mechanical properties of lamin A/C contribute to the nucleoskeletal stiffness and consequently to the regulation of cell migration and differentiation. Nuclear lamin A/C determines cell migration through the regulation of nucleoskeletal stiffness and rigidity and involve in nuclear-cytoskeletal coupling. Moreover, lamin A/C is the essential core module regulating stem cell differentiation. The cells with higher migration ability tend to have enhanced differentiation potential, while the optimum amount of lamin A/C in migration and differentiation of MSCs is in conflict. This contrary phenomenon may be the result of mechanical microenvironment modulation.
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Affiliation(s)
- Liujing Chen
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
| | - Fulin Jiang
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
| | - Yini Qiao
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
| | - Hong Li
- Hangzhou Dental Hospital, School of Stomatology, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhangming Wei
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
| | - Tu Huang
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
| | - Jingxiang Lan
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
| | - Yue Xia
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
| | - Juan Li
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
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Quantification of Bone Fatty Acid Metabolism and Its Regulation by Adipocyte Lipoprotein Lipase. Int J Mol Sci 2017; 18:ijms18061264. [PMID: 28608812 PMCID: PMC5486086 DOI: 10.3390/ijms18061264] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 06/03/2017] [Accepted: 06/05/2017] [Indexed: 12/15/2022] Open
Abstract
Adipocytes are master regulators of energy homeostasis. Although the contributions of classical brown and white adipose tissue (BAT and WAT, respectively) to glucose and fatty acid metabolism are well characterized, the metabolic role of adipocytes in bone marrow remains largely unclear. Here, we quantify bone fatty acid metabolism and its contribution to systemic nutrient handling in mice. Whereas in parts of the skeleton the specific amount of nutrients taken-up from the circulation was lower than in other metabolically active tissues such as BAT or liver, the overall contribution of the skeleton as a whole organ was remarkable, placing it among the top organs involved in systemic glucose as well as fatty acid clearance. We show that there are considerable site-specific variations in bone marrow fatty acid composition throughout the skeleton and that, especially in the tibia, marrow fatty acid profiles resemble classical BAT and WAT. Using a mouse model lacking lipoprotein lipase (LPL), a master regulator of plasma lipid turnover specifically in adipocytes, we show that impaired fatty acid flux leads to reduced amounts of dietary essential fatty acids while there was a profound increase in de novo produced fatty acids in both bone marrow and cortical bone. Notably, these changes in fatty acid profiles were not associated with any gross skeletal phenotype. These results identify LPL as an important regulator of fatty acid transport to skeletal compartments and demonstrate an intricate functional link between systemic and skeletal fatty acid and glucose metabolism.
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Balci Yuce H, Akbulut N, Ocakli S, Kayir O, Elmastas M. The effect of commercial conjugated linoleic acid products on experimental periodontitis and diabetes mellitus in Wistar rats. Acta Odontol Scand 2017; 75:21-29. [PMID: 27897090 DOI: 10.1080/00016357.2016.1244355] [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] [Indexed: 01/03/2023]
Abstract
OBJECTIVE The aim of present study was to determine the effects of conjugated linoleic acid enriched milk on alveolar bone loss, hyperglycaemia, oxidative stress and apoptosis in ligature-induced periodontal disease in diabetic rat model. METHODS Wistar rats were divided into six experimental groups: 1; non-ligated (NL, n = 6) group, 2; ligature only (LO, n = 6) group, 3; streptozotocin only (STZ, n = 8) group, 4; STZ and ligature (STZ + L, n = 8) group, 5; ligature and conjugated linoleic acid (CLA) (L + CLA, n = 8) group, 6; STZ, ligature and CLA group (STZ + L + CLA, n = 8) group. Diabetes mellitus was induced by 60 mg/kg streptozotocin. Rats were fed with CLA enriched milk for four weeks. Silk ligatures were placed at the gingival margin of lower first molars of mandibular quadrant. The study duration was four weeks after diabetes induction and the animals were sacrificed at the end of this period. Changes in alveolar bone levels were clinically measured and tissues were histopathologically examined. Inducible nitric oxide synthase (iNOS) and Bax protein expressions, serum interleukin-1β (IL-1β), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride levels and tartrate resistant acid phosphatase (TRAP)+ osteoclast numbers were also evaluated. RESULTS At the end of four weeks, alveolar bone loss was significantly higher in the STZ + LO group compared to the other groups (p < .05). CLA decreased alveolar bone loss in L + CLA and STZ + L + CLA groups. CLA significantly decreased TRAP + osteoclast numbers and increased osteoblastic activity compared to the STZ + L group (p < .05). Diabetes and CLA increased Bax protein levels (p < .05) however CLA had no effect on iNOS expression (p > .05). CONCLUSION Within the limits of this study, commercial CLA product administration in addition to diet significantly reduced alveolar bone loss, increased osteoblastic activity and decreased osteoclastic activity in the diabetic Wistar rats.
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CLA Has a Useful Effect on Bone Markers in Patients with Rheumatoid Arthritis. Lipids 2016; 51:1397-1405. [PMID: 27815799 DOI: 10.1007/s11745-016-4201-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2016] [Accepted: 09/07/2016] [Indexed: 02/04/2023]
Abstract
Rheumatoid arthritis is a systemic, chronic disease which may increase the risk of osteoporosis. This study was carried out in order to examine the effect of conjugated linoleic acid (CLA) on bone markers in rheumatoid arthritis disease which is the most common autoimmune disease. The present study is a randomized double-blind clinical trial. Subjects included 52 patients with active rheumatoid arthritis who were divided into two groups. Group I received standard treatment plus 2 daily 1.25 g capsules (Containing about 2 g of 9-cis 11-trans isomer and 10-cis 12-trans isomer in ratio of 50 -50 CLA in glycerinated form), Group II received standard treatment plus 2 Placebo 1.25 g capsules containing sunflower oil with high oleic acid. Telopeptides C, osteocalcin, and MMP3 were analyzed by ELISA method, PGE2 was done by competitive enzymatic immunoassay method, and IGF-1 was analyzed by the IRMA method based on the sandwich method and ALK-P of bone. Before and after the intervention, the questionnaires about general information, nutrition assessment and medical history were filled out by the subjects. Nutritional assessment was done by a 24-h record questionnaire for the three-day diet. The results were analyzed using SPSS software (version 18). FINDINGS There was no significant difference between the groups in enzyme activity of ALK-P of bone, PGE2 and MMP3 variables. However, differences between the two groups in terms of activity of telopeptides C, Osteocalcin, and IGF1 were significant (P < 0.05). CLA has a potentially beneficial effect on bone markers in patients with rheumatoid arthritis. Therefore, in order to study the effect of CLA on bone health in patients with RA and all patients with autoimmune and bone diseases more studies with longer duration and evaluation of bone mass density are required.
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Abstract
Stem cells are characterized by their self-renewal and multi-lineage differentiation potential. Stem cell differentiation is a prerequisite for the application of stem cells in regenerative medicine and clinical therapy. In addition to chemical stimulation, mechanical cues play a significant role in regulating stem cell differentiation. The integrity of mechanical sensors is necessary for the ability of cells to respond to mechanical signals. The nucleus, the largest and stiffest cellular organelle, interacts with the cytoskeleton as a key mediator of cell mechanics. Nuclear mechanics are involved in the complicated interactions of lamins, chromatin and nucleoskeleton-related proteins. Thus, stem cell differentiation is intimately associated with nuclear mechanics due to its indispensable role in mechanotransduction and mechanical response. This paper reviews several main contributions of nuclear mechanics, highlights the hallmarks of the nuclear mechanics of stem cells, and provides insight into the relationship between nuclear mechanics and stem cell differentiation, which may guide clinical applications in the future.
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Chaplin A, Palou A, Serra F. Body fat loss induced by calcium in co-supplementation with conjugated linoleic acid is associated with increased expression of bone formation genes in adult mice. J Nutr Biochem 2015; 26:1540-6. [DOI: 10.1016/j.jnutbio.2015.07.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 07/21/2015] [Accepted: 07/22/2015] [Indexed: 01/03/2023]
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Anti-adipogenic effects of sesamol on human mesenchymal stem cells. Biochem Biophys Res Commun 2015; 469:49-54. [PMID: 26616060 DOI: 10.1016/j.bbrc.2015.11.070] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 11/16/2015] [Indexed: 01/09/2023]
Abstract
Human mesenchymal stem cells (hMSCs) from adult bone marrow are able to differentiate into adipocytes, osteoblasts, chondrocytes and neuronal cells. Adipocytes in bone marrow are primarily responsible for the maintenance of bone structure by maintaining cell number balance with other stromal cells. However, the number of adipocytes in the bone marrow increases with age, leading to an imbalance of the bone marrow microenvironment, which results in a disruption of bone structure. In addition, the excessive number of adipocytes in bone marrow can cause diseases, such as osteoporosis or anemia. In this study, we investigated the effect of sesamol, a major natural phenolic compound of sesame oil, on the adipogenic differentiation of hMSCs. Numerous studies have reported the anti-oxidant property of sesamol, but its effect on cell differentiation has not yet been shown. We first found that sesamol treatment during adipogenic differentiation of hMSCs reduced intracellular lipid accumulation, which was unrelated to lipolysis. Interestingly, sesamol diminished the expression of genes responsible for adipogenesis, but increased the expression of osteogenic genes. In addition, sesamol decreased the expression of genes necessary for adipocyte maturation without affecting the expression of hMSC-specific genes. Studies concerning intracellular signaling in hMSCs showed that the extracellular signal-regulated kinase 1/2 (ERK1/2) was decreased by sesamol, which was similar with the effect of an ERK1/2 inhibitor. Overall, this study demonstrates that sesamol can attenuate the adipogenic differentiation of hMSCs without affecting its characteristics through the inhibition of ERK1/2 pathway. Herein, this study reports for the first time the effect of sesamol on hMSC differentiation and suggests the possibility of using sesamol as a therapeutic agent to treat intraosseous disruption triggered by the excessive adipogenesis of hMSCs.
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Ramírez-Espinosa JJ, González-Dávalos L, Shimada A, Piña E, Varela-Echavarria A, Mora O. Bovine (Bos taurus) Bone Marrow Mesenchymal Cell Differentiation to Adipogenic and Myogenic Lineages. Cells Tissues Organs 2015; 201:51-64. [PMID: 26565958 DOI: 10.1159/000440878] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2015] [Indexed: 11/19/2022] Open
Abstract
PURPOSE We evaluated the effect of peroxisome proliferator-activated receptor (PPAR) agonists on the differentiation and metabolic features of bovine bone marrow-derived mesenchymal cells induced to adipogenic or myogenic lineages. METHODS Cells isolated from 7-day-old calves were cultured in basal medium (BM). For adipogenic differentiation, cells were cultured for one passage in BM and then transferred to a medium supplemented with either rosiglitazone, telmisartan, sirtinol or conjugated c-9, t-11 linoleic acid; for myogenic differentiation, third-passage cells were added with either bezafibrate, telmisartan or sirtinol. The expression of PPARx03B3; (an adipogenic differentiation marker), myosin heavy chain (MyHC; a myogenic differentiation marker) and genes related to energy metabolism were measured by quantitative real-time PCR in a completely randomized design. RESULTS For adipogenic differentiation, 20 µM telmisartan showed the highest PPARx03B3; expression (15.58 ± 0.62-fold, p < 0.0001), and differences in the expression of energy metabolism-related genes were found for hexokinase II, phosphofructokinase, adipose triglyceride lipase, acetyl-CoA carboxylase α(ACACα) and fatty acid synthase (p < 0.001), but not for ACACβ (p = 0.4275). For myogenic differentiation, 200 µM bezafibrate showed the highest MyHC expression (73.98 ± 11.79-fold), and differences in the expression of all energy metabolism-related genes were found (p < 0.05). CONCLUSIONS Adipocyte and myocyte differentiation are enhanced with telmisartan and bezafibrate, respectively, and energy uptake, storage and mobilization are improved with both.
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Affiliation(s)
- Jesus J Ramírez-Espinosa
- Programa de Posgrado en Ciencias de la Produccix00F3;n y de la Salud Animal, Universidad Nacional Autx00F3;noma de Mx00E9;xico (UNAM), Mexico City, Mexico
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Zhang J, Li ZG, Si YM, Chen B, Meng J. The difference on the osteogenic differentiation between periodontal ligament stem cells and bone marrow mesenchymal stem cells under inflammatory microenviroments. Differentiation 2014; 88:97-105. [PMID: 25498523 DOI: 10.1016/j.diff.2014.10.001] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 09/26/2014] [Accepted: 10/29/2014] [Indexed: 12/14/2022]
Abstract
Periodontitis is a major cause of tooth loss in adults and periodontal ligament stem cells (PDLSCs) is the most favorable candidate for the reconstruction of tissues destroyed by periodontal diseases. However, pathological alterations caused by inflammatory insults might impact the regenerative capacities of these cells. Bone-marrow-derived human mesenchymal stem cells (hBMSCs) would accelerate alveolar bone regeneration by transplantation, compared to PDLSCs. Therefore, a better understanding of the osteogenic differentiation between PDLSCs and BMSCs in inflammatory microenviroments is therefore warranted. In this study, human PDLSCs were investigated for their stem cell characteristics via analysis of cell surface marker expression, colony forming unit efficiency, osteogenic differentiation and adipogenic differentiation, and compared to BMSCs. To determine the impact of both inflammation and the NF-κβ signal pathway on osteogenic differentiation, cells were challenged with TNF-α under osteogenic induction conditions and investigated for mineralization, alkaline phosphatase (ALP) activity, cell proliferation and relative genes expression. Results showed that PDLSCs exhibit weaker mineralization and ALP activity compared to BMSCs. TNF-α inhibited genes expression of osteogenic differentiation in PDLSCs, while, it stimulates gene expressions (BSP and Runx2) in BMSCs. Enhanced NF-κβ activity in PDLSCs decreases expression of Runx2 but it does not impede the osteogenic differentiation of BMSCs. Taken together, these results may suggest that the BMSCs owned the stronger immunomodulation in local microenvironment via anti-inflammatory functions, compared to PDLSCs.
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Affiliation(s)
- Jing Zhang
- Department of Stomatology, The Affiliated School of Clinical Medicine of Xuzhou Medical College, Xuzhou Central Hospital, Xuzhou, China
| | - Zhi-Gang Li
- Department of Urology, The Affiliated School of Clinical Medicine of Xuzhou Medical College, Xuzhou Central Hospital, Xuzhou, China
| | - Ya-Meng Si
- Department of Stomatology, The Affiliated School of Clinical Medicine of Xuzhou Medical College, Xuzhou Central Hospital, Xuzhou, China
| | - Bin Chen
- Department of Stomatology, The Affiliated School of Clinical Medicine of Xuzhou Medical College, Xuzhou Central Hospital, Xuzhou, China
| | - Jian Meng
- Department of Stomatology, The Affiliated School of Clinical Medicine of Xuzhou Medical College, Xuzhou Central Hospital, Xuzhou, China.
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Kim J, Park Y, Park Y. trans-10, cis-12 CLA promotes osteoblastogenesis via SMAD mediated mechanism in bone marrow mesenchymal stem cells. J Funct Foods 2014; 8:367-376. [PMID: 25035711 PMCID: PMC4095819 DOI: 10.1016/j.jff.2014.04.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
The inverse relationship between osteoblast and adipocyte differentiation in bone marrow mesenchymal stem cells has been linked to overall bone mass. It has previously been reported that conjugated linoleic acid (CLA) inhibits adipogenesis via a peroxisome-proliferator activated receptor-γ (PPARγ) mediated mechanism, while it increases osteoblastogenesis via a PPARγ-independent mechanism in mesenchymal stem cells. This suggests potential implication of CLA on improving bone mass. Thus the purpose of this study was to determine involvement of CLA on regulation of osteoblastogenesis in murine mesenchymal stem cells by focusing on the Mothers against decapentaplegic (MAD)-related family of molecules 8 (SMAD8), one of key regulators of osteoblastogenesis. The trans-10,cis-12 CLA, but not the cis-9,trans-11, significantly increased osteoblastogenesis via SMAD8, and inhibited adipogenesis independent of SMAD8, while inhibiting factors regulating osteoclastogenesis in this model. These suggest that CLA may help improve osteoblastogenesis via a SMAD8 mediated mechanism.
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Affiliation(s)
- Jonggun Kim
- Department of Food Science, University of Massachusetts, Amherst, 102
Holdsworth Way, Amherst, MA 01003
| | - Yooheon Park
- Department of Food Science, University of Massachusetts, Amherst, 102
Holdsworth Way, Amherst, MA 01003
| | - Yeonhwa Park
- Department of Food Science, University of Massachusetts, Amherst, 102
Holdsworth Way, Amherst, MA 01003
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Rahman MM, Fernandes G, Williams P. Conjugated linoleic Acid prevents ovariectomy-induced bone loss in mice by modulating both osteoclastogenesis and osteoblastogenesis. Lipids 2013; 49:211-24. [PMID: 24338525 DOI: 10.1007/s11745-013-3872-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Accepted: 11/27/2013] [Indexed: 11/29/2022]
Abstract
Postmenopausal osteoporosis due to estrogen deficiency is associated with severe morbidity and mortality. Beneficial effects of conjugated linoleic acid (CLA) on bone mineral density (BMD) have been reported in mice, rats and humans, but the effect of long term CLA supplementation against ovariectomy-induced bone loss in mice and the mechanisms underlying this effect have not been studied yet. Eight-week old ovariectomized (Ovx) and sham operated C57BL/6 mice were fed either a diet containing 0.5 % safflower oil (SFO) or 0.5 % CLA for 24 weeks to examine BMD, bone turn over markers and osteotropic factors. Bone marrow (BM) cells were cultured to determine the effect on inflammation, osteoclastogenesis, and osteoblastogenesis. SFO/Ovx mice had significantly lower femoral, tibial and lumbar BMD compared to SFO/Sham mice; whereas, no difference was found between CLA/Ovx and CLA/Sham mice. CLA inhibited bone resorption markers whereas enhanced bone formation markers in Ovx mice as compared to SFO-fed mice. Reverse transcriptase polymerase chain reaction and fluorescence activated cell sorting analyses of splenocytes revealed that CLA inhibited pro-osteoclastogenic receptor activator of NF-κB (RANKL) and stimulated decoy receptor of RANKL, osteoprotegerin expression. CLA also inhibited pro-inflammatory cytokine and enhanced anti-inflammatory cytokine production of lipopolysaccharide-stimulated splenocytes and BM cells. Furthermore, CLA inhibited osteoclast differentiation in BM and stimulated osteoblast differentiation in BM stromal cells as confirmed by tartrate resistant acid phosphatase and Alizarin Red staining, respectively. In conclusion, CLA may prevent postmenopausal bone loss not only by inhibiting excessive bone resorption due to estrogen deficiency but also by stimulating new bone formation. CLA might be a potential alternative therapy against osteoporotic bone loss.
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Affiliation(s)
- Md Mizanur Rahman
- Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX, 78229-3900, USA,
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Sadie-Van Gijsen H, Hough FS, Ferris WF. Determinants of bone marrow adiposity: the modulation of peroxisome proliferator-activated receptor-γ2 activity as a central mechanism. Bone 2013; 56:255-65. [PMID: 23800517 DOI: 10.1016/j.bone.2013.06.016] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Revised: 06/04/2013] [Accepted: 06/12/2013] [Indexed: 12/23/2022]
Abstract
Although the presence of adipocytes in the bone marrow is a normal physiological phenomenon, the role of these cells in bone homeostasis and during pathological states has not yet been fully delineated. As osteoblasts and adipocytes originate from a common progenitor, with an inverse relationship existing between osteoblastogenesis and adipogenesis, bone marrow adiposity often negatively correlates with osteoblast number and bone mineral density. Bone adiposity can be affected by several physiological and pathophysiological factors, with abnormal, elevated marrow fat resulting in a pathological state. This review focuses on the regulation of bone adiposity by physiological factors, including aging, mechanical loading and growth factor expression, as well as the pathophysiological factors, including diseases such as anorexia nervosa and dyslipidemia, and pharmacological agents such as thiazolidinediones and statins. Although these factors regulate bone marrow adiposity via a plethora of different intracellular signaling pathways, these diverse pathways often converge on the modulation of the expression and/or activity of the pro-adipogenic transcription factor peroxisome proliferator-activated receptor (PPAR)-γ2, suggesting that any factor that affects PPAR-γ2 may have an impact on the fat content of bone.
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Affiliation(s)
- H Sadie-Van Gijsen
- Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Francie van Zijl Drive, Tygerberg 7505, South Africa.
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Park Y, Kim J, Scrimgeour AG, Condlin ML, Kim D, Park Y. Conjugated linoleic acid and calcium co-supplementation improves bone health in ovariectomised mice. Food Chem 2013; 140:280-8. [PMID: 23578644 PMCID: PMC3625250 DOI: 10.1016/j.foodchem.2012.12.067] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Revised: 12/10/2012] [Accepted: 12/14/2012] [Indexed: 01/18/2023]
Abstract
Osteoporosis is a significant health concern for the elderly; conjugated linoleic acid (CLA) has been shown to improve overall bone mass when calcium is included as a co-supplement. However, potential effects of CLA and calcium on bone mass during a period of bone loss have not been reported. The purpose of this study was to determine how dietary calcium modulates the effects of conjugated linoleic acid (CLA) in preventing bone loss, using an ovariectomised mouse model. CLA supplementation significantly prevented ovariectomy-associated weight and fat mass gain, compared to non-supplemented controls. CLA significantly increased bone markers without major changes in bone mineral composition in the femur compared to respective controls. CLA treatment increased serum parathyroid hormone (PTH) significantly (p=0.0172), while serum 1,25-dihydroxyvitamin D3 concentration was not changed by CLA. Meanwhile, CLA significantly reduced femur tartrate resistant acid phosphatase (TRAP) activity, suggesting potential reduction of osteoclastogenesis. The data suggest that CLA, along with dietary calcium, has great potential to be used to prevent bone loss and weight gain associated with menopause.
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Affiliation(s)
- Yooheon Park
- Department of Food Science, University of Massachusetts, 102 Holdsworth Way, Amherst, MA 01003
| | - Jonggun Kim
- Department of Food Science, University of Massachusetts, 102 Holdsworth Way, Amherst, MA 01003
| | - Angus G. Scrimgeour
- Military Nutrition Division, US Army Research Institute of Environmental Medicine (USARIEM), Kansas Street, Natick, MA 01760
| | - Michelle L. Condlin
- Military Nutrition Division, US Army Research Institute of Environmental Medicine (USARIEM), Kansas Street, Natick, MA 01760
| | - Daeyoung Kim
- Department of Mathematics and Statistics, University of Massachusetts, 710 North Pleasant Street, Amherst, MA 01003
| | - Yeonhwa Park
- Department of Food Science, University of Massachusetts, 102 Holdsworth Way, Amherst, MA 01003
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Wu X, Wang W, Meng C, Yang S, Duan D, Xu W, Liu X, Tang M, Wang H. Regulation of differentiation in trabecular bone‑derived mesenchymal stem cells by T cell activation and inflammation. Oncol Rep 2013; 30:2211-9. [PMID: 23970332 DOI: 10.3892/or.2013.2687] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 06/04/2013] [Indexed: 11/05/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells with the ability to migrate to sites of inflammation and injury, where they participate in tissue regeneration and repair. The present study aimed to investigate the effects of T cell activation and inflammation on the differentiation of MSCs. Human trabecular bone‑derived MSCs were isolated from patients undergoing total hip replacement, and T cells were isolated and purified from peripheral blood mononuclear cells (PBMCs) using CD3 MicroBeads. MSCs were co‑cultured with activated T cells to mimic the inflammatory microenvironment. MTS assay was used to detect cell proliferation.qRT‑PCR, western blotting, histology and immunohistochemical staining were used to detect the adipo‑/osteo‑specific gene expression and the relative signaling pathway. The MTS results showed that higher concentrations of T cells significantly increased the proliferation of MSCs. Expression of the inflammatory gene IL‑6 was upregulated, while expression of IL‑10 and INFγ was downregulated in MSCs exposed to activated T cells. The results also showed that PHA‑activated T cells significantly upregulated the expression of PPARγ and FABP4 (adipo‑specific genes) in MSCs, but no difference was noted in the expression of RUNX2, osteocalcin and ALP (osteo‑specific genes) at the protein level. T cell treatment and inflammation inhibited the protein expression of TGF‑β1 and the phosphorylation of Smad3, resulting in the weakening of the TGF‑β/Smad pathway and enhancing the adipogenic differentiation of MSCs. The results indicated that PHA‑activated T cells and inflammation could promote adipogenesis without affecting the late stage of osteogenesis of MSCs, by increasing the expression of key adipogenic genes through TGF‑β/Smad3 signaling.
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Affiliation(s)
- Xinghuo Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan 430022, P.R. China
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Spilmont M, Léotoing L, Davicco MJ, Lebecque P, Mercier S, Miot-Noirault E, Pilet P, Rios L, Wittrant Y, Coxam V. Pomegranate seed oil prevents bone loss in a mice model of osteoporosis, through osteoblastic stimulation, osteoclastic inhibition and decreased inflammatory status. J Nutr Biochem 2013; 24:1840-8. [PMID: 23953990 DOI: 10.1016/j.jnutbio.2013.04.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Revised: 04/09/2013] [Accepted: 04/15/2013] [Indexed: 11/19/2022]
Abstract
In the current context of longer life expectancy, the prevalence of osteoporosis is increasingly important. This is why development of new strategies of prevention is highly suitable. Pomegranate seed oil (PSO) and its major component, punicic acid (a conjugated linolenic acid), have potent anti-inflammatory and anti-oxidative properties both in vitro and in vivo, two processes strongly involved in osteoporosis establishment. In this study, we demonstrated that PSO consumption (5% of the diet) improved significantly bone mineral density (240.24±11.85 vs. 203.04±34.19 mg/cm(3)) and prevented trabecular microarchitecture impairment in ovariectomized (OVX) mice C57BL/6J, compared to OVX control animals. Those findings are associated with transcriptional changes in bone tissue, suggesting involvement of both osteoclastogenesis inhibition and osteoblastogenesis improvement. In addition, thanks to an ex vivo experiment, we provided evidence that serum from mice fed PSO (5% by gavage) had the ability to significantly down-regulate the expression of specific osteoclast differentiation markers and RANK-RANKL downstream signaling targets in osteoclast-like cells (RAW264.7) (RANK: negative 0.49-fold vs. control conditions). Moreover, in osteoblast-like cells (MC3T3-E1), it elicited significant increase in alkaline phosphatase activity (+159% at day 7), matrix mineralization (+271% on day 21) and transcriptional levels of major osteoblast lineage markers involving the Wnt/β-catenin signaling pathways. Our data also reveal that PSO inhibited pro-inflammatory factors expression while stimulating anti-inflammatory ones. These results demonstrate that PSO is highly relevant regarding osteoporosis. Indeed, it offers promising alternatives in the design of new strategies in nutritional management of age-related bone complications.
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Affiliation(s)
- Mélanie Spilmont
- INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France; Equipe Alimentation, Squelette et Métabolismes, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France; Greentech SA, Biopôle, Clermont-Limagne, 63360 Saint Beauzire, France
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Kim Y, Kelly OJ, Ilich JZ. Synergism of α-linolenic acid, conjugated linoleic acid and calcium in decreasing adipocyte and increasing osteoblast cell growth. Lipids 2013; 48:787-802. [PMID: 23757205 DOI: 10.1007/s11745-013-3803-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Accepted: 05/07/2013] [Indexed: 11/30/2022]
Abstract
Whole fat milk and dairy products (although providing more energy compared to low- or non-fat products), are good sources of α-linolenic acid (ALA), conjugated linoleic acid (CLA) and calcium, which may be favorable in modulating bone and adipose tissue metabolism. We examined individual and/or synergistic effects of ALA, CLA and calcium (at levels similar to those in whole milk/dairy products) in regulating bone and adipose cell growth. ST2 stromal, MC3T3-L1 adipocyte-like and MC3T3-E1 osteoblast-like cells were treated with: (a) linoleic acid (LNA):ALA ratios = 1-5:1; (b) individual/combined 80-90 % c9, t11 (9,11) and 5-10 % t10, c12 (10,12) CLA isomers; (c) 0.5-3.0 mM calcium; (d) combinations of (a), (b), (c); and (e) control. Local mediators, including eicosanoids and growth factors, were measured. (a) The optimal effect was found at the 4:1 LNA:ALA ratio where insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) production was the lowest in MC3T3-L1 cells. (b) All CLA isomer blends decreased MC3T3-L1 and increased MC3T3-E1 cell differentiation. (c) 1.5-2.5 mM calcium increased ST2 and MC3T3-E1, and decreased MC3T3-L1 cell proliferation. (d) Combination of 4:1 LNA:ALA + 90:10 % CLA + 2.0 mM calcium lowered MC3T3-L1 and increased MC3T3-E1 cell differentiation. Overall, the optimal LNA:ALA ratio to enhance osteoblastogenesis and inhibit adipogenesis was 4:1. This effect was enhanced by 90:10 % CLA + 2.0 mM calcium, indicating possible synergism of these dietary factors in promoting osteoblast and inhibiting adipocyte differentiation in cell cultures.
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Affiliation(s)
- Youjin Kim
- Bayer CropScience Ltd., Gangnam-gu, Seoul 135-979, South Korea
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Kim J, Park Y, Lee SH, Park Y. trans-10,cis-12 conjugated linoleic acid promotes bone formation by inhibiting adipogenesis by peroxisome proliferator activated receptor-γ-dependent mechanisms and by directly enhancing osteoblastogenesis from bone marrow mesenchymal stem cells. J Nutr Biochem 2013; 24:672-9. [PMID: 22832076 PMCID: PMC3482420 DOI: 10.1016/j.jnutbio.2012.03.017] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Revised: 03/07/2012] [Accepted: 03/19/2012] [Indexed: 12/14/2022]
Abstract
The bone undergoes continuous remodeling of osteoblastic bone formation and osteoclastic bone resorption to maintain proper bone mass. It is also reported that bone marrow adiposity has a reciprocal role in osteoblasts due to their same origin from mesenchymal stem cells. In addition, one of the key mediators of adipogenesis, peroxisome-proliferator activated receptor-γ (PPARγ), plays a significant role in osteoblastogenesis in bone marrow mesenchymal stem cells. One dietary component that is known to have significant impact on adiposity and bone mass is conjugated linoleic acid (CLA). However, the link between controlling adiposity to improving bone mass by CLA has not been studied intensively. Thus, the purpose of this study is to determine the role of CLA on bone marrow adiposity and bone formation using murine mesenchymal stem cells. The results confirmed that the trans-10,cis-12 CLA, but not the cis-9,trans-11 CLA isomer, significantly inhibited adipogenesis and promoted osteoblastogenesis from mesenchymal stem cells. The inhibition of adipogenesis by the trans-10,cis-12 CLA was mediated by PPARγ; however, the trans-10,cis-12 CLA had a direct effect on osteoblastogenesis which was independent to PPARγ in this model. The trans-10,cis-12 CLA also had significant effects on osteoclastogenesis inhibitory factor, which suggests potential influence of CLA on osteoclastogenesis. Overall, the results suggest that the trans-10,cis-12, but not the cis-9,trans-11 CLA isomer, has a positive impact on bone health by both PPARγ mediated and independent mechanisms in mesenchymal stem cells.
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Affiliation(s)
- Jonggun Kim
- Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA
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Brown PM, Hutchison JD, Crockett JC. Absence of glutamine supplementation prevents differentiation of murine calvarial osteoblasts to a mineralizing phenotype. Calcif Tissue Int 2011; 89:472-82. [PMID: 21972050 DOI: 10.1007/s00223-011-9537-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Accepted: 09/11/2011] [Indexed: 10/17/2022]
Abstract
Osteoblasts in vitro differentiate from a proliferating to a mineralizing phenotype upon transfer to a medium rich in beta-glycerophosphate and ascorbic acid. The nutritional requirements of the cells at different stages of this differentiation process are not known. In other cell types, nutritional supplementation during surgery can improve the outcome in terms of speed of patient recovery and prognosis. There is therefore the potential for supplementation at the site of fracture repair or bone grafting with critical osteoblast nutritional factors to potentially accelerate healing. In this study we investigate which common cell nutrients are required for the proliferating and mineralizing stages of osteoblast differentiation. Medium containing 5.5 mM glucose was sufficient to achieve maximal proliferation of primary calvarial osteoblasts and human osteoblast cell lines, with some added benefit of additional glutamine supplementation. However, when cells were stimulated to mineralize, glucose was insufficient to support their energetic requirements. Only when cells were supplemented with glucose together with glutamine were high levels of osteocalcin expression observed together with mineralized nodules in culture, suggesting that this would be a useful combination to assess in cultures of primary human osteoblasts to determine whether it may have beneficial effects during fracture surgery, bone grafting, and fixation of uncemented arthroplasty implants.
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Affiliation(s)
- Philip M Brown
- Musculoskeletal Research Programme, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, UK
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40
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Rahman MM, Halade GV, Williams PJ, Fernandes G. t10c12-CLA maintains higher bone mineral density during aging by modulating osteoclastogenesis and bone marrow adiposity. J Cell Physiol 2011; 226:2406-14. [PMID: 21660964 PMCID: PMC3103755 DOI: 10.1002/jcp.22578] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Conjugated linoleic acid (CLA) has been shown to positively influence calcium and bone metabolism. Earlier, we showed that CLA (equal mixture of c9t11-CLA and t10c12-CLA) could protect age-associated bone loss by modulating inflammatory markers and osteoclastogenesis. Since, c9t11-CLA and t10c12-CLA isomers differentially regulate functional parameters and gene expression in different cell types, we examined the efficacy of individual CLA isomers against age-associated bone loss using 12 months old C57BL/6 female mice fed for 6 months with 10% corn oil (CO), 9.5% CO + 0.5% c9t11-CLA, 9.5% CO + 0.5% t10c12-CLA or 9.5% CO + 0.25% c9t11-CLA + 0.25% t10c12-CLA. Mice fed a t10c12-CLA diet maintained a significantly higher bone mineral density (BMD) in femoral, tibial and lumbar regions than those fed CO and c9t11-CLA diets as measured by dual-energy-X-ray absorptiometry (DXA). The increased BMD was accompanied by a decreased production of osteoclastogenic factors, that is, RANKL, TRAP5b, TNF-alpha and IL-6 in serum. Moreover, a significant reduction of high fat diet-induced bone marrow adiposity was observed in t10c12-CLA fed mice as compared to that of CO and c9t11-CLA fed mice, as measured by Oil-Red-O staining of bone marrow sections. In addition, a significant reduction of osteoclast differentiation and bone resorbing pit formation was observed in t10c12-CLA treated RAW 264.7 cell culture stimulated with RANKL as compared to that of c9t11-CLA and linoleic acid treated cultures. In conclusion, these findings suggest that t10c12-CLA is the most potent CLA isomer and it exerts its anti-osteoporotic effect by modulating osteoclastogenesis and bone marrow adiposity.
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Affiliation(s)
- Md M Rahman
- Department of Medicine, University of Texas Health Science Center at San Antonio, Texas 78229-3900, USA.
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41
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Wang H, Liu T, Wang J, Qi Y, Ge D, Guan S. Isomer-specific effects of conjugated linoleic acid on proliferative activity of cultured neural progenitor cells. Mol Cell Biochem 2011; 358:13-20. [DOI: 10.1007/s11010-011-0914-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2010] [Accepted: 05/28/2011] [Indexed: 11/25/2022]
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Park Y, Terk M, Park Y. Interaction between dietary conjugated linoleic acid and calcium supplementation affecting bone and fat mass. J Bone Miner Metab 2011; 29:268-78. [PMID: 20697754 DOI: 10.1007/s00774-010-0212-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2010] [Accepted: 06/29/2010] [Indexed: 12/22/2022]
Abstract
Dietary conjugated linoleic acid (CLA) has shown wide biologically beneficial effects, such as anticancer, antiatherosclerotic, antidiabetic, immunomodulating, and antiobesity effects. However, the effects of CLA on total body ash, reflective of bone mineral content, have not been consistent. We hypothesized that the inconsistency of the CLA effect on ash may be linked to interaction between CLA and dietary calcium levels. Thus, we investigated the effects of CLA on body ash in conjunction with various calcium levels. Male ICR mice were fed three different levels of calcium (0.01, 0.5, and 1%) with or without 0.5% CLA for 4 weeks for Experiment 1 and separate CLA isomers at 0.22% level with 1% calcium in Experiment 2. CLA feeding reduced body fat regardless of dietary calcium level, whereas CLA supplementation increased body ash compared to control only in animals fed the 1% calcium. In Experiment 2 it was confirmed that this observation was associated with the trans-10, cis-12 CLA isomer, but not with the cis-9, trans-11 isomer. CLA administration with 1% dietary calcium significantly improved total ash percent (%) in femurs, confirming that CLA has the potential to be used to improve bone mass.
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Affiliation(s)
- Yooheon Park
- Department of Food Science, University of Massachusetts, Amherst, 100 Holdsworth Way, Amherst, MA 01003, USA
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43
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Ing SW, Belury MA. Impact of conjugated linoleic acid on bone physiology: proposed mechanism involving inhibition of adipogenesis. Nutr Rev 2011; 69:123-31. [PMID: 21348876 PMCID: PMC3814018 DOI: 10.1111/j.1753-4887.2011.00376.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Conjugated linoleic acid (CLA) supplementation decreases adipose mass and increases bone mass in mice. Recent clinical studies demonstrate a beneficial effect of CLA on reducing weight and adipose mass in humans. This article reviews possible biological mechanisms of action of CLA on bone metabolism, focusing on modulation of nuclear receptor peroxisome proliferator-activated receptor gamma activity to steer mesenchymal stem cell differentiation toward an adipose and away from an osteoblast lineage. Clinical studies of the effects of CLA on bone mass and clinical implications of the effects of CLA on bone health in humans are summarized and discussed.
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Affiliation(s)
- Steven W Ing
- Division of Endocrinology, Diabetes, & Metabolism, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio 43210-1296, USA.
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A role for suppressed bone formation favoring catch-up fat in the pathophysiology of catch-up growth after food restriction. Eur J Nutr 2011; 50:645-55. [DOI: 10.1007/s00394-011-0174-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2010] [Accepted: 01/27/2011] [Indexed: 10/18/2022]
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45
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Spaeth EL, Marini FC. Dissecting mesenchymal stem cell movement: migration assays for tracing and deducing cell migration. Methods Mol Biol 2011; 750:241-59. [PMID: 21618096 DOI: 10.1007/978-1-61779-145-1_17] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Targeted migration is a necessary attribute for any gene delivery vehicle. Mesenchymal stem cells (MSC) have been used as effective delivery vehicles for treatments against cancer, graft versus host disease, -arthritis, multiple sclerosis, and many other diseases. MSC migrate toward sites of inflammation, however, the true migratory mechanism has yet to be elucidated. There are several receptors and respective chemokines known to be involved in the migration of the MSC. Further insight to MSC migration will be revealed both in vivo and in vitro through the application of migration assays from the most simple, to the more technologically demanding.
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Affiliation(s)
- Erika L Spaeth
- Department of Stem Cell Transplantation and Cellular Therapy, Section of Molecular Hematology and Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
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Han C, Yang Z, Zhou W, Jin F, Song Y, Wang Y, Huo N, Chen L, Qian H, Hou R, Duan Y, Jin Y. Periapical Follicle Stem Cell: A Promising Candidate for Cementum/Periodontal Ligament Regeneration and Bio-Root Engineering. Stem Cells Dev 2010; 19:1405-15. [DOI: 10.1089/scd.2009.0277] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Affiliation(s)
- Chun Han
- Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
- Research and Development Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Zhenhua Yang
- Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
- Research and Development Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Wei Zhou
- Department of Prosthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Fang Jin
- Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
- Research and Development Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Yingliang Song
- Department of Oral Implant Dentistry, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Yinxiong Wang
- Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
- Research and Development Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Na Huo
- Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
- Research and Development Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Lei Chen
- Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
- Research and Development Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Hong Qian
- Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Rui Hou
- Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Yinzhong Duan
- Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Yan Jin
- Research and Development Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
- Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
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Siddiqui JA, Swarnkar G, Sharan K, Chakravarti B, Sharma G, Rawat P, Kumar M, Khan FM, Pierroz D, Maurya R, Chattopadhyay N. 8,8''-Biapigeninyl stimulates osteoblast functions and inhibits osteoclast and adipocyte functions: Osteoprotective action of 8,8''-biapigeninyl in ovariectomized mice. Mol Cell Endocrinol 2010; 323:256-67. [PMID: 20380869 DOI: 10.1016/j.mce.2010.03.024] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2010] [Revised: 03/19/2010] [Accepted: 03/31/2010] [Indexed: 01/09/2023]
Abstract
8,8''-Biapigeninyl (BA), a condensation product of two apigenin molecules, is found abundantly in the nuts of Cupressus sempervirens. We investigated the effects of BA on murine bone cells in vitro and in ovariectomized (OVx) mice. BA at 10(-10)M and 10(-8)M, inhibited osteoclastogenesis of bone marrow cells (BMCs) and displayed concentration dependence. BA at 10(-8) M and 10(-6) M inhibited differentiation of 3T3-L1 and BMCs to mature adipocytes. BA (10(-10)M) stimulated osteoblast proliferation, differentiation and mineralization. In stimulating osteoblast function, BA was found to be 10(4)-fold more potent than apigenin. The effect of BA in osteoblasts appeared to be mediated via estrogen receptors (ER) as antiestrogen, ICI-182780 abolished BA-stimulated osteoblast differentiation. In OVx mice BA treatment (at 1.0-, 5.0- and 10.0 mg kg(-1) day(-1) doses) given orally for 30 days dose-dependently inhibited mRNA levels of osteoclastic genes including tartrate-resistant acid phosphatase, receptor activator of nuclear factor (RANK), tumor necrosis factor alpha, interleukin-6 and the ratio of RANK ligand/osteoprotegerin ratio in bones compared with OVx mice treated with vehicle. In addition, BA treatment to OVx mice dose-dependently stimulated production of osteoprogenitor cells in the bone marrow and increased mRNA levels of osteogenic genes core binding factor alpha-1, type I collagen and bone morphogenic protein-2 in bones compared with OVx+vehicle group. Microcomputed tomography revealed that BA treatment to OVx mice improved parameters of trabecular and cortical architecture. BA exhibited no uterine estrogenicity. From these data, we conclude that BA exerts osteoprotective effect in OVx mice by multiple beneficial effects on bone cells.
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Affiliation(s)
- Jawed A Siddiqui
- Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, P.O. Box 173, Lucknow 226001, India
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Olfa G, Christophe C, Philippe L, Romain S, Khaled H, Pierre H, Odile B, Jean-Christophe D. RUNX2 regulates the effects of TNFalpha on proliferation and apoptosis in SaOs-2 cells. Bone 2010; 46:901-10. [PMID: 20053387 DOI: 10.1016/j.bone.2009.12.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2009] [Revised: 12/08/2009] [Accepted: 12/27/2009] [Indexed: 10/20/2022]
Abstract
The runt-related transcriptional factor RUNX2 is an essential mediator of the osteoblast phenotype and plays a pivotal role in the process of osteoblast differentiation. The involvement of RUNX2 includes the regulation of genes that are important in committing cells to the osteoblast lineage. Increasing evidences are consistent with a requirement of RUNX2 for stringent control of osteoblast proliferation and recent data even suggested that RUNX2 might act as a proapoptotic factor. Among the cytokines described as modulators of osteoblast functions, TNFalpha affects both apoptosis and the differentiation rate from mesenchymal precursor cells of osteoblast. Thus we evaluated on the human osteosarcoma cell line SaOs-2 stably transfected with a RUNX2 dominant negative construct (DeltaRUNX2) the effects of serum and TNFalpha on proliferation and apoptosis. In this study we showed that SaOs-2 clones expressing high levels of DeltaRUNX2 presented a higher proliferation rate than clones transfected with an empty vector. This increase in cell growth was accompanied by a rise in cyclins A1, B1 and E1 expression and a decrease in the cyclin inhibitor p21. Moreover we observed that the expression of the RUNX2 transgene protected the SaOs-2 cells from the antiproliferative and the apoptotic effects induced by TNFalpha. This was accompanied by the inhibition of Bax and activation of Bcl2 expression. Experiments done on SaOs-2 cells transiently transfected with siRNA confirmed that RUNX2 represents a critical link between cell fate, proliferation and growth control. This study also suggested that RUNX2 might control osteoblastic growth depending on the differentiation stage of the cells by regulating expression of elements involved in hormones and cytokines sensitivity.
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Affiliation(s)
- Ghali Olfa
- LR2B/LBCM - EA 2603 - IFR 114. Université Lille Nord de France. Boulogne-sur-mer. France
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Elbaz A, Wu X, Rivas D, Gimble JM, Duque G. Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro. J Cell Mol Med 2010; 14:982-91. [PMID: 19382912 PMCID: PMC2891630 DOI: 10.1111/j.1582-4934.2009.00751.x] [Citation(s) in RCA: 128] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2009] [Accepted: 03/10/2009] [Indexed: 01/08/2023] Open
Abstract
Although increased bone marrow fat in age-related bone loss has been associated with lower trabecular mass, the underlying mechanism responsible remains unknown. We hypothesized that marrow adipocytes exert a lipotoxic effect on osteoblast function and survival through the reversible biosynthesis of fatty acids (FA) into the bone marrow microenvironment. We have used a two-chamber system to co-culture normal human osteoblasts (NHOst) with differentiating pre-adipocytes in the absence or presence of an inhibitor of FA synthase (cerulenin) and separated by an insert that allowed unidirectional trafficking of soluble factors only and prevented direct cell-cell contact. Supernatants were assayed for the presence of FA using mass spectophotometry. After 3 weeks in co-culture, NHOst showed significantly lower levels of differentiation and function based on lower mineralization and expression of alkaline phosphatase, osterix, osteocalcin and Runx2. In addition, NHOst survival was affected by the presence of adipocytes as determined by MTS-formazan and TUNEL assays as well as higher activation of caspases 3/7. These toxic effects were inhibited by addition of cerulenin. Furthermore, culture of NHOst with either adipocyte-conditioned media alone in the absence of adipocytes themselves or with the addition of the most predominant FA (stearate or palmitate) produced similar toxic results. Finally, Runx2 nuclear binding was affected by addition of either adipocyte conditioned media or FA into the osteogenic media. We conclude that the presence of FA within the marrow milieu can contribute to the age-related changes in bone mass and can be prevented by the inhibition of FA synthase.
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Affiliation(s)
- Alexandre Elbaz
- Lady Davis Institute for Medical Research, McGill University, MontrealQuebec, Canada
| | - Xiying Wu
- Stem Cell Laboratory, Pennington Biomedical Research CenterBaton Rouge, LA, USA
| | - Daniel Rivas
- Lady Davis Institute for Medical Research, McGill University, MontrealQuebec, Canada
| | - Jeffrey M Gimble
- Stem Cell Laboratory, Pennington Biomedical Research CenterBaton Rouge, LA, USA
| | - Gustavo Duque
- Lady Davis Institute for Medical Research, McGill University, MontrealQuebec, Canada
- Aging Bone Research Program, Nepean Clinical School, University of SydneyPenrith, NSW, Australia
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Alexander LS, Mahajan A, Odle J, Flann KL, Rhoads RP, Stahl CH. Dietary phosphate restriction decreases stem cell proliferation and subsequent growth potential in neonatal pigs. J Nutr 2010; 140:477-82. [PMID: 20053936 DOI: 10.3945/jn.109.117390] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Although mesenchymal stem cells (MSC) and satellite cells are essential for postnatal muscle and bone development and phosphate (PO(4)) restriction reduces both muscle and skeletal tissue growth, no research to our knowledge has investigated the possible mechanism by which this mineral may affect early cell programming. Twenty piglets obtained at 1 d of age (1.8 +/- 0.3 kg) received either a PO(4)-adequate diet or a 25% less PO(4)-available diet over a 15-d trial. Feed intake and body weight were recorded daily and blood samples collected every 5 d. After 15 d, pigs were given an intraperitoneal injection of bromodeoxyuridine 4 h prior to tissue collection. As expected, PO(4) deficiency resulted in reduced growth (P < 0.05), feed conversion efficiency (P < 0.05), and bone mineral content (P < 0.05), as well as lower plasma concentrations of both PO(4) (P < 0.01) and parathyroid hormone (P < 0.05). In addition to these classical indicators of PO(4) deficiency, there was also reduced proliferation of both MSC (P < 0.01) and satellite cells (P < 0.05) in vivo. The expression of osteocalcin mRNA in bone marrow was also 2-fold greater (P < 0.01) within the PO(4)-adequate treatment group. These data indicate that in addition to reductions in muscle and bone growth, dietary PO(4) affects proliferation of tissue-specific stem cells in vivo. Nutritional programming of tissue-specific stem cells by dietary PO(4) may have profound implications for life-long growth potential.
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Affiliation(s)
- Lindsey S Alexander
- Laboratory of Developmental Nutrition, Department of Animal Science, North Carolina State University, Raleigh, NC 27695, USA
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