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Wang J, Zhou D, Li R, Sheng S, Li G, Sun Y, Wang P, Mo Y, Liu H, Chen X, Geng Z, Zhang Q, Jing Y, Bai L, Xu K, Su J. Protocol for engineering bone organoids from mesenchymal stem cells. Bioact Mater 2025; 45:388-400. [PMID: 39687559 PMCID: PMC11647664 DOI: 10.1016/j.bioactmat.2024.11.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/12/2024] [Accepted: 11/12/2024] [Indexed: 12/18/2024] Open
Abstract
Bone organoids are emerging as powerful tools for studying bone development and related diseases. However, the simplified design of current methods somewhat limits their application potential, as these methods produce single-tissue organoids that fail to replicate the bone microarchitecture or achieve effective mineralization. To address this issue, we propose a three-dimensional (3D) construction strategy for generating mineralized bone structures using bone marrow-derived mesenchymal stem cells (BMSCs). By mixing BMSCs with hydrogel to create a bone matrix-mimicking bioink and employing projection-based light-curing 3D printing technology, we constructed 3D-printed structures, which were then implanted subcutaneously into nude mice, away from the native bone microenvironment. Even without external stimulation, these implants spontaneously formed mineralized bone domains. With long-term culture, these structures gradually matured into fully differentiated bone tissue, completing both mineralization and vascularization. This in vivo bone organoid model offers a novel platform for studying bone development, exploring congenital diseases, testing drugs, and developing therapeutic applications.
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Affiliation(s)
- Jian Wang
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Trauma Orthopedics Center, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Institute of Musculoskeletal Injury and Translational Medicine of Organoids, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
- School of Medicine, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, 200444, China
| | - Dongyang Zhou
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, 200444, China
| | - Ruiyang Li
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Trauma Orthopedics Center, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Institute of Musculoskeletal Injury and Translational Medicine of Organoids, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Shihao Sheng
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Trauma Orthopedics Center, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Institute of Musculoskeletal Injury and Translational Medicine of Organoids, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Guangfeng Li
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
- School of Medicine, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, 200444, China
- Department of Orthopedics, Shanghai Zhongye Hospital, Shanghai, 200941, China
| | - Yue Sun
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
- School of Medicine, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, 200444, China
| | - Peng Wang
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Trauma Orthopedics Center, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Institute of Musculoskeletal Injury and Translational Medicine of Organoids, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Yulin Mo
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
- School of Medicine, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, 200444, China
| | - Han Liu
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, 200444, China
| | - Xiao Chen
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Trauma Orthopedics Center, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Institute of Musculoskeletal Injury and Translational Medicine of Organoids, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, 200444, China
| | - Zhen Geng
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, 200444, China
| | - Qin Zhang
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, 200444, China
| | - Yingying Jing
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, 200444, China
| | - Long Bai
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, 200444, China
| | - Ke Xu
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, 200444, China
| | - Jiacan Su
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Trauma Orthopedics Center, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Institute of Musculoskeletal Injury and Translational Medicine of Organoids, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, 200444, China
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Wang N, Zuo Z, Meng T, Liu Y, Zheng X, Ma Y. Salidroside alleviates simulated microgravity-induced bone loss by activating the Nrf2/HO-1 pathway. J Orthop Surg Res 2024; 19:531. [PMID: 39218922 PMCID: PMC11367893 DOI: 10.1186/s13018-024-05030-1] [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: 07/11/2024] [Accepted: 08/24/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Bone loss caused by microgravity exposure presents a serious threat to the health of astronauts, but existing treatment strategies have specific restrictions. This research aimed to investigate whether salidroside (SAL) can mitigate microgravity-induced bone loss and its underlying mechanism. METHODS In this research, we used hindlimb unloading (HLU) and the Rotary Cell Culture System (RCCS) to imitate microgravity in vivo and in vitro. RESULTS The results showed that salidroside primarily enhances bone density, microstructure, and biomechanical properties by stimulating bone formation and suppressing bone resorption, thereby preserving bone mass in HLU rats. In MC3T3-E1 cells cultured under simulated microgravity in rotary wall vessel bioreactors, the expression of osteogenic genes significantly increased after salidroside administration, indicating that salidroside can promote osteoblast differentiation under microgravity conditions. Furthermore, the Nrf2 inhibitor ML385 diminished the therapeutic impact of salidroside on microgravity-induced bone loss. Overall, this research provides the first evidence that salidroside can mitigate bone loss induced by microgravity exposure through stimulating the Nrf2/HO-1 pathway. CONCLUSION These findings indicate that salidroside has great potential for treating space-related bone loss in astronauts and suggest that Nrf2/HO-1 is a viable target for counteracting microgravity-induced bone damage.
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Affiliation(s)
- Nan Wang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhuan Zuo
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tong Meng
- Department of Orthopedic Surgery, Xi'an City First Hospital, Xi'an, China
| | - Yuliang Liu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiwei Zheng
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yongsheng Ma
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
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Ma Q, Miri Z, Haugen HJ, Moghanian A, Loca D. Significance of mechanical loading in bone fracture healing, bone regeneration, and vascularization. J Tissue Eng 2023; 14:20417314231172573. [PMID: 37251734 PMCID: PMC10214107 DOI: 10.1177/20417314231172573] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 04/13/2023] [Indexed: 05/31/2023] Open
Abstract
In 1892, J.L. Wolff proposed that bone could respond to mechanical and biophysical stimuli as a dynamic organ. This theory presents a unique opportunity for investigations on bone and its potential to aid in tissue repair. Routine activities such as exercise or machinery application can exert mechanical loads on bone. Previous research has demonstrated that mechanical loading can affect the differentiation and development of mesenchymal tissue. However, the extent to which mechanical stimulation can help repair or generate bone tissue and the related mechanisms remain unclear. Four key cell types in bone tissue, including osteoblasts, osteoclasts, bone lining cells, and osteocytes, play critical roles in responding to mechanical stimuli, while other cell lineages such as myocytes, platelets, fibroblasts, endothelial cells, and chondrocytes also exhibit mechanosensitivity. Mechanical loading can regulate the biological functions of bone tissue through the mechanosensor of bone cells intraosseously, making it a potential target for fracture healing and bone regeneration. This review aims to clarify these issues and explain bone remodeling, structure dynamics, and mechano-transduction processes in response to mechanical loading. Loading of different magnitudes, frequencies, and types, such as dynamic versus static loads, are analyzed to determine the effects of mechanical stimulation on bone tissue structure and cellular function. Finally, the importance of vascularization in nutrient supply for bone healing and regeneration was further discussed.
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Affiliation(s)
- Qianli Ma
- Department of Biomaterials, Institute
of Clinical Dentistry, University of Oslo, Norway
- Department of Immunology, School of
Basic Medicine, Fourth Military Medical University, Xi’an, PR China
| | - Zahra Miri
- Department of Materials Engineering,
Isfahan University of Technology, Isfahan, Iran
| | - Håvard Jostein Haugen
- Department of Biomaterials, Institute
of Clinical Dentistry, University of Oslo, Norway
| | - Amirhossein Moghanian
- Department of Materials Engineering,
Imam Khomeini International University, Qazvin, Iran
| | - Dagnjia Loca
- Rudolfs Cimdins Riga Biomaterials
Innovations and Development Centre, Institute of General Chemical Engineering,
Faculty of Materials Science and Applied Chemistry, Riga Technical University, Riga,
Latvia
- Baltic Biomaterials Centre of
Excellence, Headquarters at Riga Technical University, Riga, Latvia
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Changes in interstitial fluid flow, mass transport and the bone cell response in microgravity and normogravity. Bone Res 2022; 10:65. [PMID: 36411278 PMCID: PMC9678891 DOI: 10.1038/s41413-022-00234-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 08/17/2022] [Accepted: 08/29/2022] [Indexed: 11/22/2022] Open
Abstract
In recent years, our scientific interest in spaceflight has grown exponentially and resulted in a thriving area of research, with hundreds of astronauts spending months of their time in space. A recent shift toward pursuing territories farther afield, aiming at near-Earth asteroids, the Moon, and Mars combined with the anticipated availability of commercial flights to space in the near future, warrants continued understanding of the human physiological processes and response mechanisms when in this extreme environment. Acute skeletal loss, more severe than any bone loss seen on Earth, has significant implications for deep space exploration, and it remains elusive as to why there is such a magnitude of difference between bone loss on Earth and loss in microgravity. The removal of gravity eliminates a critical primary mechano-stimulus, and when combined with exposure to both galactic and solar cosmic radiation, healthy human tissue function can be negatively affected. An additional effect found in microgravity, and one with limited insight, involves changes in dynamic fluid flow. Fluids provide the most fundamental way to transport chemical and biochemical elements within our bodies and apply an essential mechano-stimulus to cells. Furthermore, the cell cytoplasm is not a simple liquid, and fluid transport phenomena together with viscoelastic deformation of the cytoskeleton play key roles in cell function. In microgravity, flow behavior changes drastically, and the impact on cells within the porous system of bone and the influence of an expanding level of adiposity are not well understood. This review explores the role of interstitial fluid motion and solute transport in porous bone under two different conditions: normogravity and microgravity.
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Wang R, Shan H, Zhang G, Li Q, Wang J, Yan Q, Li E, Diao Y, Wei L. An inulin-type fructan (AMP1-1) from Atractylodes macrocephala with anti-weightlessness bone loss activity. Carbohydr Polym 2022; 294:119742. [DOI: 10.1016/j.carbpol.2022.119742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 06/13/2022] [Accepted: 06/14/2022] [Indexed: 11/02/2022]
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Zamarioli A, Adam G, Maupin KA, Childress PJ, Brinker A, Ximenez JPB, Chakraborty N, Gautam A, Hammamieh R, Kacena MA. Systemic effects of BMP2 treatment of fractures on non-injured skeletal sites during spaceflight. Front Endocrinol (Lausanne) 2022; 13:910901. [PMID: 36046782 PMCID: PMC9421301 DOI: 10.3389/fendo.2022.910901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 07/18/2022] [Indexed: 11/17/2022] Open
Abstract
Unloading associated with spaceflight results in bone loss and increased fracture risk. Bone morphogenetic protein 2 (BMP2) is known to enhance bone formation, in part, through molecular pathways associated with mechanical loading; however, the effects of BMP2 during spaceflight remain unclear. Here, we investigated the systemic effects of BMP2 on mice sustaining a femoral fracture followed by housing in spaceflight (International Space Station or ISS) or on Earth. We hypothesized that in spaceflight, the systemic effects of BMP2 on weight-bearing bones would be blunted compared to that observed on Earth. Nine-week-old male mice were divided into four groups: 1) Saline+Earth; 2) BMP+Earth; 3) Saline+ISS; and 4) BMP+ISS (n = 10 mice/group, but only n = 5 mice/group were reserved for micro-computed tomography analyses). All mice underwent femoral defect surgery and were followed for approximately 4 weeks. We found a significant reduction in trabecular separation within the lumbar vertebrae after administering BMP2 at the fracture site of mice housed on Earth. In contrast, BMP2 treatment led to a significant increase in trabecular separation concomitant with a reduction in trabecular number within spaceflown tibiae. Although these and other lines of evidence support our hypothesis, the small sample size associated with rodent spaceflight studies limits interpretations. That said, it appears that a locally applied single dose of BMP2 at the femoral fracture site can have a systemic impact on distant bones, affecting bone quantity in several skeletal sites. Moreover, our results suggest that BMP2 treatment works through a pathway involving mechanical loading in which the best outcomes during its treatment on Earth occurred in the weight-bearing bones and in spaceflight occurred in bones subjected to higher muscle contraction.
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Affiliation(s)
- Ariane Zamarioli
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Orthopaedics and Anaesthesiology, Ribeirão Preto Medical School, São Paulo, Brazil
| | - Gremah Adam
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Kevin A. Maupin
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Paul J. Childress
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Alexander Brinker
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Joao P. B. Ximenez
- Laboratory of Molecular Biology, Blood Center of Ribeirão Preto, Medical School, São Paulo, Brazil
| | - Nabarun Chakraborty
- Medical Readiness Systems Biology, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD, United States
| | - Aarti Gautam
- Medical Readiness Systems Biology, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD, United States
| | - Rasha Hammamieh
- Medical Readiness Systems Biology, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD, United States
| | - Melissa A. Kacena
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States
- *Correspondence: Melissa A. Kacena,
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Crous A, Abrahamse H. The Signalling Effects of Photobiomodulation on Osteoblast Proliferation, Maturation and Differentiation: A Review. Stem Cell Rev Rep 2021; 17:1570-1589. [PMID: 33686595 DOI: 10.1007/s12015-021-10142-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2021] [Indexed: 02/06/2023]
Abstract
Proliferation of osteoblasts is essential for maturation and mineralization of bone matrix. Ossification, the natural phase of bone-forming and hardening is a carefully regulated phase where deregulation of this process may result in insufficient or excessive bone mineralization or ectopic calcification. Osteoblasts can also be differentiated into osteocytes, populating short interconnecting passages within the bone matrix. Over the past few decades, we have seen a significant improvement in awareness and techniques using photobiomodulation (PBM) to stimulate cell function. One of the applications of PBM is the promotion of osteoblast proliferation and maturation. PBM research results on osteoblasts showed increased mitochondrial ATP production, increased osteoblast activity and proliferation, increased and pro-osteoblast expression in the presence of red and NIR radiation. Osteocyte differentiation was also accomplished using blue and green light, showing that different light parameters have various signalling effects. The current review addresses osteoblast function and control, a new understanding of PBM on osteoblasts and its therapeutic impact using various parameters to optimize osteoblast function that may be clinically important. Graphical Abstract.
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Affiliation(s)
- Anine Crous
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, PO Box 17011, Johannesburg, 2028, South Africa.
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, PO Box 17011, Johannesburg, 2028, South Africa
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Feng Y, Liu S, Zha R, Sun X, Li K, Robling A, Li B, Yokota H. Mechanical Loading-Driven Tumor Suppression Is Mediated by Lrp5-Dependent and Independent Mechanisms. Cancers (Basel) 2021; 13:cancers13020267. [PMID: 33450808 PMCID: PMC7828232 DOI: 10.3390/cancers13020267] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/06/2021] [Accepted: 01/07/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Advanced breast cancer and prostate cancer metastasize to varying organs including the bone. We show here that mechanical loading to the knee suppresses tumor growth in the loaded bone and the non-loaded mammary pad. Although lipoprotein receptor-related protein 5 (Lrp5) in osteocytes is necessary to induce loading-driven bone formation, loading-driven tumor suppression is regulated by Lrp5-dependent and independent mechanisms. Lrp5 overexpression in osteocytes enhances tumor suppression, but without Lrp5 in osteocytes, mechanical loading elevates dopamine, chemerin, p53, and TNF-related apoptosis-inducing ligand (TRAIL) and reduces cholesterol and nexin. Their systemic changes contribute to inhibiting tumors without Lrp5. Osteoclast development is also inhibited by the load-driven regulation of chemerin and nexin. Abstract Bone is mechanosensitive and lipoprotein receptor-related protein 5 (Lrp5)-mediated Wnt signaling promotes loading-driven bone formation. While mechanical loading can suppress tumor growth, the question is whether Lrp5 mediates loading-driven tumor suppression. Herein, we examined the effect of Lrp5 using osteocyte-specific Lrp5 conditional knockout mice. All mice presented noticeable loading-driven tumor suppression in the loaded tibia and non-loaded mammary pad. The degree of suppression was more significant in wild-type than knockout mice. In all male and female mice, knee loading reduced cholesterol and elevated dopamine. It reduced tumor-promoting nexin, which was elevated by cholesterol and reduced by dopamine. By contrast, it elevated p53, TNF-related apoptosis-inducing ligand (TRAIL), and chemerin, and they were regulated reversely by dopamine and cholesterol. Notably, Lrp5 overexpression in osteocytes enhanced tumor suppression, and osteoclast development was inhibited by chemerin. Collectively, this study identified Lrp5-dependent and independent mechanisms for tumor suppression. Lrp5 in osteocytes contributed to the loaded bone, while the Lrp5-independent regulation of dopamine- and cholesterol-induced systemic suppression.
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Affiliation(s)
- Yan Feng
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China; (Y.F.); (R.Z.); (X.S.); (K.L.)
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA;
| | - Shengzhi Liu
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA;
| | - Rongrong Zha
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China; (Y.F.); (R.Z.); (X.S.); (K.L.)
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA;
| | - Xun Sun
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China; (Y.F.); (R.Z.); (X.S.); (K.L.)
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA;
| | - Kexin Li
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China; (Y.F.); (R.Z.); (X.S.); (K.L.)
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA;
| | - Alexander Robling
- Department of Anatomy Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Baiyan Li
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China; (Y.F.); (R.Z.); (X.S.); (K.L.)
- Correspondence: (B.L.); (H.Y.); Tel.: +86-451-8667-1354 (B.L.); +317-278-5177 (H.Y.); Fax: +86-451-8667-1354 (B.L.); +317-278-2455 (H.Y.)
| | - Hiroki Yokota
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China; (Y.F.); (R.Z.); (X.S.); (K.L.)
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA;
- Department of Anatomy Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Correspondence: (B.L.); (H.Y.); Tel.: +86-451-8667-1354 (B.L.); +317-278-5177 (H.Y.); Fax: +86-451-8667-1354 (B.L.); +317-278-2455 (H.Y.)
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Tyson J, Bundy K, Roach C, Douglas H, Ventura V, Segars MF, Schwartz O, Simpson CL. Mechanisms of the Osteogenic Switch of Smooth Muscle Cells in Vascular Calcification: WNT Signaling, BMPs, Mechanotransduction, and EndMT. Bioengineering (Basel) 2020; 7:bioengineering7030088. [PMID: 32781528 PMCID: PMC7552614 DOI: 10.3390/bioengineering7030088] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/27/2020] [Accepted: 08/01/2020] [Indexed: 12/16/2022] Open
Abstract
Characterized by the hardening of arteries, vascular calcification is the deposition of hydroxyapatite crystals in the arterial tissue. Calcification is now understood to be a cell-regulated process involving the phenotypic transition of vascular smooth muscle cells into osteoblast-like cells. There are various pathways of initiation and mechanisms behind vascular calcification, but this literature review highlights the wingless-related integration site (WNT) pathway, along with bone morphogenic proteins (BMPs) and mechanical strain. The process mirrors that of bone formation and remodeling, as an increase in mechanical stress causes osteogenesis. Observing the similarities between the two may aid in the development of a deeper understanding of calcification. Both are thought to be regulated by the WNT signaling cascade and bone morphogenetic protein signaling and can also be activated in response to stress. In a pro-calcific environment, integrins and cadherins of vascular smooth muscle cells respond to a mechanical stimulus, activating cellular signaling pathways, ultimately resulting in gene regulation that promotes calcification of the vascular extracellular matrix (ECM). The endothelium is also thought to contribute to vascular calcification via endothelial to mesenchymal transition, creating greater cell plasticity. Each of these factors contributes to calcification, leading to increased cardiovascular mortality in patients, especially those suffering from other conditions, such as diabetes and kidney failure. Developing a better understanding of the mechanisms behind calcification may lead to the development of a potential treatment in the future.
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Simpson LJ, Reader JS, Tzima E. Mechanical Regulation of Protein Translation in the Cardiovascular System. Front Cell Dev Biol 2020; 8:34. [PMID: 32083081 PMCID: PMC7006472 DOI: 10.3389/fcell.2020.00034] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 01/15/2020] [Indexed: 12/12/2022] Open
Abstract
The cardiovascular system can sense and adapt to changes in mechanical stimuli by remodeling the physical properties of the heart and blood vessels in order to maintain homeostasis. Imbalances in mechanical forces and/or impaired sensing are now not only implicated but are, in some cases, considered to be drivers for the development and progression of cardiovascular disease. There is now growing evidence to highlight the role of mechanical forces in the regulation of protein translation pathways. The canonical mechanism of protein synthesis typically involves transcription and translation. Protein translation occurs globally throughout the cell to maintain general function but localized protein synthesis allows for precise spatiotemporal control of protein translation. This Review will cover studies on the role of biomechanical stress -induced translational control in the heart (often in the context of physiological and pathological hypertrophy). We will also discuss the much less studied effects of mechanical forces in regulating protein translation in the vasculature. Understanding how the mechanical environment influences protein translational mechanisms in the cardiovascular system, will help to inform disease pathogenesis and potential areas of therapeutic intervention.
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Affiliation(s)
- Lisa J Simpson
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - John S Reader
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - Ellie Tzima
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
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Frotzler A, Krebs J, Göhring A, Hartmann K, Tesini S, Lippuner K. Osteoporosis in the lower extremities in chronic spinal cord injury. Spinal Cord 2019; 58:441-448. [DOI: 10.1038/s41393-019-0383-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 10/30/2019] [Accepted: 10/30/2019] [Indexed: 12/27/2022]
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González-Durruthy M, Scanavachi G, Rial R, Liu Z, Cordeiro MNDS, Itri R, Ruso JM. Structural and energetic evolution of fibrinogen toward to the betablocker interactions. Int J Biol Macromol 2019; 137:405-419. [PMID: 31265849 DOI: 10.1016/j.ijbiomac.2019.06.229] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 06/10/2019] [Accepted: 06/28/2019] [Indexed: 11/29/2022]
Abstract
We present a computational analysis coupled with experimental studies, focusing on the binding-interaction between beta-adrenoreceptor blocking agents (acebutolol and propranolol) with fibrinogen protein (E-region). Herein, computational modeling on structural validation and flexibility properties of fibrinogen E-region showed that the E-region interacting residues, which form the funnel-shaped hydrophobic cavity for ligand-binding, can be efficiently modeled. The obtained free energy of binding (FEB) values for the docking complexes, namely acebutolol/fibrinogen E-region and propranolol/fibrinogen E-region, were very close and amounted to - 6.9 kcal/mol and - 6.8 kcal/mol, respectively. They were supported by a high binding-accuracy (R.M.S.D < 2 Å) for the best crystallographic binding-poses in both cases. In this regard, we identify a docking-mechanism of interaction for the propranolol and acebutolol mainly based on non-covalent hydrophobic contacts with the fibrinogen E-region binding-site. Besides, the beta-adrenoreceptor blocking agents are able to induce local perturbations affecting particularly the fibrinogen E-region allosteric residues linked to significant changes in the inter-residue communication and flexibility properties of residue network. In this sense, we show that the key biophysical parameters like frequency and collectivity degree may be compromised in different ways by the interaction with acebutolol and propranolol. Isothermal titration calorimetry, zeta potential and small angle X-ray scattering (SAXS) measurements were performed to complete and corroborate computational analysis. The combined experimental results point out that acebutolol acts to a lesser extent to fibrinogen structure than propranolol.
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Affiliation(s)
- Michael González-Durruthy
- Soft Matter and Molecular Biophysics Group, Department of Applied Physics, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; LAQV-REQUIMTE of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Gustavo Scanavachi
- Department of Applied Physics, Institute of Physics, University of São Paulo, SP, Brazil
| | - Ramón Rial
- Soft Matter and Molecular Biophysics Group, Department of Applied Physics, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Zhen Liu
- Department of Physics and Engineering, Frostburg State University, Frostburg, MD 21532, United States
| | - M Natália D S Cordeiro
- LAQV-REQUIMTE of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Rosangela Itri
- Department of Applied Physics, Institute of Physics, University of São Paulo, SP, Brazil
| | - Juan M Ruso
- Soft Matter and Molecular Biophysics Group, Department of Applied Physics, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
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Elmlund AO, Kartus J, Ejerhed L. Bone mineral decreases in the calcanei in men after arthroscopic shoulder surgery: a prospective study over 5 years. Knee Surg Sports Traumatol Arthrosc 2016; 24:3848-3854. [PMID: 26294056 DOI: 10.1007/s00167-015-3760-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 08/11/2015] [Indexed: 01/23/2023]
Abstract
PURPOSE It is well known that injuries and surgical procedures in the lower extremities affect bone mineral both in the injured limb and in the contralateral limb. The possible effect on bone mineral after upper extremity surgery is not well studied, and the aim of this study was to study the effect on bone mineral in the calcanei after arthroscopic shoulder surgery. METHODS Twenty-two men scheduled for arthroscopic shoulder surgery underwent bone mineral area (BMA) mass measurements in both calcanei using the Calscan DXL device prior to surgery and after 6, 18, 36 and 60 months. On every occasion, the Tegner activity score and EuroQoL 5-dimensions (EQ-5D) were assessed. RESULTS During 5 years, there was a significant decrease in the BMA in both calcanei (p = 0.003). The Tegner activity score decreased from preinjury to the operation and did not increase significantly after the operation. The EQ-5D increased significantly after the operation. CONCLUSION The bone mineral in the calcanei in men during the 5-year study period decreased more than the expected age-dependent decline after arthroscopic shoulder surgery. There was an increase in health-related quality of life as measured with the EQ-5D after arthroscopic Bankart reconstruction. LEVEL OF EVIDENCE Case-control study, Level III.
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Affiliation(s)
- Anna O Elmlund
- Department of Research and Development, NU-Hospital Group, SE-461 85, Trollhättan/Uddevalla, Sweden
- Department of Orthopaedics, Danderyd Hospital AB, Stockholm, Sweden
- Institute of Clinical Sciences at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jüri Kartus
- Department of Orthopaedics, NU-Hospital Group, Trollhättan/Uddevalla, Sweden
- Department of Research and Development, NU-Hospital Group, SE-461 85, Trollhättan/Uddevalla, Sweden
- Institute of Clinical Sciences at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lars Ejerhed
- Department of Research and Development, NU-Hospital Group, SE-461 85, Trollhättan/Uddevalla, Sweden.
- Institute of Clinical Sciences at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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Wuermser LA, Beck LA, Lamb JL, Atkinson EJ, Amin S. The effect of low-magnitude whole body vibration on bone density and microstructure in men and women with chronic motor complete paraplegia. J Spinal Cord Med 2015; 38:178-86. [PMID: 24621040 PMCID: PMC4397199 DOI: 10.1179/2045772313y.0000000191] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
OBJECTIVE To examine the effect of low-magnitude whole body vibration on bone density and microstructure in women and men with chronic motor complete paraplegia. METHODS We studied nine subjects (four women and five men) with motor complete paraplegia of 2 years duration or more, age 20-50 years. Subjects were instructed to stand on a low-magnitude vibration plate within a standing frame for 20 minutes per day, 5 days a week, and for 6 months. Bone density at the proximal femur by dual-energy X-ray absorptiometry and bone microstructure at the distal tibia by high-resolution peripheral quantitative computed tomography were assessed at four timepoints over 12 months (baseline, at 3 months and 6 months while on intervention, and after 6 months off intervention). RESULTS Standing on the low-magnitude vibration plate with a standing frame was well tolerated by participants. However, most subjects did not show an improvement in bone density or microstructure after 6 months of intervention, or any relevant changes 6 months following the discontinuation of the low-magnitude vibration. CONCLUSION We were unable to identify an improvement in either bone density or microstructure following 6 months use of a low-magnitude vibration plate in women or men with chronic motor complete paraplegia. Longer duration of use may be necessary, or it is possible that this intervention is of limited benefit following chronic spinal cord injury.
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Affiliation(s)
- Lisa-Ann Wuermser
- Department of Rehabilitation Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Lisa A. Beck
- Department of Physical Medicine and Rehabilitation, College of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Jeffry L. Lamb
- Department of Physical Medicine and Rehabilitation, College of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Elizabeth J. Atkinson
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Shreyasee Amin
- Correspondence to: Shreyasee Amin, Division of Rheumatology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
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Cao Q, Zhang J, Liu H, Wu Q, Chen J, Chen GQ. The mechanism of anti-osteoporosis effects of 3-hydroxybutyrate and derivatives under simulated microgravity. Biomaterials 2014; 35:8273-83. [DOI: 10.1016/j.biomaterials.2014.06.020] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 06/09/2014] [Indexed: 10/25/2022]
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Spyropoulou A, Basdra EK. Mechanotransduction in bone: Intervening in health and disease. World J Exp Med 2013; 3:74-86. [DOI: 10.5493/wjem.v3.i4.74] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 09/06/2013] [Accepted: 11/03/2013] [Indexed: 02/06/2023] Open
Abstract
Mechanotransduction has been proven to be one of the most significant variables in bone remodeling and its alterations have been shown to result in a variety of bone diseases. Osteoporosis, Paget’s disease, orthopedic disorders, osteopetrosis as well as hyperparathyroidism and hyperthyroidism all comprise conditions which have been linked with deregulated bone remodeling. Although the significance of mechanotransduction for bone health and disease is unquestionable, the mechanisms behind this important process have not been fully understood. This review will discuss the molecules that have been found to be implicated in mechanotransduction, as well as the mechanisms underlying bone health and disease, emphasizing on what is already known as well as new molecules potentially taking part in conveying mechanical signals from the cell surface towards the nucleus under physiological or pathologic conditions. It will also focus on the model systems currently used in mechanotransduction studies, like osteoblast-like cells as well as three-dimensional constructs and their applications among others. It will also examine the role of mechanostimulatory techniques in preventing and treating bone degenerative diseases and consider their applications in osteoporosis, craniofacial development, skeletal deregulations, fracture treatment, neurologic injuries following stroke or spinal cord injury, dentistry, hearing problems and bone implant integration in the near future.
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A rehabilitation exercise program induces severe bone mineral deficits in estrogen-deficient rats after extended disuse. Menopause 2013; 19:1267-76. [PMID: 22713863 DOI: 10.1097/gme.0b013e318255657f] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
OBJECTIVE Both estrogen and mechanical loading regulate bone maintenance. However, mechanical overload seems less effective in enhancing bone mineral density (BMD) in estrogen-deficient women. The aim of this study was to determine whether estradiol (E2) influences early-phase bone adaptations to reambulation (REAMB) and/or rehabilitation exercises after hindlimb unloading (HLU) of ovariectomized rats. METHODS Eighty-one 5-month-old female Sprague-Dawley rats were randomized into the following groups: (1) intact controls, (2) ovariectomy (OVX), (3) OVX + E2, (4) OVX + 4 weeks of HLU, (5) OVX + E2 + HLU, (6) OVX + HLU + 2 weeks of quadrupedal REAMB, (7) OVX + E2 + HLU + REAMB, (8) OVX + HLU + REAMB + supplemental climbing, jumping, and balance exercises (EX), or (9) OVX + E2 + HLU + REAMB + EX. Serial dual-energy x-ray absorptiometry scans were performed to track total body bone characteristics throughout the study, and peripheral quantitative computerized tomography was used to determine distal femoral metaphyseal bone mineral characteristics. RESULTS Total body BMD increased by 4% to 8% in all animals receiving supplemental E2, whereas BMD did not change in animals without E2. OVX reduced trabecular BMD at the femoral metaphysis, and HLU exacerbated this loss while also reducing cortical BMD. E2 protected against OVX + HLU-induced bone loss at the femoral metaphysis. Conversely, REAMB did not alter BMD, regardless of estrogen status. In the absence of E2, REAMB + EX resulted in severe bone loss after OVX + HLU, with trabecular BMD and cortical BMD measurements that were 91% and 7% below those of controls, respectively (P ≤ 0.001). However, in the presence of E2, REAMB + EX did not negatively influence bone mineral characteristics. CONCLUSIONS E2 protects against bone loss resulting from combined OVX + HLU of rodents. In the absence of estrogen, exercise induces disadvantageous early-phase bone adaptations after extended disuse.
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Chang G, Rajapakse CS, Diamond M, Honig S, Recht MP, Weiss DS, Regatte RR. Micro-finite element analysis applied to high-resolution MRI reveals improved bone mechanical competence in the distal femur of female pre-professional dancers. Osteoporos Int 2013; 24:1407-17. [PMID: 22893356 PMCID: PMC3719856 DOI: 10.1007/s00198-012-2105-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Accepted: 07/10/2012] [Indexed: 02/07/2023]
Abstract
UNLABELLED Micro-finite element analysis applied to high-resolution (0.234-mm length scale) MRI reveals greater whole and cancellous bone stiffness, but not greater cortical bone stiffness, in the distal femur of female dancers compared to controls. Greater whole bone stiffness appears to be mediated by cancellous, rather than cortical bone adaptation. INTRODUCTION The purpose of this study was to compare bone mechanical competence (stiffness) in the distal femur of female dancers compared to healthy, relatively inactive female controls. METHODS This study had institutional review board approval. We recruited nine female modern dancers (25.7±5.8 years, 1.63±0.06 m, 57.1±4.6 kg) and ten relatively inactive, healthy female controls matched for age, height, and weight (32.1±4.8 years, 1.6±0.04 m, 55.8±5.9 kg). We scanned the distal femur using a 7-T MRI scanner and a three-dimensional fast low-angle shot sequence (TR/TE=31 ms/5.1 ms, 0.234 mm×0.234 mm×1 mm, 80 slices). We applied micro-finite element analysis to 10-mm-thick volumes of interest at the distal femoral diaphysis, metaphysis, and epiphysis to compute stiffness and cross-sectional area of whole, cortical, and cancellous bone, as well as cortical thickness. We applied two-tailed t-tests and ANCOVA to compare groups. RESULTS Dancers demonstrated greater whole and cancellous bone stiffness and cross-sectional area at all locations (p<0.05). Cortical bone stiffness, cross-sectional area, and thickness did not differ between groups (>0.08). At all locations, the percent of intact whole bone stiffness for cortical bone alone was lower in dancers (p<0.05). Adjustment for cancellous bone cross-sectional area eliminated significant differences in whole bone stiffness between groups (p>0.07), but adjustment for cortical bone cross-sectional area did not (p<0.03). CONCLUSIONS Modern dancers have greater whole and cancellous bone stiffness in the distal femur compared to controls. Elevated whole bone stiffness in dancers may be mediated via cancellous, rather than cortical bone adaptation.
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Affiliation(s)
- G Chang
- Quantitative Multinuclear Musculoskeletal Imaging Group, Center for Biomedical Imaging, NYU Langone Medical Center, 660 First Avenue, 2nd Floor, New York, NY 10016, USA.
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Colman RJ, Beasley TM, Allison DB, Weindruch R. Skeletal effects of long-term caloric restriction in rhesus monkeys. AGE (DORDRECHT, NETHERLANDS) 2012; 34:1133-43. [PMID: 22189911 PMCID: PMC3448987 DOI: 10.1007/s11357-011-9354-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Accepted: 12/01/2011] [Indexed: 05/31/2023]
Abstract
Age-related bone loss is well established in humans and is known to occur in nonhuman primates. There is little information, however, on the effect of dietary interventions, such as caloric restriction (CR), on age-related bone loss. This study examined the effects of long-term, moderate CR on skeletal parameters in rhesus monkeys. Thirty adult male rhesus monkeys were subjected to either a restricted (R, n = 15) or control (C, n = 15) diet for 20 years and examined throughout for body composition and biochemical markers of bone turnover. Total body, spine, and radius bone mass and density were assessed by dual-energy X-ray absorptiometry. Assessment of biochemical markers of bone turnover included circulating serum levels of osteocalcin, carboxyterminal telopeptide of type I collagen, cross-linked aminoterminal telopeptide of type I collagen, parathyroid hormone, and 25(OH)vitamin D. Overall, we found that bone mass and density declined over time with generally higher levels in C compared to R animals. Circulating serum markers of bone turnover were not different between C and R with nonsignficant diet-by-time interactions. We believe the lower bone mass in R animals reflects the smaller body size and not pathological osteopenia.
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Affiliation(s)
- Ricki J Colman
- Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA.
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Weight bearing through lower limbs in a standing frame with and without arm support and low-magnitude whole-body vibration in men and women with complete motor paraplegia. Am J Phys Med Rehabil 2012; 91:300-8. [PMID: 22407161 DOI: 10.1097/phm.0b013e31824aab03] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
OBJECTIVE The aim of the study was to determine the proportion of body weight borne through the lower limbs in persons with complete motor paraplegia using a standing frame, with and without the support of their arms. We also examined the effect of low-magnitude whole-body vibration on loads borne by the lower limbs. DESIGN Vertical ground reaction forces (GRFs) were measured in 11 participants (six men and five women) with paraplegia of traumatic origin (injury level T3-T12) standing on a low-magnitude vibrating plate using a standing frame. GRFs were measured in four conditions: (1) no vibration with arms on standing frame tray, (2) no vibration with arms at side, (3) vibration with arms on tray, and (4) vibration with arms at side. RESULTS GRF with arms on tray, without vibration, was 0.76 ± 0.07 body weight. With arms at the side, GRF increased to 0.85 ± 0.12 body weight. With vibration, mean GRF did not significantly differ from no-vibration conditions for either arm positions. Oscillation of GRF with vibration was significantly different from no-vibration conditions (P < 0.001) but similar in both arm positions. CONCLUSIONS Men and women with paraplegia using a standing frame bear most of their weight through their lower limbs. Supporting their arms on the tray reduces the GRF by approximately 10% body weight. Low-magnitude vibration provided additional oscillation of the load-bearing forces and was proportionally similar regardless of arm position.
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Lenertz LY, Gavala ML, Zhu Y, Bertics PJ. Transcriptional control mechanisms associated with the nucleotide receptor P2X7, a critical regulator of immunologic, osteogenic, and neurologic functions. Immunol Res 2011; 50:22-38. [PMID: 21298493 PMCID: PMC3203638 DOI: 10.1007/s12026-011-8203-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
The nucleotide receptor P2X(7) is an attractive therapeutic target and potential biomarker for multiple inflammatory and neurologic disorders, and it is expressed in several immune, osteogenic, and neurologic cell types. Aside from its role in the nervous system, it is activated by ATP released at sites of tissue damage, inflammation, and infection. Ligand binding to P2X(7) stimulates many cell responses, including calcium fluxes, MAPK activation, inflammatory mediator release, and apoptosis. Much work has centered on P2X(7) action in cell death and mediator processing (e.g., pro-interleukin-1 cleavage by the inflammasome), but the contribution of P2X(7) to transcriptional regulation is less well defined. This review will focus on the growing evidence for the importance of nucleotide-mediated gene expression, highlight several animal models, human genetic, and clinical studies that support P2X(7) as a therapeutic target, and discuss the latest developments in anti-P2X(7) clinical trials.
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Affiliation(s)
- Lisa Y. Lenertz
- Department of Biomolecular Chemistry, School of Medicine and Public Health, The University of Wisconsin-Madison, Madison, Wisconsin 53706
| | - Monica L. Gavala
- Department of Biomolecular Chemistry, School of Medicine and Public Health, The University of Wisconsin-Madison, Madison, Wisconsin 53706
| | - Yiming Zhu
- Department of Biomolecular Chemistry, School of Medicine and Public Health, The University of Wisconsin-Madison, Madison, Wisconsin 53706
| | - Paul J. Bertics
- Department of Biomolecular Chemistry, School of Medicine and Public Health, The University of Wisconsin-Madison, Madison, Wisconsin 53706
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Klika V. Comparison of the effects of possible mechanical stimuli on the rate of biochemical reactions. J Phys Chem B 2010; 114:10567-72. [PMID: 20701387 DOI: 10.1021/jp1000072] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The aim of this work is to address the question of what constitutes a mechanical stimulation of biochemical reactions in general and further to compare the importance of the two possible mechanical stimulations: shear rate and the rate of volume variation. Using linear nonequilibrium thermodynamics, the Curie principle (the relation for coupling phenomena) is retrieved for a phenomenological relation for a scalar flux in an isotropic system. From these phenomenological relations for the rate of chemical reaction, it is established that the only scalar quantity related to the rate of deformation tensor D that cannot be neglected is the rate of volume variation D((1)). This leads us to the conclusion that, although tissues are exposed to all variety of mechanical factors: straining, shear, pressure, and even dynamic electric fields, the volume variation rate D((1)) is the most important mechanical stimulus driving the processes in them.
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Affiliation(s)
- Václav Klika
- Department of Mathematics, FNSPE, Czech Technical University in Prague, Trojanova 13, 120 00 Prague, Czech Republic.
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