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Xiao P, Liu J, Du C, Cheng S, Liu S, Liu J, Zhan J, Chen Z, Yang Y, Lei Y, Huang W, Zhao C. Injectable mineralized hydrogel microspheres for accelerated osteocyte network reconstruction and intelligent bone regeneration. J Control Release 2025; 380:240-255. [PMID: 39909282 DOI: 10.1016/j.jconrel.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/18/2025] [Accepted: 02/02/2025] [Indexed: 02/07/2025]
Abstract
The disruption and limited reconstruction capacity of the osteocyte network are pivotal factors underlying impaired bone regeneration. This study developed an injectable mineralized hydrogel microsphere that provides a mineral-rich environment and optimal matrix stiffness for osteocyte network restoration. Furthermore, it spatially activates Notch signaling through osteocyte-derived vesicles with high Jagged1 expression, promoting osteocyte differentiation and enhancing angiogenic regulatory function. Specifically, hydrogel microspheres combining gelatin methacrylate (GelMA), alginate methacrylate (AlgMA), and osteocyte membrane vesicles (OMVs) were fabricated via gas-shear microfluidics and photopolymerization, followed by in situ pre-mineralization to produce mineralized microspheres. Findings indicate that mineralized hydrogel microspheres exhibit significantly increased compressive modulus and in situ formation of amorphous calcium phosphate particles within the gel matrix. In vitro, the mineralized microspheres effectively facilitated osteogenic differentiation in bone marrow-derived mesenchymal stem cells (BMSCs), with adherent cells displaying accelerated osteocyte marker expression. Co-culture experiments further revealed enhanced vascular formation potential. Ectopic bone regeneration studies demonstrated that mineralized hydrogel microspheres promote rapid formation of mature osteocyte networks in vivo. Moreover, in a femoral critical bone defect model, these microspheres accelerated defect healing. Collectively, mineralized hydrogel microspheres expedite osteocyte network reconstruction, supporting intelligent bone regeneration, and present a promising approach for critical-sized bone defect repair.
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Affiliation(s)
- Pengcheng Xiao
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, 400016 Chongqing, PR China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, PR China
| | - Junyan Liu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, 400016 Chongqing, PR China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, PR China
| | - Chengcheng Du
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, 400016 Chongqing, PR China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, PR China
| | - Shengwen Cheng
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, 400016 Chongqing, PR China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, PR China
| | - Senrui Liu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, 400016 Chongqing, PR China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, PR China
| | - Jiacheng Liu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, 400016 Chongqing, PR China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, PR China
| | - Jingdi Zhan
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, 400016 Chongqing, PR China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, PR China
| | - Zhuolin Chen
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, 400016 Chongqing, PR China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, PR China
| | - Yaji Yang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, 400016 Chongqing, PR China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, PR China
| | - Yiting Lei
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, 400016 Chongqing, PR China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, PR China; Department of Biomedical Engineering, The Chinese University of Hong Kong, NT 999077, Hong Kong Special Administrative Region.
| | - Wei Huang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, 400016 Chongqing, PR China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, PR China.
| | - Chen Zhao
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, 400016 Chongqing, PR China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, PR China.
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Jeon HH, Huang X, Rojas Cortez L, Sripinun P, Lee JM, Hong JJ, Graves DT. Inflammation and mechanical force-induced bone remodeling. Periodontol 2000 2024. [PMID: 39740162 DOI: 10.1111/prd.12619] [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: 01/25/2024] [Revised: 09/25/2024] [Accepted: 10/27/2024] [Indexed: 01/02/2025]
Abstract
Periodontitis arises from imbalanced host-microbe interactions, leading to dysbiosis and destructive inflammation. The host's innate and adaptive immune responses produce pro-inflammatory mediators that stimulate destructive events, which cause loss of alveolar bone and connective tissue attachment. There is no consensus on the factors that lead to a conversion from gingivitis to periodontitis, but one possibility is the proximity of the inflammation to the bone, which promotes bone resorption and inhibits subsequent bone formation during coupled bone formation. Conversely, orthodontic tooth movement is triggered by the mechanical force applied to the tooth, resulting in bone resorption on the compression side and new bone formation on the tension side. However, the environment around orthodontic brackets readily retains dental plaque and may contribute to inflammation and bone remodeling. The immune, epithelial, stromal, endothelial and bone cells of the host play an important role in setting the stage for bone remodeling that occurs in both periodontitis and orthodontic tooth movement. Recent advancements in single-cell RNA sequencing have provided new insights into the roles and interactions of different cell types in response to challenges. In this review, we meticulously examine the functions of key cell types such as keratinocytes, leukocytes, stromal cells, osteocytes, osteoblasts, and osteoclasts involved in inflammation- and mechanical force-driven bone remodeling. Moreover, we explore the combined effects of these two conditions: mechanical force-induced bone remodeling combined with periodontal disease (chronic inflammation) and periodontally accelerated osteogenic orthodontics (acute transient inflammation). This comprehensive review enhances our understanding of inflammation- and mechanical force-induced bone remodeling.
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Affiliation(s)
- Hyeran Helen Jeon
- Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Xin Huang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Leticia Rojas Cortez
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Puttipong Sripinun
- Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Muang, Chiang Mai, Thailand
| | - Jung-Me Lee
- Division of Nutritional Sciences, College of Human Ecology, Cornell University, Ithaca, New York, USA
| | - Julie J Hong
- Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Dana T Graves
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Bernero M, Zauchner D, Müller R, Qin XH. Interpenetrating network hydrogels for studying the role of matrix viscoelasticity in 3D osteocyte morphogenesis. Biomater Sci 2024; 12:919-932. [PMID: 38231154 PMCID: PMC10863643 DOI: 10.1039/d3bm01781h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 01/08/2024] [Indexed: 01/18/2024]
Abstract
During bone formation, osteoblasts are embedded in a collagen-rich osteoid tissue and differentiate into an extensive 3D osteocyte network throughout the mineralizing matrix. However, how these cells dynamically remodel the matrix and undergo 3D morphogenesis remains poorly understood. Although previous reports investigated the impact of matrix stiffness in osteocyte morphogenesis, the role of matrix viscoelasticity is often overlooked. Here, we report a viscoelastic alginate-collagen interpenetrating network (IPN) hydrogel for 3D culture of murine osteocyte-like IDG-SW3 cells. The IPN hydrogels consist of an ionically crosslinked alginate network to tune stress relaxation as well as a permissive collagen network to promote cell adhesion and matrix remodeling. Two IPN hydrogels were developed with comparable stiffnesses (4.4-4.7 kPa) but varying stress relaxation times (t1/2, 1.5 s and 14.4 s). IDG-SW3 cells were pre-differentiated in 2D under osteogenic conditions for 14 days to drive osteoblast-to-osteocyte transition. Cellular mechanosensitivity to fluid shear stress (2 Pa) was confirmed by live-cell calcium imaging. After embedding in the IPN hydrogels, cells remained highly viable following 7 days of 3D culture. After 24 h, osteocytes in the fast-relaxing hydrogels showed the largest cell area and long dendritic processes. However, a significantly larger increase of some osteogenic markers (ALP, Dmp1, hydroxyapatite) as well as intercellular connections via gap junctions were observed in slow-relaxing hydrogels on day 14. Our results imply that fast-relaxing IPN hydrogels promote early cell spreading, whereas slow relaxation favors osteogenic differentiation. These findings may advance the development of 3D in vivo-like osteocyte models to better understand bone mechanobiology.
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Affiliation(s)
| | | | - Ralph Müller
- Institute for Biomechanics, ETH Zürich, Switzerland.
| | - Xiao-Hua Qin
- Institute for Biomechanics, ETH Zürich, Switzerland.
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Atria PJ, Castillo AB. Skeletal adaptation to mechanical cues during homeostasis and repair: the niche, cells, and molecular signaling. Front Physiol 2023; 14:1233920. [PMID: 37916223 PMCID: PMC10616261 DOI: 10.3389/fphys.2023.1233920] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 10/02/2023] [Indexed: 11/03/2023] Open
Abstract
Bones constantly change and adapt to physical stress throughout a person's life. Mechanical signals are important regulators of bone remodeling and repair by activating skeletal stem and progenitor cells (SSPCs) to proliferate and differentiate into bone-forming osteoblasts using molecular signaling mechanisms not yet fully understood. SSPCs reside in a dynamic specialized microenvironment called the niche, where external signals integrate to influence cell maintenance, behavior and fate determination. The nature of the niche in bone, including its cellular and extracellular makeup and regulatory molecular signals, is not completely understood. The mechanisms by which the niche, with all of its components and complexity, is modulated by mechanical signals during homeostasis and repair are virtually unknown. This review summarizes the current view of the cells and signals involved in mechanical adaptation of bone during homeostasis and repair, with an emphasis on identifying novel targets for the prevention and treatment of age-related bone loss and hard-to-heal fractures.
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Affiliation(s)
- Pablo J. Atria
- Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, NY, United States
| | - Alesha B. Castillo
- Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, NY, United States
- Department of Biomedical Engineering, New York University Tandon School of Engineering, New York, NY, United States
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Wang Y, Dong H, Yan Y, Yu J, Wu X, Wang Y, Xue Y, Wang X, Wei X, Li P, Chen W. Biomechanical analysis of a lacunar-canalicular system under different cyclic displacement loading. Comput Methods Biomech Biomed Engin 2023; 26:1806-1821. [PMID: 36377250 DOI: 10.1080/10255842.2022.2145889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 11/01/2022] [Indexed: 11/16/2022]
Abstract
The objective of this study is to use the finite element (FE) method to predict the mechanical signals (interstitial fluid velocity, strain, pore pressure, and pore fluid velocity) produced by osteocyte during physiological activities. The model predicts that the amplitude and distribution of the mechanical signals are mainly affected by the loading rate. The magnitude of mechanical signals in the lacunar-canalicular system increases as the amplitude, frequency and amount of direction of load increase. Collagen hillocks can effectively amplify strain signals at the process. The established model can be used for studying the mechanism of bone mechanotransduction at the micro-level.
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Affiliation(s)
- Yan Wang
- College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan, China
| | - Hao Dong
- College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan, China
| | - Yang Yan
- College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan, China
| | - Jianhao Yu
- College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan, China
| | - Xiaogang Wu
- College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan, China
- Shanxi Provincial Key Laboratory for Repair of Bone and Soft Tissue Injury, Second hospital of Shanxi Medical University, Taiyuan, China
| | - Yanqin Wang
- College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan, China
| | - Yanru Xue
- College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan, China
| | - Xiyu Wang
- College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan, China
| | - Xiaochun Wei
- Shanxi Provincial Key Laboratory for Repair of Bone and Soft Tissue Injury, Second hospital of Shanxi Medical University, Taiyuan, China
| | - Pengcui Li
- Shanxi Provincial Key Laboratory for Repair of Bone and Soft Tissue Injury, Second hospital of Shanxi Medical University, Taiyuan, China
| | - Weiyi Chen
- College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan, China
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Zheng C, Liu H, Zhao P, Lu W, Song S, He T, Fan J, Wang D, Yang P, Jie Q, Zheng HF, Luo Z, Yang L. Targeting sulfation-dependent mechanoreciprocity between matrix and osteoblasts to mitigate bone loss. Sci Transl Med 2023; 15:eadg3983. [PMID: 37611084 DOI: 10.1126/scitranslmed.adg3983] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Accepted: 08/04/2023] [Indexed: 08/25/2023]
Abstract
Sulfation is a widespread modification of biomolecules that has been incompletely explored to date. Through cross-phenotype meta-analysis of bone mineral density in up to 426,824 genotyped human participants along with phenotypic characterization of multiple mutant mouse lines, we identified a causative role for sulfate transporter solute carrier family 26 member A2 (SLC26A2) deficiency in osteoporosis. Ablation of SLC26A2 in osteoblasts caused severe bone loss and accumulation of immature bone cells and elicited peculiar pericellular matrix (PCM) production characterized by undersulfation coupled with decreased stiffness. These altered chemophysical properties of the PCM disrupted the formation of focal adhesions in osteoblasts. Bulk RNA sequencing and functional assays revealed that the mechanoreciprocal inhibition of focal adhesion kinase (FAK) and Yes1-associated transcriptional regulator (YAP)/WW domain containing transcription regulator 1 (TAZ) signaling impinged osteoblast maturation upon SLC26A2 deficiency. Moreover, pharmacological abrogation of the Hippo kinases and forced wheel-running ameliorated SLC26A2-deficient osteoporosis by promoting YAP/TAZ activity. Analysis of mouse single-cell RNA sequencing data suggested coordination among sulfate metabolism, focal adhesion, and YAP/TAZ activity during osteoblast-to-osteocyte transition. In addition to the SLC26A2-deficient setting, altered FAK and YAP/TAZ signaling was also observed in bone cells of ovariectomized mice and patients with osteoporosis, and pharmacological enforcing of YAP/TAZ activity ameliorated bone loss in ovariectomized mice. Collectively, these data unveil a role for sulfation in the developmental mechanoreciprocity between matrix and osteoblasts, which could be leveraged to prevent bone loss.
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Affiliation(s)
- Chao Zheng
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - He Liu
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Pianpian Zhao
- Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University, Hangzhou 310030, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China
| | - Weiguang Lu
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Shiju Song
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Ting He
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Jing Fan
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Di Wang
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Pengfei Yang
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China
| | - Qiang Jie
- Department of Orthopedic Surgery, Hong Hui Hospital, Xi'an Jiaotong University, College of Medicine, Xi'an 710049, China
- Research Center for Skeletal Developmental Deformity and Injury repair, College of Life Science and Medicine, Northwest University, Xi'an 710069, China
| | - Hou-Feng Zheng
- Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University, Hangzhou 310030, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China
| | - Zhuojing Luo
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
- Medical Research Institute, Northwestern Polytechnical University, Xi'an 710072, China
| | - Liu Yang
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
- Medical Research Institute, Northwestern Polytechnical University, Xi'an 710072, China
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Wang H, Zhang C, Zhu S, Gao C, Gao Q, Huang R, Liu S, Wei X, Zhang H, Wei Q, He C. Low-frequency whole-body vibration can enhance cartilage degradation with slight changes in subchondral bone in mice with knee osteoarthritis and does not have any morphologic effect on normal joints. PLoS One 2023; 18:e0270074. [PMID: 37590222 PMCID: PMC10434961 DOI: 10.1371/journal.pone.0270074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 07/20/2023] [Indexed: 08/19/2023] Open
Abstract
PURPOSES To evaluate the effects of low frequency whole-body vibration (WBV) on degeneration of articular cartilage and subchondral bone in mice with destabilization of the medial meniscus (DMM)induced osteoarthritis(OA) and mice with normal knee. METHODS Ten-week-old C57BL/6J male mice received DMM on right knees, while the left knees performed sham operation. There were six groups: DMM, SHAM DMM, DMM+WBV,SHAM DMM+WBV, DMM+ NON-WBV and SHAM DMM+NON-WBV. After four weeks, the knees were harvested from the DMM and SHAM DMM group. The remaining groups were treated with WBV (10 Hz) or NON-WBV. Four weeks later, the knees were harvested. Genes, containing Aggrecan(Acan) and CollagenⅡ(Col2a1), Matrix Metalloproteinases 3 and 13(MMP3,13), TNFα and IL6, were measured and staining was also performed. OA was graded with OARSI scores, and tibial plateaubone volume to tissue volume ratio(BV/TV), bone surface area to bone volume ratio (BS/BV), trabecular number(Tb.N) and trabecular thickness separation(TS) between groups were analyzed. RESULTS Increased OARSI scores and cartilage degradation were observed after WBV. BV/TV, Tb.N and TS were not significant between the groups. Significant reductions were observed in MMP3, MMP13, Col2a1, Acan, TNFα and IL6 in the DMM+WBV compared to SHAM DMM+WBV group. BV/TV, BS/BV, Tb.N, TS and OARSI scores were not significantly changed in the left knees. IL6 expression in the SHAM DMM+WBV group was significantly increased compared with the SHAM DMM+ NON-WBV group, while Col2a1, Acan and MMP13 expression decreased. CONCLUSION WBV accelerated cartilage degeneration and caused slight changes in subchondral bone in a DMM-induced OA model. WBV had no morphologic effect on normal joints.
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Affiliation(s)
- Haiming Wang
- Rehabilitation Medicine Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Center of Rehabilitation Engineering Technology Research, Henan Province, Zhengzhou, Henan, China
| | - Chi Zhang
- Rehabilitation Medicine Department, The Affiliated Hospital Of Southwest Medical University, Luzhou, Sichuan, China
- Department of Rehabilitation Medicine, Southwest Medical University, Luzhou, Sichuan, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, China
| | - Siyi Zhu
- Rehabilitation Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Rehabilitation Medicine Key Laboratory of Sichuan Province, Sichuan University, Chengdu, Sichuan, China
| | - Chengfei Gao
- Rehabilitation Medicine Department, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong, China
| | - Qiang Gao
- Rehabilitation Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Rehabilitation Medicine Key Laboratory of Sichuan Province, Sichuan University, Chengdu, Sichuan, China
| | - Ridong Huang
- Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Sijia Liu
- Rehabilitation Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Rehabilitation Medicine Key Laboratory of Sichuan Province, Sichuan University, Chengdu, Sichuan, China
| | - Xiangyang Wei
- Rehabilitation Medicine Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Center of Rehabilitation Engineering Technology Research, Henan Province, Zhengzhou, Henan, China
| | - Huakai Zhang
- Medical College of Zhengzhou University of Industrial technology, Zhengzhou, Henan, China
| | - Quan Wei
- Rehabilitation Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Rehabilitation Medicine Key Laboratory of Sichuan Province, Sichuan University, Chengdu, Sichuan, China
| | - Chengqi He
- Rehabilitation Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Rehabilitation Medicine Key Laboratory of Sichuan Province, Sichuan University, Chengdu, Sichuan, China
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Matthews M, Cook E, Naguib N, Wiesner U, Lewis K. Intravital imaging of osteocyte integrin dynamic with locally injectable fluorescent nanoparticles. Bone 2023:116830. [PMID: 37327917 DOI: 10.1016/j.bone.2023.116830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 06/05/2023] [Accepted: 06/13/2023] [Indexed: 06/18/2023]
Abstract
Osteocytes are the resident mechanosensory cells in bone. They are responsible for skeletal homeostasis and adaptation to mechanical cues. Integrin proteins play a prominent role in osteocyte mechanotransduction, but the details are not well stratified. Intravital imaging with multiphoton microscopy presents an opportunity to study molecular level mechanobiological events in vivo and presents an opportunity to study integrin dynamics in osteocytes. However, fluorescent imaging limitations with respect to excessive optical scattering and low signal to noise ratio caused by mineralized bone matrix make such investigations non-trivial. Here, we demonstrate that ultra-small and bright fluorescent core-shell silica nanoparticles (<7 nm diameter), known as Cornell Prime Dots (C'Dots), are well-suited for the in vivo bone microenvironment and can improve intravital imaging capabilities. We report validation studies for C'Dots as a novel, locally injectable in vivo osteocyte imaging tool for both non-specific cellular uptake and for targeting integrins. The pharmacokinetics of C'Dots reveal distinct sex differences in nanoparticle intracellular dynamics and clearance in osteocytes, which represents a novel topic of study in bone biology. Integrin-targeted C'Dots were used to study osteocyte integrin dynamics. To the best of our knowledge, we report here the first evidence of osteocyte integrin endocytosis and recycling in vivo. Our results provide novel insights in osteocyte biology and will open up new lines of investigation that were previously unavailable in vivo.
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Affiliation(s)
- Melia Matthews
- Department of Biomedical Engineering, Cornell University, 237 Tower Rd, Ithaca 14850, NY, USA
| | - Emily Cook
- Department of Biomedical Engineering, Cornell University, 237 Tower Rd, Ithaca 14850, NY, USA
| | - Nada Naguib
- Department of Biomedical Engineering, Cornell University, 237 Tower Rd, Ithaca 14850, NY, USA
| | - Uli Wiesner
- Department of Materials Science and Engineering, Cornell University, Bard Hall 210, Ithaca 14850, NY, USA
| | - Karl Lewis
- Department of Biomedical Engineering, Cornell University, 237 Tower Rd, Ithaca 14850, NY, USA.
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Alam K, Qamar SZ, Iqbal M, Piya S, Al-Kindi M, Qureshi A, Al-Ghaithi A, Al-Sumri B, Silberschmidt VV. Effect of drill quality on biological damage in bone drilling. Sci Rep 2023; 13:6234. [PMID: 37069203 PMCID: PMC10110507 DOI: 10.1038/s41598-023-33381-y] [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: 01/16/2022] [Accepted: 04/12/2023] [Indexed: 04/19/2023] Open
Abstract
Bone drilling is a universal procedure in orthopaedics for fracture fixation, installing implants, or reconstructive surgery. Surgical drills are subjected to wear caused by their repeated use, thermal fatigue, irrigation with saline solution, and sterilization process. Wear of the cutting edges of a drill bit (worn drill) is detrimental for bone tissues and can seriously affect its performance. The aim of this study is to move closer to minimally invasive surgical procedures in bones by investigating the effect of wear of surgical drill bits on their performance. The surface quality of the drill was found to influence the bone temperature, the axial force, the torque and the extent of biological damage around the drilling region. Worn drill produced heat above the threshold level related to thermal necrosis at a depth equal to the wall thickness of an adult human bone. Statistical analysis showed that a sharp drill bit, in combination with a medium drilling speed and drilling at shallow depth, was favourable for safe drilling in bone. This study also suggests the further research on establishing a relationship between surface integrity of a surgical drill bit and irreversible damage that it can induce in delicate tissues of bone using different drill sizes as well as drilling parameters and conditions.
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Affiliation(s)
- Khurshid Alam
- Department of Mechanical and Industrial Engineering, College of Engineering, Sultan Qaboos University, P.O. Box 33, Al-Khoud, 123, Sultanate of Oman.
| | - Sayyad Zahid Qamar
- Department of Mechanical and Industrial Engineering, College of Engineering, Sultan Qaboos University, P.O. Box 33, Al-Khoud, 123, Sultanate of Oman
| | - Muhammad Iqbal
- Creative Engineering & Management Services, Saddar Road, Peshawar, Pakistan
| | - Sujan Piya
- Department of Industrial Engineering and Engineering Management, College of Engineering, University of Sharjah, Sharjah, UAE
| | - Mahmood Al-Kindi
- Department of Mechanical and Industrial Engineering, College of Engineering, Sultan Qaboos University, P.O. Box 33, Al-Khoud, 123, Sultanate of Oman
| | - Asim Qureshi
- Department of Pathology, Sultan Qaboos University, Al-Khoud, 123, Sultanate of Oman
| | - Ahmed Al-Ghaithi
- Department of Surgery, Sultan Qaboos University Hospital, Al-Khoud, 123, Sultanate of Oman
| | - Badar Al-Sumri
- Histopathology Laboratory, Sultan Qaboos University Hospital, Al-Khoud, 123, Sultanate of Oman
| | - Vadim V Silberschmidt
- School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Loughborough, UK
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10
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Dienes B, Bazsó T, Szabó L, Csernoch L. The Role of the Piezo1 Mechanosensitive Channel in the Musculoskeletal System. Int J Mol Sci 2023; 24:ijms24076513. [PMID: 37047487 PMCID: PMC10095409 DOI: 10.3390/ijms24076513] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/23/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
Since the recent discovery of the mechanosensitive Piezo1 channels, many studies have addressed the role of the channel in various physiological or even pathological processes of different organs. Although the number of studies on their effects on the musculoskeletal system is constantly increasing, we are still far from a precise understanding. In this review, the knowledge available so far regarding the musculoskeletal system is summarized, reviewing the results achieved in the field of skeletal muscles, bones, joints and cartilage, tendons and ligaments, as well as intervertebral discs.
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11
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Boucetta A, Ramtani S, Garzón-Alvarado DA. Both network architecture and micro cracks effects on lacuno-canalicular liquid flow efficiency within the context of multiphysics approach for bone remodeling. J Mech Behav Biomed Mater 2023; 141:105780. [PMID: 36989871 DOI: 10.1016/j.jmbbm.2023.105780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 02/27/2023] [Accepted: 03/12/2023] [Indexed: 03/18/2023]
Abstract
When physical forces are applied to bone, its mechanical adaptive behaviors change according to the microarchitecture configuration. This leads to changes in biological and physical thresholds in the remodeling cell population, involving sensor cells (osteocytes) interacting with each other and changes in osteocyte shape due to variation in lacunar shape. The resulting alterations in fluid flow leads to changes in the membrane electrical potential and shear stress. Eventual creation of microcracks, may lead in turn to modify cell activity. In contrast, the redundancy in the lacuno canalicular network (LCN) interconnectivity maintains partial flow. Our goal was to investigate the role of fluid flow in LCN by proposing a model of electro-mechanical energy spread through inhomogeneous microarchitectures. We focused on mechano-sensitivity to changes in load-induced flow impacted by neighboring micro cracks and quantifying its critical role in changing, velocity, shear stress and orientation of liquid mass transportation from one cell to another. To enhance the concept of intricacy LCN micro-structure to fluid flow, we provide a new combined effects factor considered as osteocytes sensor efficiency. We customized an influence function for each osteocyte, coupling: in one hand, the spatial distribution within remodeling influence areas, conducting a significant fluid spread, leading hydro-dynamic behavior and impacted further by presence of micro cracks and; in other hand, the fluid electro kinetic behavior. As an attempt to fill the limitations stated by many of the recent studies, we reveal in numerical simulation, some results which cannot be measured in vitro/in vivo studies. Numerical calculations were performed in order to evaluate, among many others, how liquid flow conditions changes between lacunas, how the orientation and the magnitude of the governing flow in LCN can regulate osteocytes efficiency. In addition to be regulated by osteocytes, a direct effects of fluid flow are also acting on osteoblast activity. In summary, this new approach considers mechano-sensitivity in relation to liquid flow dynamic and suggests additional pathway for Osseo integration via osteoblast regulation. However, this novel modeling approach may help improve the mapping and design bone scaffolds and/or selection of scaffold implantation regions.
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Affiliation(s)
- Abdelkader Boucetta
- Université Sorbonne Paris Nord, CSPBA-LBPS, UMR CNRS 7244, Inst Galilee, 99 Ave JB Clement, Villetaneuse, France; GE VERNOVA, SS&O-OPS-O&M EMEA Regions, Algiers, Algeria.
| | - Salah Ramtani
- Université Sorbonne Paris Nord, CSPBA-LBPS, UMR CNRS 7244, Inst Galilee, 99 Ave JB Clement, Villetaneuse, France.
| | - Diego A Garzón-Alvarado
- Universidad Nacional de Colombia, Biomimetics Laboratory-Biotechnology Institute, Bogota, 571, Republic of Colombia.
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12
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Han Z, Sun LW, Wu XT, Yang X, Fan YB. Nonlinear dynamics of membrane skeleton in osteocyte. Comput Methods Biomech Biomed Engin 2023; 26:249-260. [PMID: 35363098 DOI: 10.1080/10255842.2022.2057796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Osteocytes play an important role in mechanosensation and conduction in bone tissue, and the change of mechanical environment can affect the sensitivity of osteocytes to external stimulation. The structure of osteocytes will be changed when they are subjected to vibrations, which influence the mechanosensitivity of osteocytes and alter the regulation of bone remodeling process. As an important mechanotransduction structure in osteocytes, the membrane skeleton greatly affects the mechanosensation and conduction of osteocytes. However, the dynamic responses of membrane skeleton to the vibration and the structural changes of membrane skeleton are unclear. Therefore, we applied a nonlinear dynamics method to explain the time-dependent changes of membrane skeleton. The semi-ellipsoidal reticulate shell structure of membrane skeleton is built based on the experimental observation in our previous work. Then, the nonlinear dynamic equations of membrane skeleton are established according to the theory of plate and shell dynamics, and the displacement-time curves, phase portraits, and Poincaré maps of membrane skeleton structure were obtained. The numeration results show that under the vibration stimulation of 15 Hz, 30 Hz, 60 Hz, and 90 Hz, the membrane skeleton is destroyed after a transient equilibrium position vibration. The vibration of 15 Hz has the most destructive effect on the membrane skeleton, the natural frequency of membrane skeleton may be less than 15 Hz. In addition, the chaos phenomenon occurs to the membrane skeleton during vibration. As a damping factor, the existence of viscosity alleviates the damage of structure. This study can help us to understand the oscillation characteristic of membrane skeleton in osteocyte.
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Affiliation(s)
- Zhuang Han
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Lian-Wen Sun
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Xin-Tong Wu
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Xiao Yang
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Yu-Bo Fan
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
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13
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Wang JS, Wein MN. Pathways Controlling Formation and Maintenance of the Osteocyte Dendrite Network. Curr Osteoporos Rep 2022; 20:493-504. [PMID: 36087214 PMCID: PMC9718876 DOI: 10.1007/s11914-022-00753-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/22/2022] [Indexed: 01/30/2023]
Abstract
PURPOSE OF REVIEW The purpose of this review is to discuss the molecular mechanisms involved in osteocyte dendrite formation, summarize the similarities between osteocytic and neuronal projections, and highlight the importance of osteocyte dendrite maintenance in human skeletal disease. RECENT FINDINGS It is suggested that there is a causal relationship between the loss of osteocyte dendrites and the increased osteocyte apoptosis during conditions including aging, microdamage, and skeletal disease. A few mechanisms are proposed to control dendrite formation and outgrowth, such as via the regulation of actin polymerization dynamics. This review addresses the impact of osteocyte dendrites in bone health and disease. Recent advances in multi-omics, in vivo and in vitro models, and microscopy-based imaging have provided novel approaches to reveal the underlying mechanisms that regulate dendrite development. Future therapeutic approaches are needed to target the process of osteocyte dendrite formation.
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Affiliation(s)
- Jialiang S Wang
- Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Marc N Wein
- Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- Harvard Stem Cell Institute, Cambridge, MA, USA.
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14
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Chen Y, Lu C, Shang X, Wu K, Chen K. Primary cilia: The central role in the electromagnetic field induced bone healing. Front Pharmacol 2022; 13:1062119. [DOI: 10.3389/fphar.2022.1062119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 11/07/2022] [Indexed: 12/03/2022] Open
Abstract
Primary cilia have emerged as the cellular “antenna” that can receive and transduce extracellular chemical/physical signals, thus playing an important role in regulating cellular activities. Although the electromagnetic field (EMF) is an effective treatment for bone fractures since 1978, however, the detailed mechanisms leading to such positive effects are still unclear. Primary cilia may play a central role in receiving EMF signals, translating physical signals into biochemical information, and initiating various signalingsignaling pathways to transduce signals into the nucleus. In this review, we elucidated the process of bone healing, the structure, and function of primary cilia, as well as the application and mechanism of EMF in treating fracture healing. To comprehensively understand the process of bone healing, we used bioinformatics to analyze the molecular change and associated the results with other studies. Moreover, this review summarizedsummarized some limitations in EMFs-related research and provides an outlook for ongoing studies. In conclusion, this review illustrated the primary cilia and related molecular mechanisms in the EMF-induced bone healing process, and it may shed light on future research.
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15
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Ardura JA, Martín-Guerrero E, Heredero-Jiménez S, Gortazar AR. Primary cilia and PTH1R interplay in the regulation of osteogenic actions. VITAMINS AND HORMONES 2022; 120:345-370. [PMID: 35953116 DOI: 10.1016/bs.vh.2022.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Primary cilia are subcellular structures specialized in sensing different stimuli in a diversity of cell types. In bone, the primary cilium is involved in mechanical sensing and transduction of signals that regulate the behavior of mesenchymal osteoprogenitors, osteoblasts and osteocytes. To perform its functions, the primary cilium modulates a plethora of molecules including those stimulated by the parathyroid hormone (PTH) receptor type I (PTH1R), a master regulator of osteogenesis. Binding of the agonists PTH or PTH-related protein (PTHrP) to the PTH1R or direct agonist-independent stimulation of the receptor activate PTH1R signaling pathways. In turn, activation of PTH1R leads to regulation of bone formation and remodeling. Herein, we describe the structure, function and molecular partners of primary cilia in the context of bone, playing special attention to those signaling pathways that are mediated directly or indirectly by PTH1R in association with primary cilia during the process of osteogenesis.
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Affiliation(s)
- Juan A Ardura
- Bone Physiopathology Laboratory, Department of Basic Medical Sciences, CEU San Pablo University, CEU Universities, Madrid, Spain.
| | - Eduardo Martín-Guerrero
- Bone Physiopathology Laboratory, Department of Basic Medical Sciences, CEU San Pablo University, CEU Universities, Madrid, Spain
| | - Sara Heredero-Jiménez
- Bone Physiopathology Laboratory, Department of Basic Medical Sciences, CEU San Pablo University, CEU Universities, Madrid, Spain
| | - Arancha R Gortazar
- Bone Physiopathology Laboratory, Department of Basic Medical Sciences, CEU San Pablo University, CEU Universities, Madrid, Spain
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16
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Rayat Pisheh H, Ansari M, Eslami H. How is mechanobiology involved in bone regenerative medicine? Tissue Cell 2022; 76:101821. [DOI: 10.1016/j.tice.2022.101821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/27/2022] [Accepted: 05/10/2022] [Indexed: 10/18/2022]
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Cui J, Shibata Y, Zhu T, Zhou J, Zhang J. Osteocytes in bone aging: Advances, challenges, and future perspectives. Ageing Res Rev 2022; 77:101608. [PMID: 35283289 DOI: 10.1016/j.arr.2022.101608] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/28/2022] [Accepted: 03/07/2022] [Indexed: 02/08/2023]
Abstract
Osteocytes play a critical role in maintaining bone homeostasis and in regulating skeletal response to hormones and mechanical loading. Substantial evidence have demonstrated that osteocytes and their lacunae exhibit morphological changes in aged bone, indicating the underlying involvement of osteocytes in bone aging. Notably, recent studies have deciphered aged osteocytes to have characteristics such as impaired mechanosensitivity, accumulated cellular senescence, dysfunctional perilacunar/canalicular remodeling, and degenerated lacuna-canalicular network. However, detailed molecular mechanisms of osteocytes remain unclear. Nonetheless, osteocyte transcriptomes analyzed via advanced RNA sequencing (RNA-seq) techniques have identified several bone aging-related genes and signaling pathways, such as Wnt, Bmp/TGF, and Jak-STAT. Moreover, inflammation, immune dysfunction, energy shortage, and impaired hormone responses possibly affect osteocytes in age-related bone deterioration. In this review, we summarize the hallmarks of aging bone and osteocytes and discuss osteocytic mechanisms in age-related bone loss and impaired bone quality. Furthermore, we provide insights into the challenges faced and their possible solutions when investigating osteocyte transcriptomes. We also highlight that single-cell RNA-seq can decode transcriptomic messages in aged osteocytes; therefore, this technique can promote novel single cell-based investigations in osteocytes once a well-established standardized protocol specific for osteocytes is developed. Interestingly, improved understanding of osteocytic mechanisms have helped identify promising targets and effective therapies for aging-related osteoporosis and fragile fractures.
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18
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Tang H, Zeng R, He E, Zhang I, Ding C, Zhang A. Piezo-Type Mechanosensitive Ion Channel Component 1 (Piezo1): A Promising Therapeutic Target and Its Modulators. J Med Chem 2022; 65:6441-6453. [DOI: 10.1021/acs.jmedchem.2c00085] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Hairong Tang
- Pharm-X Center, Laboratory of Medicinal Chemical Biology & Frontiers on Drug Discovery (RLMCBFDD), School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ruoqing Zeng
- Pharm-X Center, Laboratory of Medicinal Chemical Biology & Frontiers on Drug Discovery (RLMCBFDD), School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ende He
- Pharm-X Center, Laboratory of Medicinal Chemical Biology & Frontiers on Drug Discovery (RLMCBFDD), School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
| | | | - Chunyong Ding
- Pharm-X Center, Laboratory of Medicinal Chemical Biology & Frontiers on Drug Discovery (RLMCBFDD), School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ao Zhang
- Pharm-X Center, Laboratory of Medicinal Chemical Biology & Frontiers on Drug Discovery (RLMCBFDD), School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
- Shanghai Lingang National Laboratory, Shanghai 200210,China
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19
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Abstract
PURPOSE OF REVIEW Osteocytes are the conductors of bone adaptation and remodelling. Buried inside the calcified matrix, they sense mechanical cues and signal osteoclasts in case of low activity, and osteoblasts when stresses are high. How do osteocytes detect mechanical stress? What physical signal do they perceive? Finite element analysis is a useful tool to address these questions as it allows calculating stresses, strains and fluid flow where they cannot be measured. The purpose of this review is to evaluate the capabilities and challenges of finite element models of bone, in particular the osteocytes and load-induced activation mechanisms. RECENT FINDINGS High-resolution imaging and increased computational power allow ever more detailed modelling of osteocytes, either in isolation or embedded within the mineralised matrix. Over the years, homogeneous models of bone and osteocytes got replaced by heterogeneous and microstructural models, including, e.g. the lacuno-canalicular network and the cytoskeleton. The lacuno-canalicular network induces strain amplifications and the osteocyte protrusions seem to be stimulated much more than the cell body, both by strain and fluid flow. More realistic cell geometries, like minute constrictions of the canaliculi, increase this effect. Microstructural osteocyte models describe the transduction of external stimuli to the nucleus. Supracellular multiscale models (e.g. of a tunnelling osteon) allow to study differential loading of osteocytes and to distinguish between strain and fluid flow as the pivotal stimulatory cue. In the future, the finite element models may be enhanced by including chemical transport and intercellular communication between osteocytes, osteoclasts and osteoblasts.
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Affiliation(s)
- Theodoor H Smit
- Department of Medical Biology, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands.
- Department of Orthopaedic Surgery, Amsterdam Movement Sciences Research Institute, Amsterdam, The Netherlands.
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20
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Bai S, Lu X, Pan Q, Wang B, Pong U K, Yang Y, Wang H, Lin S, Feng L, Wang Y, Li Y, Lin W, Wang Y, Zhang X, Li Y, Li L, Yang Z, Wang M, Lee WYW, Jiang X, Li G. Cranial Bone Transport Promotes Angiogenesis, Neurogenesis, and Modulates Meningeal Lymphatic Function in Middle Cerebral Artery Occlusion Rats. Stroke 2022; 53:1373-1385. [PMID: 35135326 DOI: 10.1161/strokeaha.121.037912] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 12/23/2021] [Indexed: 11/16/2022]
Abstract
BACKGROUND Ischemic stroke is a leading cause of death and disability worldwide. However, the time window for quickly dissolving clots and restoring cerebral blood flow, using tissue-type plasminogen activator treatment is rather limited, resulting in many patients experiencing long-term functional impairments if not death. This study aims to determine the roles of cranial bone transport (CBT), a novel, effective, and simple surgical technique, in the recovery of ischemic stroke using middle cerebral artery occlusion (MCAO) rat model. METHODS CBT was performed by slowly sliding a bone segment in skull with a special frame and a speed of 0.25 mm/12 hours for 10 days following MCAO. Morris water maze, rotarod test, and catwalk gait analysis were used to study the neurological behaviors, and infarct area and cerebral flow were evaluated during CBT process. Immunofluorescence staining of CD31 and Nestin/Sox2 (sex determining region Y box 2) was performed to study the angiogenesis and neurogenesis. OVA-A647 (ovalbumin-Alexa Fluor 647) was intracisterna magna injected to evaluate the meningeal lymphatic drainage function. RESULTS CBT treatment has significantly reduced the ischemic lesions areas and improved the neurological deficits in MCAO rats compared with the rats in the control groups. CBT treatment significantly promoted angiogenesis and neurogenesis in the brain of MCAO rats. The drainage function of meningeal lymphatic vessels in MCAO rats was significantly impaired compared with normal rats. Ablation of meningeal lymphatic drainage led to increased neuroinflammation and aggravated neurological deficits and ischemic injury in MCAO rats. CBT treatment significantly improved the meningeal lymphatic drainage function and alleviated T-cell infiltration in MCAO rats. CONCLUSIONS This study provided evidence for the possible mechanisms on how CBT attenuates ischemic stroke injury and facilitates rapid neuronal function recovery, suggesting that CBT may be an alternative treatment strategy for managing ischemic stroke.
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Affiliation(s)
- Shanshan Bai
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | - Xuan Lu
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | - Qi Pan
- Department of Pediatric Orthopaedics, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, PR China (Q.P.)
| | - Bin Wang
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | - Kin Pong U
- Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, PR China (K.P.U., X.J.)
| | - Yongkang Yang
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | - Haixing Wang
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | - Sien Lin
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | - Lu Feng
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | - Yan Wang
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | - Yucong Li
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | | | | | - Xiaoting Zhang
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | - Yuan Li
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | - Linlong Li
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | - Zhengmeng Yang
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | - Ming Wang
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | - Wayne Yuk-Wai Lee
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
| | - Xiaohua Jiang
- Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, PR China (K.P.U., X.J.)
| | - Gang Li
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, PR China (S.B., X.L., B.W., Y.Y., H.W., S.L., L.F., Yan Wang, Yucong Li, W.L., Yujia Wang, X.Z., Yuan Li, L.L., Z.Y., M.W., W.Y.-W.L., G.L.)
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21
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Choi JUA, Kijas AW, Lauko J, Rowan AE. The Mechanosensory Role of Osteocytes and Implications for Bone Health and Disease States. Front Cell Dev Biol 2022; 9:770143. [PMID: 35265628 PMCID: PMC8900535 DOI: 10.3389/fcell.2021.770143] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/13/2021] [Indexed: 12/14/2022] Open
Abstract
Bone homeostasis is a dynamic equilibrium between bone-forming osteoblasts and bone-resorbing osteoclasts. This process is primarily controlled by the most abundant and mechanosensitive bone cells, osteocytes, that reside individually, within chambers of porous hydroxyapatite bone matrix. Recent studies have unveiled additional functional roles for osteocytes in directly contributing to local matrix regulation as well as systemic roles through endocrine functions by communicating with distant organs such as the kidney. Osteocyte function is governed largely by both biochemical signaling and the mechanical stimuli exerted on bone. Mechanical stimulation is required to maintain bone health whilst aging and reduced level of loading are known to result in bone loss. To date, both in vivo and in vitro approaches have been established to answer important questions such as the effect of mechanical stimuli, the mechanosensors involved, and the mechanosensitive signaling pathways in osteocytes. However, our understanding of osteocyte mechanotransduction has been limited due to the technical challenges of working with these cells since they are individually embedded within the hard hydroxyapatite bone matrix. This review highlights the current knowledge of the osteocyte functional role in maintaining bone health and the key regulatory pathways of these mechanosensitive cells. Finally, we elaborate on the current therapeutic opportunities offered by existing treatments and the potential for targeting osteocyte-directed signaling.
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Affiliation(s)
- Jung Un Ally Choi
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
| | - Amanda W Kijas
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
| | - Jan Lauko
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
| | - Alan E Rowan
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
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22
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Datta HK, Kringen MK, Tuck SP, Salpingidou G, Olstad OK, Gautvik KM, Cockell SJ, Gautvik VT, Prediger M, Wu JJ, Birch MA, Reppe S. Mechanical-Stress-Related Epigenetic Regulation of ZIC1 Transcription Factor in the Etiology of Postmenopausal Osteoporosis. Int J Mol Sci 2022; 23:ijms23062957. [PMID: 35328378 PMCID: PMC8955993 DOI: 10.3390/ijms23062957] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/02/2022] [Accepted: 03/05/2022] [Indexed: 12/21/2022] Open
Abstract
Mechanical loading exerts a profound influence on bone density and architecture, but the exact mechanism is unknown. Our study shows that expression of the neurological transcriptional factor zinc finger of the cerebellum 1 (ZIC1) is markedly increased in trabecular bone biopsies in the lumbar spine compared with the iliac crest, skeletal sites of high and low mechanical stress, respectively. Human trabecular bone transcriptome analyses revealed a strong association between ZIC1 mRNA levels and gene transcripts characteristically associated with osteoblasts, osteocytes and osteoclasts. This supposition is supported by higher ZIC1 expression in iliac bone biopsies from postmenopausal women with osteoporosis compared with age-matched control subjects, as well as strongly significant inverse correlation between ZIC1 mRNA levels and BMI-adjusted bone mineral density (BMD) (Z-score). ZIC1 promoter methylation was decreased in mechanically loaded vertebral bone compared to unloaded normal iliac bone, and its mRNA levels correlated inversely with ZIC1 promoter methylation, thus linking mechanical stress to epigenetic control of gene expression. The findings were corroborated in cultures of rat osteoblast progenitors and osteoblast-like cells. This study demonstrates for the first time how skeletal epigenetic changes that are affected by mechanical forces give rise to marked alteration in bone cell transcriptional activity and translate to human bone pathophysiology.
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Affiliation(s)
- Harish K. Datta
- Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (S.P.T.); (M.A.B.)
- Blood Sciences, South Tees Hospitals NHS Foundation Trust, Middlesbrough TS4 3BW, UK
- Correspondence: ; Tel.: +44-01642-854161
| | | | - Stephen P. Tuck
- Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (S.P.T.); (M.A.B.)
| | - Georgia Salpingidou
- Department of Engineering, Faculty of Science, Durham University, Durham DH1 3 LE, UK; (G.S.); (J.J.W.)
| | - Ole K. Olstad
- Department of Medical Biochemistry, Oslo University Hospital, 0424 Oslo, Norway; (O.K.O.); (S.R.)
| | - Kaare M. Gautvik
- Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, 0440 Oslo, Norway; (K.M.G.); (V.T.G.)
| | - Simon J. Cockell
- School of Biomedical, Nutritional and Sport Sciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
| | - Vigdis T. Gautvik
- Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, 0440 Oslo, Norway; (K.M.G.); (V.T.G.)
| | - Michael Prediger
- Blood Sciences, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Royal Victoria Infirmary, Newcastle upon Tyne NE2 4HH, UK;
| | - Jun Jie Wu
- Department of Engineering, Faculty of Science, Durham University, Durham DH1 3 LE, UK; (G.S.); (J.J.W.)
| | - Mark A. Birch
- Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (S.P.T.); (M.A.B.)
| | - Sjur Reppe
- Department of Medical Biochemistry, Oslo University Hospital, 0424 Oslo, Norway; (O.K.O.); (S.R.)
- Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, 0440 Oslo, Norway; (K.M.G.); (V.T.G.)
- Department of Plastic and Reconstructive Surgery, Oslo University Hospital, 0424 Oslo, Norway
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23
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The mechanosensory and mechanotransductive processes mediated by ion channels and the impact on bone metabolism: A systematic review. Arch Biochem Biophys 2021; 711:109020. [PMID: 34461086 DOI: 10.1016/j.abb.2021.109020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/25/2021] [Accepted: 08/26/2021] [Indexed: 02/06/2023]
Abstract
Mechanical environments were associated with alterations in bone metabolism. Ion channels present on bone cells are indispensable for bone metabolism and can be directly or indirectly activated by mechanical stimulation. This review aimed to discuss the literature reporting the mechanical regulatory effects of ion channels on bone cells and bone tissue. An electronic search was conducted in PubMed, Embase and Web of Science. Studies about mechanically induced alteration of bone cells and bone tissue by ion channels were included. Ion channels including TRP family channels, Ca2+ release-activated Ca2+ channels (CRACs), Piezo1/2 channels, purinergic receptors, NMDA receptors, voltage-sensitive calcium channels (VSCCs), TREK2 potassium channels, calcium- and voltage-dependent big conductance potassium (BKCa) channels, small conductance, calcium-activated potassium (SKCa) channels and epithelial sodium channels (ENaCs) present on bone cells and bone tissue participate in the mechanical regulation of bone development in addition to contributing to direct or indirect mechanotransduction such as altered membrane potential and ionic flux. Physiological (beneficial) mechanical stimulation could induce the anabolism of bone cells and bone tissue through ion channels, but abnormal (harmful) mechanical stimulation could also induce the catabolism of bone cells and bone tissue through ion channels. Functional expression of ion channels is vital for the mechanotransduction of bone cells. Mechanical activation (opening) of ion channels triggers ion influx and induces the activation of intracellular modulators that can influence bone metabolism. Therefore, mechanosensitive ion channels provide new insights into therapeutic targets for the treatment of bone-related diseases such as osteopenia and aseptic implant loosening.
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24
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Qin L, He T, Chen S, Yang D, Yi W, Cao H, Xiao G. Roles of mechanosensitive channel Piezo1/2 proteins in skeleton and other tissues. Bone Res 2021; 9:44. [PMID: 34667178 PMCID: PMC8526690 DOI: 10.1038/s41413-021-00168-8] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 06/16/2021] [Accepted: 07/08/2021] [Indexed: 12/12/2022] Open
Abstract
Mechanotransduction is a fundamental ability that allows living organisms to receive and respond to physical signals from both the external and internal environments. The mechanotransduction process requires a range of special proteins termed mechanotransducers to convert mechanical forces into biochemical signals in cells. The Piezo proteins are mechanically activated nonselective cation channels and the largest plasma membrane ion channels reported thus far. The regulation of two family members, Piezo1 and Piezo2, has been reported to have essential functions in mechanosensation and transduction in different organs and tissues. Recently, the predominant contributions of the Piezo family were reported to occur in the skeletal system, especially in bone development and mechano-stimulated bone homeostasis. Here we review current studies focused on the tissue-specific functions of Piezo1 and Piezo2 in various backgrounds with special highlights on their importance in regulating skeletal cell mechanotransduction. In this review, we emphasize the diverse functions of Piezo1 and Piezo2 and related signaling pathways in osteoblast lineage cells and chondrocytes. We also summarize our current understanding of Piezo channel structures and the key findings about PIEZO gene mutations in human diseases.
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Affiliation(s)
- Lei Qin
- Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, China
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Tailin He
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Sheng Chen
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, Guangdong, China
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Dazhi Yang
- Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Weihong Yi
- Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, China.
| | - Huiling Cao
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Guozhi Xiao
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, Guangdong, China.
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25
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García-Aznar JM, Nasello G, Hervas-Raluy S, Pérez MÁ, Gómez-Benito MJ. Multiscale modeling of bone tissue mechanobiology. Bone 2021; 151:116032. [PMID: 34118446 DOI: 10.1016/j.bone.2021.116032] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 04/25/2021] [Accepted: 06/02/2021] [Indexed: 02/07/2023]
Abstract
Mechanical environment has a crucial role in our organism at the different levels, ranging from cells to tissues and our own organs. This regulatory role is especially relevant for bones, given their importance as load-transmitting elements that allow the movement of our body as well as the protection of vital organs from load impacts. Therefore bone, as living tissue, is continuously adapting its properties, shape and repairing itself, being the mechanical loads one of the main regulatory stimuli that modulate this adaptive behavior. Here we review some key results of bone mechanobiology from computational models, describing the effect that changes associated to the mechanical environment induce in bone response, implant design and scaffold-driven bone regeneration.
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Affiliation(s)
- José Manuel García-Aznar
- Multiscale in Mechanical and Biological Engineering, Instituto de Investigación en Ingeniería de Aragón (I3A), Instituto de Investigación Sanitaria Aragón (IIS Aragón), University of Zaragoza, Zaragoza, Spain.
| | - Gabriele Nasello
- Multiscale in Mechanical and Biological Engineering, Instituto de Investigación en Ingeniería de Aragón (I3A), Instituto de Investigación Sanitaria Aragón (IIS Aragón), University of Zaragoza, Zaragoza, Spain; Biomechanics Section, KU Leuven, Leuven, Belgium
| | - Silvia Hervas-Raluy
- Multiscale in Mechanical and Biological Engineering, Instituto de Investigación en Ingeniería de Aragón (I3A), Instituto de Investigación Sanitaria Aragón (IIS Aragón), University of Zaragoza, Zaragoza, Spain
| | - María Ángeles Pérez
- Multiscale in Mechanical and Biological Engineering, Instituto de Investigación en Ingeniería de Aragón (I3A), Instituto de Investigación Sanitaria Aragón (IIS Aragón), University of Zaragoza, Zaragoza, Spain
| | - María José Gómez-Benito
- Multiscale in Mechanical and Biological Engineering, Instituto de Investigación en Ingeniería de Aragón (I3A), Instituto de Investigación Sanitaria Aragón (IIS Aragón), University of Zaragoza, Zaragoza, Spain
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26
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Casanova M, Schindeler A, Peacock L, Lee L, Schneider P, Little DG, Müller R. Characterization of the Developing Lacunocanalicular Network During Fracture Repair. JBMR Plus 2021; 5:e10525. [PMID: 34532613 PMCID: PMC8441443 DOI: 10.1002/jbm4.10525] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 05/23/2021] [Accepted: 06/06/2021] [Indexed: 11/09/2022] Open
Abstract
Fracture repair is a normal physiological response to bone injury. During the process of bony callus formation, a lacunocanalicular network (LCN) is formed de novo that evolves with callus remodeling. Our aim was the longitudinal assessment of the development and evolution of the LCN during fracture repair. To this end, 45 adult wild‐type C57BL/6 mice underwent closed tibial fracture surgery. Fractured and intact contralateral tibias were harvested after 2, 3, and 6 weeks of bone healing (n = 15/group). High‐resolution micro–computed tomography (μCT) and deconvolution microscopy (DV) approaches were applied to quantify lacunar number density from the calluses and intact bone. On histological sections, Goldner's trichrome staining was used to assess lacunar occupancy, fluorescein isothiocyanate staining to visualize the canalicular network, and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate‐biotin nick end labeling (TUNEL) staining to examine osteocyte apoptosis. Analysis of μCT scans showed progressive decreases in mean lacuna volume over time (−27% 2–3 weeks; −13% 3–6 weeks). Lacunar number density increased considerably between 2 and 3 weeks (+156%). Correlation analysis was performed, showing a positive linear relationship between canalicular number density and trabecular thickness (R2 = 0.56, p < 0.001) and an inverse relationship between mean lacuna volume and trabecular thickness (R2 = 0.57, p < 0.001). Histology showed increases in canalicular number density over time (+22% 2–3 weeks, +51% 3–6 weeks). Lacunar occupancy in new bone of the callus was high (>90%), but the old cortical bone within the fracture site appeared necrotic as it underwent resorption. In conclusion, our data shows a progressive increase in the complexity of the LCN over time during fracture healing and demonstrates that this network is initiated during the early stages of repair. Further studies are needed to address the functional importance of osteocytes in bone healing, particularly in detecting and translating the effects of micromotion in the fracture. © 2021 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)
| | - Aaron Schindeler
- Orthopaedic Research & Biotechnology The Children's Hospital at Westmead Westmead Australia.,Discipline of Child and Adolescent Health University of Sydney Camperdown Australia
| | - Lauren Peacock
- Orthopaedic Research & Biotechnology The Children's Hospital at Westmead Westmead Australia
| | - Lucinda Lee
- Orthopaedic Research & Biotechnology The Children's Hospital at Westmead Westmead Australia.,Discipline of Child and Adolescent Health University of Sydney Camperdown Australia
| | - Philipp Schneider
- Institute for Biomechanics ETH Zurich Zurich Switzerland.,Bioengineering Science Research Group, Faculty of Engineering and Physical Sciences University of Southampton Southampton UK.,High-Performance Vision Systems, Center for Vision, Automation & Control Austrian Institute of Technology (AIT) Vienna Austria
| | - David G Little
- Orthopaedic Research & Biotechnology The Children's Hospital at Westmead Westmead Australia.,Discipline of Child and Adolescent Health University of Sydney Camperdown Australia
| | - Ralph Müller
- Institute for Biomechanics ETH Zurich Zurich Switzerland
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27
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Larcher I, Scheiner S. Parameter reduction, sensitivity studies, and correlation analyses applied to a mechanobiologically regulated bone cell population model of the bone metabolism. Comput Biol Med 2021; 136:104717. [PMID: 34426166 DOI: 10.1016/j.compbiomed.2021.104717] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 07/27/2021] [Accepted: 07/27/2021] [Indexed: 11/30/2022]
Abstract
When striving for reconstructing and predicting bone remodeling processes by means of mathematical models, cell population models have become a popular option. From a conceptual point of view, these models are able to take into account an arbitrary amount of regulatory mechanisms driving the development of bone cells and their activities. However, in most cases, the models include a large number of parameters; and most of those parameters cannot be measured, which certainly compromises the credibility of cell population models. Here, new insights are presented as to the potential improvement of this unsatisfactory situation. In particular, a previously published bone remodeling model was considered, and based on combination and merging of the original parameters, the total number of parameters could be reduced from 28 to 18, without impairing the model's versatility and significance. Furthermore, a comprehensive number of one- and two-variable sensitivity studies were performed, pointing out which parameters (alone and in combination with other parameters) influence the model predictions significantly - for that purpose, the mean squared relative error (MSRE) between simulations based on the original parameters and based on varied parameters was considered as failure measure. It has turned out that the model is significantly more sensitive to parameters which can be considered as phenomenological (such as differentiation, proliferation, and apoptosis rates) than to parameters which are directly related to specific processes (such as dissociation rate constants, and maximum concentrations of the involved factors). Using common correlation measures (such as Pearson, Spearman, and partial ranked correlation coefficients), correlation studies revealed that the correlations between most parameters and the MSRE are weak, while a few parameters exhibited moderate correlations. In conclusion, the results shown in this paper provide valuable insights concerning the design of new experiments allowing for measurement of the parameters which are most influential in the context of bone remodeling simulation.
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Affiliation(s)
- Isabella Larcher
- Institute for Mechanics of Materials and Structures, (TU Wien) Vienna University of Technology, Karlsplatz 13/202, 1040, Vienna, Austria
| | - Stefan Scheiner
- Institute for Mechanics of Materials and Structures, (TU Wien) Vienna University of Technology, Karlsplatz 13/202, 1040, Vienna, Austria.
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28
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Insights into the Cellular and Molecular Mechanisms That Govern the Fracture-Healing Process: A Narrative Review. J Clin Med 2021; 10:jcm10163554. [PMID: 34441849 PMCID: PMC8397080 DOI: 10.3390/jcm10163554] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 08/07/2021] [Accepted: 08/10/2021] [Indexed: 12/28/2022] Open
Abstract
Fracture-healing is a complex multi-stage process that usually progresses flawlessly, resulting in restoration of bone architecture and function. Regrettably, however, a considerable number of fractures fail to heal, resulting in delayed unions or non-unions. This may significantly impact several aspects of a patient’s life. Not surprisingly, in the past few years, a substantial amount of research and number of clinical studies have been designed, aiming at shedding light into the cellular and molecular mechanisms that regulate fracture-healing. Herein, we present the current knowledge on the pathobiology of the fracture-healing process. In addition, the role of skeletal cells and the impact of marrow adipose tissue on bone repair is discussed. Unveiling the pathogenetic mechanisms that govern the fracture-healing process may lead to the development of novel, smarter, and more effective therapeutic strategies for the treatment of fractures, especially of those with large bone defects.
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29
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Chen Y, Aspera-Werz RH, Menger MM, Falldorf K, Ronniger M, Stacke C, Histing T, Nussler AK, Ehnert S. Exposure to 16 Hz Pulsed Electromagnetic Fields Protect the Structural Integrity of Primary Cilia and Associated TGF-β Signaling in Osteoprogenitor Cells Harmed by Cigarette Smoke. Int J Mol Sci 2021; 22:7036. [PMID: 34210094 PMCID: PMC8268780 DOI: 10.3390/ijms22137036] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 01/01/2023] Open
Abstract
Cigarette smoking (CS) is one of the main factors related to avoidable diseases and death across the world. Cigarette smoke consists of numerous toxic compounds that contribute to the development of osteoporosis and fracture nonunion. Exposure to pulsed electromagnetic fields (PEMF) was proven to be a safe and effective therapy to support bone fracture healing. The aims of this study were to investigate if extremely low frequency (ELF-) PEMFs may be beneficial to treat CS-related bone disease, and which effect the duration of the exposure has. In this study, immortalized human mesenchymal stem cells (SCP-1 cells) impaired by 5% cigarette smoke extract (CSE) were exposed to ELF-PEMFs (16 Hz) with daily exposure ranging from 7 min to 90 min. Cell viability, adhesion, and spreading were evaluated by Sulforhodamine B, Calcein-AM staining, and Phalloidin-TRITC/Hoechst 33342 staining. A migration assay kit was used to determine cell migration. Changes in TGF-β signaling were evaluated with an adenoviral Smad2/3 reporter assay, RT-PCR, and Western blot. The structure and distribution of primary cilia were analyzed with immunofluorescent staining. Our data indicate that 30 min daily exposure to a specific ELF-PEMF most effectively promoted cell viability, enhanced cell adhesion and spreading, accelerated migration, and protected TGF-β signaling from CSE-induced harm. In summary, the current results provide evidence that ELF-PEMF can be used to support early bone healing in patients who smoke.
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Affiliation(s)
- Yangmengfan Chen
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Schnarrenbergstr. 95, D-72076 Tübingen, Germany; (Y.C.); (R.H.A.-W.); (M.M.M.); (T.H.); (S.E.)
| | - Romina H. Aspera-Werz
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Schnarrenbergstr. 95, D-72076 Tübingen, Germany; (Y.C.); (R.H.A.-W.); (M.M.M.); (T.H.); (S.E.)
| | - Maximilian M. Menger
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Schnarrenbergstr. 95, D-72076 Tübingen, Germany; (Y.C.); (R.H.A.-W.); (M.M.M.); (T.H.); (S.E.)
| | - Karsten Falldorf
- Sachtleben GmbH, Haus Spectrum am UKE, Martinistraße 64, D-20251 Hamburg, Germany; (K.F.); (M.R.); (C.S.)
| | - Michael Ronniger
- Sachtleben GmbH, Haus Spectrum am UKE, Martinistraße 64, D-20251 Hamburg, Germany; (K.F.); (M.R.); (C.S.)
| | - Christina Stacke
- Sachtleben GmbH, Haus Spectrum am UKE, Martinistraße 64, D-20251 Hamburg, Germany; (K.F.); (M.R.); (C.S.)
| | - Tina Histing
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Schnarrenbergstr. 95, D-72076 Tübingen, Germany; (Y.C.); (R.H.A.-W.); (M.M.M.); (T.H.); (S.E.)
| | - Andreas K. Nussler
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Schnarrenbergstr. 95, D-72076 Tübingen, Germany; (Y.C.); (R.H.A.-W.); (M.M.M.); (T.H.); (S.E.)
| | - Sabrina Ehnert
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Schnarrenbergstr. 95, D-72076 Tübingen, Germany; (Y.C.); (R.H.A.-W.); (M.M.M.); (T.H.); (S.E.)
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30
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Riquelme MA, Gu S, Hua R, Jiang JX. Mechanotransduction via the coordinated actions of integrins, PI3K signaling and Connexin hemichannels. Bone Res 2021; 9:8. [PMID: 33531460 PMCID: PMC7854719 DOI: 10.1038/s41413-020-00126-w] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 09/25/2020] [Accepted: 10/14/2020] [Indexed: 12/11/2022] Open
Abstract
Mechanical loading opens connexin 43 (Cx43) hemichannels (HCs), leading to the release of bone anabolic molecules, such as prostaglandins, from mechanosensitive osteocytes, which is essential for bone formation and remodeling. However, the mechanotransduction mechanism that activates HCs remains elusive. Here, we report a unique pathway by which mechanical signals are effectively transferred between integrin molecules located in different regions of the cell, resulting in HC activation. Both integrin α5 and αV were activated upon mechanical stimulation via either fluid dropping or flow shear stress (FSS). Inhibition of integrin αV activation or ablation of integrin α5 prevented HC opening on the cell body when dendrites were mechanically stimulated, suggesting mechanical transmission from the dendritic integrin αV to α5 in the cell body during HC activation. In addition, HC function was compromised in vivo, as determined by utilizing an antibody blocking αV activation and α5-deficient osteocyte-specific knockout mice. Furthermore, inhibition of integrin αV activation, but not that of α5, attenuated activation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway upon mechanical loading, and the inhibition of PI3K/AKT activation blocked integrin α5 activation and HC opening. Moreover, HC opening was blocked only by an anti-integrin αV antibody at low but not high FSS levels, suggesting that dendritic αV is a more sensitive mechanosensor than α5 for activating HCs. Together, these results reveal a new molecular mechanism of mechanotransduction involving the coordinated actions of integrins and PI3K/AKT in osteocytic dendritic processes and cell bodies that leads to HC opening and the release of key bone anabolic factors.
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Affiliation(s)
- Manuel A Riquelme
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, 78229-3900, USA
| | - Sumin Gu
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, 78229-3900, USA
| | - Rui Hua
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, 78229-3900, USA
| | - Jean X Jiang
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, 78229-3900, USA.
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Pei F, Liu J, Zhang L, Pan X, Huang W, Cen X, Huang S, Jin Y, Zhao Z. The functions of mechanosensitive ion channels in tooth and bone tissues. Cell Signal 2021; 78:109877. [PMID: 33296740 DOI: 10.1016/j.cellsig.2020.109877] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/02/2020] [Accepted: 12/03/2020] [Indexed: 02/08/2023]
Abstract
Tooth and bone are independent tissues with a close relationship. Both are composed of a highly calcified outer structure and soft inner tissue, and both are constantly under mechanical stress. In particular, the alveolar bone and tooth constitute an occlusion system and suffer from masticatory and occlusal force. Thus, mechanotransduction is a key process in many developmental, physiological and pathological processes in tooth and bone. Mechanosensitive ion channels such as Piezo1 and Piezo2 are important participants in mechanotransduction, but their functions in tooth and bone are poorly understood. This review summarizes our current understanding of mechanosensitive ion channels and their roles in tooth and bone tissues. Research in these areas may shed new light on the regulation of tooth and bone tissues and potential treatments for diseases affecting these tissues.
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Affiliation(s)
- Fang Pei
- State Key Laboratory of Oral Diseases, Department of Orthodontics, West China School of Stomatology, Sichuan University, Chengdu, PR China
| | - Jialing Liu
- State Key Laboratory of Oral Diseases, Department of Orthodontics, West China School of Stomatology, Sichuan University, Chengdu, PR China
| | - Lan Zhang
- State Key Laboratory of Oral Diseases, Department of Orthodontics, West China School of Stomatology, Sichuan University, Chengdu, PR China
| | - Xuefeng Pan
- State Key Laboratory of Oral Diseases, Department of Orthodontics, West China School of Stomatology, Sichuan University, Chengdu, PR China
| | - Wei Huang
- State Key Laboratory of Oral Diseases, Department of Orthodontics, West China School of Stomatology, Sichuan University, Chengdu, PR China
| | - Xiao Cen
- Department of the Temporomandibular Joint, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Shishu Huang
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, PR China.
| | - Ying Jin
- State Key Laboratory of Oral Diseases, Department of Orthodontics, West China School of Stomatology, Sichuan University, Chengdu, PR China.
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases, Department of Orthodontics, West China School of Stomatology, Sichuan University, Chengdu, PR China.
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Simfia I, Schiavi J, McNamara LM. ROCK-II inhibition suppresses impaired mechanobiological responses in early estrogen deficient osteoblasts. Exp Cell Res 2020; 396:112264. [PMID: 32898551 DOI: 10.1016/j.yexcr.2020.112264] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 08/27/2020] [Accepted: 08/30/2020] [Indexed: 12/22/2022]
Abstract
Mechanobiological responses by osteoblasts are governed by downstream Rho-ROCK signalling through actin cytoskeleton re-arrangements but whether these responses are influenced by estrogen deficiency during osteoporosis remains unknown. The objective of this study was to determine alterations in the mechanobiological responses of estrogen-deficient osteoblasts and investigate whether an inhibitor of the Rho-ROCK signalling can revert these changes. MC3T3-E1 cells were pre-treated with 10 nM 17-β estradiol for 7 days and further cultured with or without estradiol for next 2 days. These cells were treated with or without ROCK-II inhibitor, Y-27632, and oscillatory fluid flow (OFF, 1Pa, 0.5 Hz, 1 h) was applied. Here, we report that Prostaglandin E2 release, Runt-related transcription factor 2 and Osteopontin gene expression were significantly enhanced in response to OFF in estrogen-deficient cells than in cells with estrogen (3.73 vs 1.63 pg/ng DNA; 13.5 vs 2.6 fold, 2.1 vs 0.4 fold respectively). Upon ROCK-II inhibition, these enhanced effects of estrogen deficiency were downregulated. OFF increased the fibril anisotropy in cells pre-treated with estrogen and this increase was suppressed upon ROCK-II inhibition. This study is the first to demonstrate altered mechanobiological responses by osteoblasts during early estrogen deficiency and that these responses to OFF can be suppressed upon ROCK inhibition.
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Affiliation(s)
- Irene Simfia
- Mechanobiology and Medical Device Research Group, Biomechanics Research Centre, Biomedical Engineering, College of Engineering and Informatics, National University of Ireland Galway, Galway, Ireland
| | - Jessica Schiavi
- Mechanobiology and Medical Device Research Group, Biomechanics Research Centre, Biomedical Engineering, College of Engineering and Informatics, National University of Ireland Galway, Galway, Ireland
| | - Laoise M McNamara
- Mechanobiology and Medical Device Research Group, Biomechanics Research Centre, Biomedical Engineering, College of Engineering and Informatics, National University of Ireland Galway, Galway, Ireland.
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Naqvi SM, Panadero Pérez JA, Kumar V, Verbruggen ASK, McNamara LM. A Novel 3D Osteoblast and Osteocyte Model Revealing Changes in Mineralization and Pro-osteoclastogenic Paracrine Signaling During Estrogen Deficiency. Front Bioeng Biotechnol 2020; 8:601. [PMID: 32656194 PMCID: PMC7326002 DOI: 10.3389/fbioe.2020.00601] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 05/18/2020] [Indexed: 11/13/2022] Open
Abstract
Recent in vitro studies have revealed that the mechanobiological responses of osteoblasts and osteocytes are fundamentally impaired during estrogen deficiency. However, these two-dimensional (2D) cell culture studies do not account for in vivo biophysical cues. Thus, the objectives of this study are to (1) develop a three-dimensional (3D) osteoblast and osteocyte model integrated into a bioreactor and (2) apply this model to investigate whether estrogen deficiency leads to changes in osteoblast to osteocyte transition, mechanosensation, mineralization, and paracrine signaling associated with bone resorption by osteoclasts. MC3T3-E1s were expanded in media supplemented with estrogen (17β-estradiol). These cells were encapsulated in gelatin-mtgase before culture in (1) continued estrogen (E) or (2) no further estrogen supplementation. Constructs were placed in gas permeable and water impermeable cell culture bags and maintained at 5% CO2 and 37°C. These bags were either mechanically stimulated in a custom hydrostatic pressure (HP) bioreactor or maintained under static conditions (control). We report that osteocyte differentiation, characterized by the presence of dendrites and staining for osteocyte marker dentin matrix acidic phosphoprotein 1 (DMP1), was significantly greater under estrogen withdrawal (EW) compared to under continuous estrogen treatment (day 21). Mineralization [bone sialoprotein (BSP), osteopontin (OPN), alkaline phosphatase (ALP), calcium] and gene expression associated with paracrine signaling for osteoclastogenesis [receptor activator of nuclear factor kappa-β ligand (RANKL)/osteoprotegerin OPG ratio] were significantly increased in estrogen deficient and mechanically stimulated cells. Interestingly, BSP and DMP-1 were also increased at day 1 and day 21, respectively, which play a role in regulation of biomineralization. Furthermore, the increase in pro-osteoclastogenic signaling may be explained by altered mechanoresponsiveness of osteoblasts or osteocytes during EW. These findings highlight the impact of estrogen deficiency on bone cell function and provide a novel in vitro model to investigate the mechanisms underpinning changes in bone cells after estrogen deficiency.
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Affiliation(s)
| | | | | | | | - Laoise M. McNamara
- Mechanobiology and Medical Device Research Group, Department of Biomedical Engineering, College of Engineering and Informatics, National University of Ireland Galway, Galway, Ireland
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Qin L, Liu W, Cao H, Xiao G. Molecular mechanosensors in osteocytes. Bone Res 2020; 8:23. [PMID: 32550039 PMCID: PMC7280204 DOI: 10.1038/s41413-020-0099-y] [Citation(s) in RCA: 244] [Impact Index Per Article: 48.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/07/2020] [Accepted: 04/17/2020] [Indexed: 12/11/2022] Open
Abstract
Osteocytes, the most abundant and long-lived cells in bone, are the master regulators of bone remodeling. In addition to their functions in endocrine regulation and calcium and phosphate metabolism, osteocytes are the major responsive cells in force adaptation due to mechanical stimulation. Mechanically induced bone formation and adaptation, disuse-induced bone loss and skeletal fragility are mediated by osteocytes, which sense local mechanical cues and respond to these cues in both direct and indirect ways. The mechanotransduction process in osteocytes is a complex but exquisite regulatory process between cells and their environment, between neighboring cells, and between different functional mechanosensors in individual cells. Over the past two decades, great efforts have focused on finding various mechanosensors in osteocytes that transmit extracellular mechanical signals into osteocytes and regulate responsive gene expression. The osteocyte cytoskeleton, dendritic processes, Integrin-based focal adhesions, connexin-based intercellular junctions, primary cilium, ion channels, and extracellular matrix are the major mechanosensors in osteocytes reported so far with evidence from both in vitro and in vitro studies. This review aims to give a systematic introduction to osteocyte mechanobiology, provide details of osteocyte mechanosensors, and discuss the roles of osteocyte mechanosensitive signaling pathways in the regulation of bone homeostasis.
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Affiliation(s)
- Lei Qin
- Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, and School of Medicine, Southern University of Science and Technology, Shenzhen, 518055 China
| | - Wen Liu
- Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, and School of Medicine, Southern University of Science and Technology, Shenzhen, 518055 China
| | - Huiling Cao
- Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, and School of Medicine, Southern University of Science and Technology, Shenzhen, 518055 China
| | - Guozhi Xiao
- Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, and School of Medicine, Southern University of Science and Technology, Shenzhen, 518055 China
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Zhao D, Liu R, Li G, Chen M, Shang P, Yang H, Jiang JX, Xu H. Connexin 43 Channels in Osteocytes Regulate Bone Responses to Mechanical Unloading. Front Physiol 2020; 11:299. [PMID: 32296345 PMCID: PMC7137730 DOI: 10.3389/fphys.2020.00299] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 03/16/2020] [Indexed: 01/01/2023] Open
Abstract
Connexin (Cx) 43 forms gap junctions and hemichannels that mediate communication between osteocytes and adjacent cells or the extracellular environment in bone, respectively. To investigate the role of each channel type in response to mechanical unloading, two transgenic mouse models overexpressing dominant-negative Cx43 predominantly in osteocytes driven by a 10 kb dentin matrix protein 1 (Dmp1) promoter were generated. The R76W mutation resulted in gap junction inhibition and enhancement of hemichannels, whereas the Δ130-136 mutation inhibited both gap junctions and hemichannels. Both mutations led to cortical bone loss with increased endocortical osteoclast activity during unloading. Increased periosteal osteoclasts with decreased apoptotic osteocytes were observed only in R76W mice. These findings indicated that inhibiting osteocytic Cx43 channels promotes bone loss induced by unloading, mainly in the cortical area; moreover, hemichannels protect osteocytes against apoptosis and promote periosteal bone remodeling, whereas gap junctions modulate endocortical osteoclast activity in response to unloading.
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Affiliation(s)
- Dezhi Zhao
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
| | - Ruofei Liu
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
| | - Guobin Li
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
| | - Meng Chen
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
| | - Peng Shang
- Key Laboratory for Space Bioscience and Biotechnology, Research and Development Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen, China
| | - Hui Yang
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Research Center of Special Environmental Biomechanics and Medical Engineering, Northwestern Polytechnical University, Xi’an, China
| | - Jean X. Jiang
- Department of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, United States
| | - Huiyun Xu
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Key Laboratory for Space Bioscience and Biotechnology, Research and Development Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen, China
- Research Center of Special Environmental Biomechanics and Medical Engineering, Northwestern Polytechnical University, Xi’an, China
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Riquelme MA, Cardenas ER, Xu H, Jiang JX. The Role of Connexin Channels in the Response of Mechanical Loading and Unloading of Bone. Int J Mol Sci 2020; 21:ijms21031146. [PMID: 32050469 PMCID: PMC7038207 DOI: 10.3390/ijms21031146] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 01/31/2020] [Accepted: 02/04/2020] [Indexed: 12/13/2022] Open
Abstract
The skeleton adapts to mechanical loading to promote bone formation and remodeling. While most bone cells are involved in mechanosensing, it is well accepted that osteocytes are the principal mechanosensory cells. The osteocyte cell body and processes are surrounded by a fluid-filled space, forming an extensive lacuno-canalicular network. The flow of interstitial fluid is a major stress-related factor that transmits mechanical stimulation to bone cells. The long dendritic processes of osteocytes form a gap junction channel network connecting not only neighboring osteocytes, but also cells on the bone surface, such as osteoblasts and osteoclasts. Mechanosensitive osteocytes also form hemichannels that mediate the communication between the cytoplasmic and extracellular microenvironment. This paper will discuss recent research progress regarding connexin (Cx)-forming gap junctions and hemichannels in osteocytes, osteoblasts, and other bone cells, including those richly expressing Cx43. We will then cover the recent progress regarding the regulation of these channels by mechanical loading and the role of integrins and signals in mediating Cx43 channels, and bone cell function and viability. Finally, we will summarize the recent studies regarding bone responses to mechanical unloading in Cx43 transgenic mouse models. The osteocyte has been perceived as the center of bone remodeling, and connexin channels enriched in osteocytes are a likely major player in meditating the function of bone. Based on numerous studies, connexin channels may present as a potential new therapeutic target in the treatment of bone loss and osteoporosis. This review will primarily focus on Cx43, with some discussion in other connexins expressed in bone cells.
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Affiliation(s)
- Manuel A. Riquelme
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229, USA; (M.A.R.); (E.R.C.)
| | - Eduardo R. Cardenas
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229, USA; (M.A.R.); (E.R.C.)
| | - Huiyun Xu
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China;
| | - Jean X. Jiang
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229, USA; (M.A.R.); (E.R.C.)
- Correspondence: ; Tel.: +1-210-562-4094
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Rosalem GS, Las Casas EB, Lima TP, González-Torres LA. A mechanobiological model to study upstream cell migration guided by tensotaxis. Biomech Model Mechanobiol 2020; 19:1537-1549. [PMID: 32006123 DOI: 10.1007/s10237-020-01289-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 01/11/2020] [Indexed: 01/06/2023]
Abstract
Cell migration is a process of crucial importance for the human body. It is responsible for important processes such as wound healing and tumor metastasis. Migration may occur in response to stimuli of chemical, physical and mechanical nature occurring in the cellular microenvironment. The interstitial flow (IF) can generate mechanical stimuli in cells that influence the cell behavior and interactions of the cells with the extracellular matrix (ECM). One of the phenomena is upstream migration, which is observed in some tumors. In this work, we present a new approach to study the adherent cell migration in a porous medium using a mechanobiological model, attempting to understand if upstream migration can be generated exclusively by mechanical factors. The influence of IF on the behavior of cells and the extracellular matrix was considered. The model is based on a system of coupled nonlinear differential equations solved by the finite element method. Several simulations were performed to study the upstream cell migration and evaluate the effects of pressure, permeability, ECM stiffness and cellular concentration variations on the cell velocity. The results indicated that upstream migration can occur in the presence of mechanical stimuli generated by IF and that the tested parameters have a direct influence on the cellular velocity, especially the pressure and the permeability.
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Affiliation(s)
- Gabriel Santos Rosalem
- Department of Mechanical Engineering, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Thiago Parente Lima
- Institute of Science and Technology, Federal University of Jequitinhonha and Mucuri Valleys, Diamantina, Brazil
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van Tol AF, Roschger A, Repp F, Chen J, Roschger P, Berzlanovich A, Gruber GM, Fratzl P, Weinkamer R. Network architecture strongly influences the fluid flow pattern through the lacunocanalicular network in human osteons. Biomech Model Mechanobiol 2019; 19:823-840. [PMID: 31782029 PMCID: PMC7203595 DOI: 10.1007/s10237-019-01250-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 11/04/2019] [Indexed: 12/24/2022]
Abstract
A popular hypothesis explains the mechanosensitivity of bone due to osteocytes sensing the load-induced flow of interstitial fluid squeezed through the lacunocanalicular network (LCN). However, the way in which the intricate structure of the LCN influences fluid flow through the network is largely unexplored. We therefore aimed to quantify fluid flow through real LCNs from human osteons using a combination of experimental and computational techniques. Bone samples were stained with rhodamine to image the LCN with 3D confocal microscopy. Image analysis was then performed to convert image stacks into mathematical network structures, in order to estimate the intrinsic permeability of the osteons as well as the load-induced fluid flow using hydraulic circuit theory. Fluid flow was studied in both ordinary osteons with a rather homogeneous LCN as well as a frequent subtype of osteons-so-called osteon-in-osteons-which are characterized by a ring-like zone of low network connectivity between the inner and the outer parts of these osteons. We analyzed 8 ordinary osteons and 9 osteon-in-osteons from the femur midshaft of a 57-year-old woman without any known disease. While the intrinsic permeability was 2.7 times smaller in osteon-in-osteons compared to ordinary osteons, the load-induced fluid velocity was 2.3 times higher. This increased fluid velocity in osteon-in-osteons can be explained by the longer path length, needed to cross the osteon from the cement line to the Haversian canal, including more fluid-filled lacunae and canaliculi. This explanation was corroborated by the observation that a purely structural parameter-the mean path length to the Haversian canal-is an excellent predictor for the average fluid flow velocity. We conclude that osteon-in-osteons may be particularly significant contributors to the mechanosensitivity of cortical bone, due to the higher fluid flow in this type of osteons.
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Affiliation(s)
- Alexander F van Tol
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, 14476, Potsdam, Germany. .,Berlin-Brandenburg School of Regenerative Therapies (BSRT), Föhrer Str. 15, 13353, Berlin, Germany.
| | - A Roschger
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, 14476, Potsdam, Germany.,Chemistry and Physics of Materials, Paris Lodron University of Salzburg, Jakrob-Haringer Straße 2a, 5020, Salzburg, Austria
| | - F Repp
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, 14476, Potsdam, Germany
| | - J Chen
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, 14476, Potsdam, Germany.,College of Engineering, Mathematics, and Physical Science, University of Exeter, Exeter, EX4 4QF, UK
| | - P Roschger
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Heinrich Collin Str. 30, 1140, Vienna, Austria
| | - A Berzlanovich
- Center of Forensic Science, Medical University of Vienna, Sensengasse 2, 1090, Vienna, Austria
| | - G M Gruber
- Department of Anatomy, Center for Anatomy and Cell Biology, Medical University of Vienna, 1090, Vienna, Austria
| | - P Fratzl
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, 14476, Potsdam, Germany
| | - Richard Weinkamer
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, 14476, Potsdam, Germany
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Alfieri R, Vassalli M, Viti F. Flow-induced mechanotransduction in skeletal cells. Biophys Rev 2019; 11:729-743. [PMID: 31529361 DOI: 10.1007/s12551-019-00596-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 09/03/2019] [Indexed: 12/15/2022] Open
Abstract
Human body is subject to many and variegated mechanical stimuli, actuated in different ranges of force, frequency, and duration. The process through which cells "feel" forces and convert them into biochemical cascades is called mechanotransduction. In this review, the effects of fluid shear stress on bone cells will be presented. After an introduction to present the major players in bone system, we describe the mechanoreceptors in bone tissue that can feel and process fluid flow. In the second part of the review, we present an overview of the biological processes and biochemical cascades initiated by fluid shear stress in bone cells.
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Affiliation(s)
- Roberta Alfieri
- Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza" - National Research Council (IGM-CNR), Via Abbiategrasso, 207, 27100, Pavia, Italy
| | - Massimo Vassalli
- Institute of Biophysics - National Research Council (IBF-CNR), Via De Marini, 6, 16149, Genoa, Italy
| | - Federica Viti
- Institute of Biophysics - National Research Council (IBF-CNR), Via De Marini, 6, 16149, Genoa, Italy.
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40
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Abstract
PURPOSE OF REVIEW Osteocytes are the main mechanosensitive cells in bone. Integrin-based adhesions have been shown to facilitate mechanotransduction, and therefore play an important role in load-induced bone formation. This review outlines the role of integrins in osteocyte function (cell adhesion, signalling, and mechanotransduction) and possible role in disease. RECENT FINDINGS Both β1 and β3 integrins subunits have been shown to be required for osteocyte mechanotransduction. Antagonism of these integrin subunits in osteocytes resulted in impaired responses to fluid shear stress. Various disease states (osteoporosis, osteoarthritis, bone metastases) have been shown to result in altered integrin expression and function. Osteocyte integrins are required for normal cell function, with dysregulation of integrins seen in disease. Understanding the mechanism of faulty integrins in disease may aid in the creation of novel therapeutic approaches.
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Affiliation(s)
- Ivor P Geoghegan
- Department of Mechanical and Biomedical Engineering, Mechanobiology and Medical Device Research Group (MMDRG), Biomedical Engineering, National University of Ireland, Galway, Ireland
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland, Galway, Ireland
| | - David A Hoey
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland, Galway, Ireland
- Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
- Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin 2, Ireland
- Advanced Materials and Bioengineering Research Centre, Trinity College Dublin & RCSI, Dublin 2, Ireland
| | - Laoise M McNamara
- Department of Mechanical and Biomedical Engineering, Mechanobiology and Medical Device Research Group (MMDRG), Biomedical Engineering, National University of Ireland, Galway, Ireland.
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland, Galway, Ireland.
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Abstract
PURPOSE OF REVIEW Osteocytes are the most abundant bone cells. They are completely encased in mineralized tissue, sitting inside lacunae that are connected by a multitude of canaliculi. In recent years, the osteocyte network has been shown to fulfill endocrine functions and to communicate with a number of other organs. This review addresses emerging knowledge on the connectome of the lacunocanalicular network in different types of bone tissue. RECENT FINDINGS Recent advances in three-dimensional imaging technology started to reveal parameters that are well known from general theory to characterize the function of networks, such as network density, degree of nodes, or shortest path length through the network. The connectome of the lacunocanalicular network differs in some aspects between lamellar and woven bone and seems to change with age. More research is needed to relate network structure to function, such as intercellular transport or communication and its role in mechanosensation, as well as to understand the effect of diseases.
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Affiliation(s)
- Richard Weinkamer
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, 14424, Potsdam, Germany
| | - Philip Kollmannsberger
- Center for Computational and Theoretical Biology, Universität Würzburg, Campus Hubland Nord 32, 97074, Würzburg, Germany
| | - Peter Fratzl
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, 14424, Potsdam, Germany.
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Thibeaux R, Duval H, Smaniotto B, Vennat E, Néron D, David B. Assessment of the interplay between scaffold geometry, induced shear stresses, and cell proliferation within a packed bed perfusion bioreactor. Biotechnol Prog 2019; 35:e2880. [PMID: 31271252 DOI: 10.1002/btpr.2880] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 05/29/2019] [Accepted: 06/27/2019] [Indexed: 11/12/2022]
Abstract
By favoring cell proliferation and differentiation, perfusion bioreactors proved efficient at optimizing cell culture. The aim of this study was to quantify cell proliferation within a perfusion bioreactor and correlate it to the wall shear stress (WSS) distribution by combining 3-D imaging and computational fluid dynamics simulations.NIH-3T3 fibroblasts were cultured onto a scaffold model made of impermeable polyacetal spheres or Polydimethylsiloxane cubes. After 1, 2, and 3 weeks of culture, constructs were analyzed by micro-computed tomography (μCT) and quantification of cell proliferation was assessed. After 3 weeks, the volume of cells was found four times higher in the stacking of spheres than in the stacking of cube.3D-μCT reconstruction of bioreactors was used as input for the numerical simulations. Using a lattice-Boltzmann method, we simulated the fluid flow within the bioreactors. We retrieved the WSS distribution (PDF) on the scaffolds surface at the beginning of cultivation and correlated this distribution to the local presence of cells after 3 weeks of cultivation. We found that the WSS distributions strongly differ between spheres and cubes even if the porosity and the specific wetted area of the stackings were very similar. The PDF is narrower and the mean WSS is lower for cubes (11 mPa) than for spheres (20 mPa). For the stacking of spheres, the relative occupancy of the surface sites by cells is maximal when WSS is greater than 20 mPa. For cubes, the relative occupancy is maximal when the WSS is lower than 10 mPa. The discrepancies between spheres and cubes are attributed to the more numerous sites in stacking of spheres that may induce 3-D (multi-layered) proliferation.
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Affiliation(s)
- Roman Thibeaux
- MSSMat, CentraleSupélec, Université Paris Saclay, CNRS, Gif sur Yvette, France
| | - Hervé Duval
- LGPM, CentraleSupélec, Université Paris Saclay, Gif sur Yvette, France
| | | | - Elsa Vennat
- MSSMat, CentraleSupélec, Université Paris Saclay, CNRS, Gif sur Yvette, France
| | - David Néron
- LMT, ENS Paris-Saclay, CNRS, Université Paris-Saclay, Cachan, France
| | - Bertrand David
- MSSMat, CentraleSupélec, Université Paris Saclay, CNRS, Gif sur Yvette, France
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Alam K, Al-Ghaithi A, Piya S, Saleem A. In-vitro experimental study of histopathology of bone in vibrational drilling. Med Eng Phys 2019; 67:78-87. [PMID: 30981608 DOI: 10.1016/j.medengphy.2019.03.013] [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: 06/29/2018] [Revised: 03/09/2019] [Accepted: 03/30/2019] [Indexed: 02/06/2023]
Abstract
Drilling is a common surgical procedure for fracture treatment and reconstruction in multiple surgical fields, including orthopaedics, neurology, and dentistry. Drilling delicate tissue (such as bone) with a hard metallic tool is considered notorious for inducing mechanical and thermal damage, which can adversely affect osseointegration and may weaken the bond between the bone and implant, or other fixative devices anchoring the bone. The aim of this study is to explore the benefits of vibrational drilling (VD) in overcoming the complications associated with conventional drilling (CD). Drilling tests were performed on fresh cortical bone with the intention of investigating the effect of a range of frequencies, in combination with drilling speed and feed rate, on biological damage around the drilling region using histological sections of skeletally mature bone. The study examined the most influential factors and optimal combination of parameters for safe and efficient drilling in bone. Results from Taguchi grey relational analysis showed that a lower drilling speed and feed rate combined with a frequency of 20 kHz were favourable parameters for safe drilling in bone. Accordingly, VD using controlled parameters may be an alternative to CD in bone surgical procedures.
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Affiliation(s)
- Khurshid Alam
- Department of Mechanical and Industrial Engineering, Sultan Qaboos University, P.O. Box 33, Al-Khoud 123, Sultanate of Oman.
| | | | - Sujan Piya
- Department of Mechanical and Industrial Engineering, Sultan Qaboos University, P.O. Box 33, Al-Khoud 123, Sultanate of Oman
| | - Ashraf Saleem
- Department of Electrical and Computer Engineering, Sultan Qaboos University, P.O. Box 33, Al-Khoud 123, Sultanate of Oman
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Histological Method to Study the Effect of Shear Stress on Cell Proliferation and Tissue Morphology in a Bioreactor. Tissue Eng Regen Med 2019; 16:225-235. [PMID: 31205852 DOI: 10.1007/s13770-019-00181-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 12/26/2018] [Accepted: 01/22/2019] [Indexed: 12/15/2022] Open
Abstract
Background Tissue engineering represents a promising approach for the production of bone substitutes. The use of perfusion bioreactors for the culture of bone-forming cells on a three-dimensional porous scaffold resolves mass transport limitations and provides mechanical stimuli. Despite the recent and important development of bioreactors for tissue engineering, the underlying mechanisms leading to the production of bone substitutes remain poorly understood. Methods In order to study cell proliferation in a perfusion bioreactor, we propose a simplified experimental set-up using an impermeable scaffold model made of 2 mm diameter glass beads on which mechanosensitive cells, NIH-3T3 fibroblasts are cultured for up to 3 weeks under 10 mL/min culture medium flow. A methodology combining histological procedure, image analysis and analytical calculations allows the description and quantification of cell proliferation and tissue production in relation to the mean wall shear stress within the bioreactor. Results Results show a massive expansion of the cell phase after 3 weeks in bioreactor compared to static control. A scenario of cell proliferation within the three-dimensional bioreactor porosity over the 3 weeks of culture is proposed pointing out the essential role of the contact points between adjacent beads. Calculations indicate that the mean wall shear stress experienced by the cells changes with culture time, from about 50 mPa at the beginning of the experiment to about 100 mPa after 3 weeks. Conclusion We anticipate that our results will help the development and calibration of predictive models, which rely on estimates and morphological description of cell proliferation under shear stress.
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Huang L, Korhonen RK, Turunen MJ, Finnilä MAJ. Experimental mechanical strain measurement of tissues. PeerJ 2019; 7:e6545. [PMID: 30867989 PMCID: PMC6409087 DOI: 10.7717/peerj.6545] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 01/31/2019] [Indexed: 12/22/2022] Open
Abstract
Strain, an important biomechanical factor, occurs at different scales from molecules and cells to tissues and organs in physiological conditions. Under mechanical strain, the strength of tissues and their micro- and nanocomponents, the structure, proliferation, differentiation and apoptosis of cells and even the cytokines expressed by cells probably shift. Thus, the measurement of mechanical strain (i.e., relative displacement or deformation) is critical to understand functional changes in tissues, and to elucidate basic relationships between mechanical loading and tissue response. In the last decades, a great number of methods have been developed and applied to measure the deformations and mechanical strains in tissues comprising bone, tendon, ligament, muscle and brain as well as blood vessels. In this article, we have reviewed the mechanical strain measurement from six aspects: electro-based, light-based, ultrasound-based, magnetic resonance-based and computed tomography-based techniques, and the texture correlation-based image processing method. The review may help solving the problems of experimental and mechanical strain measurement of tissues under different measurement environments.
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Affiliation(s)
- Lingwei Huang
- Department of Applied Physics, University of Eastern Finland, Kuopio, Finland
| | - Rami K Korhonen
- Department of Applied Physics, University of Eastern Finland, Kuopio, Finland
| | - Mikael J Turunen
- Department of Applied Physics, University of Eastern Finland, Kuopio, Finland
| | - Mikko A J Finnilä
- Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.,Research Unit of Medical Imaging, Physics and Technology, University of Oulu, Oulu, Finland.,Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland
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46
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Tao SC, Guo SC. Extracellular vesicles in bone: "dogrobbers" in the "eternal battle field". Cell Commun Signal 2019; 17:6. [PMID: 30658653 PMCID: PMC6339294 DOI: 10.1186/s12964-019-0319-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 01/06/2019] [Indexed: 02/07/2023] Open
Abstract
Throughout human life, bone is constantly in a delicate dynamic equilibrium of synthesis and resorption, hosting finely-tuned bone mineral metabolic processes for bone homeostasis by collaboration or symphony among several cell types including osteoclasts (OCs), osteoblasts (OBs), osteocytes (OYs), vascular endothelial cells (ECs) and their precursors. Beyond these connections, a substantial level of communication seems to occur between bone and other tissues, and together, they form an organic unit linked to human health and disease. However, the current hypothesis, which includes growth factors, hormones and specific protein secretion, incompletely explains the close connections among bone cells or between bone and other tissues. Extracellular vesicles (EVs) are widely-distributed membrane structures consisting of lipid bilayers, membrane proteins and intravesicular cargo (including proteins and nucleic acids), ranging from 30 nm to 1000 nm in diameter, and their characters have been highly conserved throughout evolution. EVs have targeting abilities and the potential to transmit multidimensional, abundant and complicated information, as powerful and substantial "dogrobbers" mediating intercellular communications. As research has progressed, EVs have gradually become thought of as "dogrobbers" in bone tissue-the "eternal battle field" -in a delicate dynamic balance of destruction and reconstruction. In the current review, we give a brief description of the major constituent cells in bone tissues and explore the progress of current research on bone-derived EVs. In addition, this review also discusses in depth not only potential directions for future research to breakthrough in this area but also problems existing in current research that need to be solved for a better understanding of bone tissues.
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Affiliation(s)
- Shi-Cong Tao
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
| | - Shang-Chun Guo
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
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47
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Hinton PV, Rackard SM, Kennedy OD. In Vivo Osteocyte Mechanotransduction: Recent Developments and Future Directions. Curr Osteoporos Rep 2018; 16:746-753. [PMID: 30406580 DOI: 10.1007/s11914-018-0485-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
PURPOSE OF REVIEW Mechanical loading is an essential stimulus for skeletal tissues. Osteocytes are primarily responsible for sensing mechanical stimuli in bone and for orchestrating subsequent responses. This is critical for maintaining homeostasis, and responding to injury/disease. The osteocyte mechanotransduction pathway, and the downstream effects it mediates, is highly complex. In vivo models have proved invaluable in understanding this process. This review summarizes the commonly used models, as well as more recently developed ones, and describes how they are used to address emerging questions in the field. RECENT FINDINGS Minimally invasive animal models can be used to determine mechanisms of osteocyte mechanotransduction, at the cell and molecular level, while simultaneously reducing potentially confounding responses such as inflammation/wound-healing. The details of osteocyte mechanotransduction in bone are gradually becoming clearer. In vivo model systems are a key tool in pursing this question. Advances in this field are explored and discussed in this review.
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Affiliation(s)
- Paige V Hinton
- Department of Anatomy & Tissue Engineering Research Group, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland
| | - Susan M Rackard
- School of Veterinary Medicine, Veterinary Science Centre, University College Dublin, Dublin 4, Ireland
| | - Oran D Kennedy
- Department of Anatomy & Tissue Engineering Research Group, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland.
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48
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Murshid S, Takano-Yamamoto T, Kamioka H. Differential distribution of microtubules in immature osteocytes in vivo. J Oral Biosci 2018. [DOI: 10.1016/j.job.2018.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Wang P, Tang C, Wu J, Yang Y, Yan Z, Liu X, Shao X, Zhai M, Gao J, Liang S, Luo E, Jing D. Pulsed electromagnetic fields regulate osteocyte apoptosis, RANKL/OPG expression, and its control of osteoclastogenesis depending on the presence of primary cilia. J Cell Physiol 2018; 234:10588-10601. [DOI: 10.1002/jcp.27734] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 10/18/2018] [Indexed: 12/23/2022]
Affiliation(s)
- Pan Wang
- Department of Biomedical Engineering Fourth Military Medical University Xi’an China
| | - Chi Tang
- Department of Biomedical Engineering Fourth Military Medical University Xi’an China
| | - Junjie Wu
- State Key Laboratory of Military Stomatology, Department of Orthodontics School of Stomatology, Fourth Military Medical University Xi’an China
| | - Yuefan Yang
- Department of Neurosurgery 251 Hospital of Chinese People’s Liberation Army Zhangjiakou China
| | - Zedong Yan
- Department of Biomedical Engineering Fourth Military Medical University Xi’an China
| | - Xiyu Liu
- Department of Biomedical Engineering Fourth Military Medical University Xi’an China
| | - Xi Shao
- Department of Biomedical Engineering Fourth Military Medical University Xi’an China
| | - Mingming Zhai
- Department of Biomedical Engineering Fourth Military Medical University Xi’an China
| | - Jie Gao
- State Key Laboratory of Military Stomatology, Department of Orthodontics School of Stomatology, Fourth Military Medical University Xi’an China
| | - Shengru Liang
- Department of Endocrinology Xijing Hospital, Fourth Military Medical Univerisity Xi’an China
| | - Erping Luo
- Department of Biomedical Engineering Fourth Military Medical University Xi’an China
| | - Da Jing
- Department of Biomedical Engineering Fourth Military Medical University Xi’an China
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50
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Cresswell EN, Nguyen TM, Horsfield MW, Alepuz AJ, Metzger TA, Niebur GL, Hernandez CJ. Mechanically induced bone formation is not sensitive to local osteocyte density in rat vertebral cancellous bone. J Orthop Res 2018; 36:672-681. [PMID: 28513889 DOI: 10.1002/jor.23606] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Accepted: 05/10/2017] [Indexed: 02/04/2023]
Abstract
Osteocytes play an integral role in bone by sensing mechanical stimuli and releasing signaling factors that direct bone formation. The importance of osteocytes in mechanotransduction suggests that regions of bone tissue with greater osteocyte populations are more responsive to mechanical stimuli. To determine the effects of osteocyte population on bone functional adaptation we applied mechanical loads to the 8th caudal vertebra of skeletally mature female Sprague Dawley rats (6 months of age, n = 8 loaded, n = 8 sham controls). The distribution of tissue stress/strain within cancellous bone was determined using high-resolution finite element models, osteocyte distribution was determined using nano-computed tomography, and locations of bone formation were determined using three-dimensional images of fluorescent bone formation markers. Loading increased bone formation (3D MS/BS 10.82 ± 2.09% in loaded v. 3.17 ± 2.05% in sham control, mean ± SD). Bone formation occurred at regions of cancellous bone experiencing greater tissue stress/strain, however stress/strain was only a modest predictor of bone formation; even at locations of greatest stress/strain the probability of observing bone formation did not exceed 41%. The local osteocyte population was not correlated with locations of new bone formation. The findings support the idea that local tissue stress/strain influence the locations of bone formation in cancellous bone, but suggest that the size of the osteocyte population itself is not influential. We conclude that other aspects of osteocytes such as osteocyte connectivity, lacunocanilicular nano-geometry, and/or fluid pressure/shear distributions within the marrow space may be more influential in regulating bone mechanotransduction than the number of osteocytes. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:672-681, 2018.
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Affiliation(s)
- Erin N Cresswell
- Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York.,Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York
| | - Thu M Nguyen
- Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York
| | - Michael W Horsfield
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York
| | - Adrian J Alepuz
- Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York
| | - Thomas A Metzger
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, Indiana
| | - Glen L Niebur
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, Indiana
| | - Christopher J Hernandez
- Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York.,Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York.,Hospital for Special Surgery, New York, New York
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