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Beckley S, Dey R, Stinton S, van der Merwe W, Branch T, September AV, Posthumus M, Collins M. The Association of Genetic Variants Within the Type XII Collagen and Tenascin C Genes with Knee Joint Laxity Measurements. Genes (Basel) 2025; 16:164. [PMID: 40004493 PMCID: PMC11855217 DOI: 10.3390/genes16020164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/09/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES Types I, V, and XI collagen gene variants have been reported to associate with measurements of knee joint laxity and/or absolute knee ligament length changes. Type XII collagen and tenascin C are also ligament structural proteins whose expression is regulated by mechanical loading. This study investigated whether COL12A1 and TNC variants are associated with knee laxity and/or ligament length changes. METHODS Genu recurvatum, anterior-posterior tibial translation, external-internal tibial rotation, and ligament length changes were measured in 128 healthy participants. They were genotyped for COL12A1 (rs970547) and TNC (rs1061494, rs2104772, rs1138545). RESULTS Both the COL12A1 AA and TNC rs1061494 TT genotypes were associated with decreased external (p = 0.007, p = 0.010) and internal (p = 0.025, p = 0.002) rotation, as well as slack (p = 0.033, p = 0.014), in the dominant leg. Both genotypes, together with sex, weight, and/or COL1A1 genotypes, explained 26% and 32% of the variance in external and internal rotation, respectively. The TNC genotype, sex, and BMI explained 23% of the variance in slack. The COL12A1 AA and the TNC rs1061494 TT genotypes were associated with smaller changes in the MCL (aMCL: COL12A1 p = 0.009, TNC p = 0.045; iMCL: COL12A1 p = 0.004, TNC p = 0.043; pMCL: COL12A1 p = 0.003, TNC p = 0.067; aDMCL: COL12A1 p = 0.007, TNC p = 0.020; pDMCL: COL12A1 p = 0.007, TNC p = 0.023) and/or LCL (COL12A1 p = 0.652, TNC p = 0.049) lengths within the dominant knee. The TNC rs1061494 CC genotype was associated with larger changes in the non-dominant anterior (p = 0.021) and posterior (p < 0.001) ACL bundle lengths. CONCLUSIONS These findings suggest that COL12A1 and TNC variants are associated with internal-external tibial rotation and knee ligament length changes in healthy individuals.
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Affiliation(s)
- Samantha Beckley
- Health Through Physical Activity, Lifestyle and Sport Research Centre (HPALS), Division of Physiological Sciences, Department of Human Biology, University of Cape Town, Rondebosch, Cape Town 7700, South Africa; (S.B.); (W.v.d.M.); (A.V.S.); (M.P.)
| | - Roopam Dey
- Division of Biomedical Engineering and Division of Orthopaedic Surgery, Faculty of Health Sciences, University of Cape Town, Rondebosch, Cape Town 7700, South Africa;
| | - Shaun Stinton
- End Range of Motion Improvement, Atlanta, GA 30324, USA; (S.S.); (T.B.)
| | - Willem van der Merwe
- Health Through Physical Activity, Lifestyle and Sport Research Centre (HPALS), Division of Physiological Sciences, Department of Human Biology, University of Cape Town, Rondebosch, Cape Town 7700, South Africa; (S.B.); (W.v.d.M.); (A.V.S.); (M.P.)
- Sports Science Orthopaedic Clinic, Sports Science Institute of South Africa, Newlands, Cape Town 7700, South Africa
| | - Thomas Branch
- End Range of Motion Improvement, Atlanta, GA 30324, USA; (S.S.); (T.B.)
| | - Alison V. September
- Health Through Physical Activity, Lifestyle and Sport Research Centre (HPALS), Division of Physiological Sciences, Department of Human Biology, University of Cape Town, Rondebosch, Cape Town 7700, South Africa; (S.B.); (W.v.d.M.); (A.V.S.); (M.P.)
| | - Michael Posthumus
- Health Through Physical Activity, Lifestyle and Sport Research Centre (HPALS), Division of Physiological Sciences, Department of Human Biology, University of Cape Town, Rondebosch, Cape Town 7700, South Africa; (S.B.); (W.v.d.M.); (A.V.S.); (M.P.)
- Sports Science Institute of South Africa, Newlands, Cape Town 7700, South Africa
| | - Malcolm Collins
- Health Through Physical Activity, Lifestyle and Sport Research Centre (HPALS), Division of Physiological Sciences, Department of Human Biology, University of Cape Town, Rondebosch, Cape Town 7700, South Africa; (S.B.); (W.v.d.M.); (A.V.S.); (M.P.)
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Fukuyama Y, Murakami H, Iemitsu M. Single Nucleotide Polymorphisms and Tendon/Ligament Injuries in Athletes: A Systematic Review and Meta-analysis. Int J Sports Med 2025; 46:3-21. [PMID: 39437988 DOI: 10.1055/a-2419-4359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
This systematic review and meta-analysis aimed to identify the association between genetic polymorphisms and tendon and ligament injuries in adolescent and adult athletes of multiple competition sports. The PubMed, Web of Science, EBSCO, Cochrane Library, and MEDLINE databases were searched until July 7, 2023. Eligible articles included genetic studies on tendon and ligament injuries and comparisons between injured and non-injured athletes. This review included 31 articles, comprising 1,687 injury cases and 2,227 controls, from a meta-analysis of 12 articles. We identified 144 candidate gene polymorphisms (only single nucleotide polymorphisms were identified). The meta-analyses included vascular endothelial growth factor A (VEGFA) rs699947, collagen type I alpha 1 rs1800012, collagen type V alpha 1 rs12722, and matrix metalloproteinase 3 rs679620. The VEGFA rs699947 polymorphism showed a lower risk of injuries in athletes with the C allele ([C vs. A]: OR=0.80, 95% CI: 0.65-0.98, I 2 =3.82%, p=0.03). The risk of these injuries were not affected by other polymorphisms. In conclusion, the VEGFA rs699947 polymorphism is associated with the risk of tendon and ligament injuries in athletes. This study provides insights into genetic variations that contribute to our understanding of the risk factors for such injuries in athletes.
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Affiliation(s)
- Yumi Fukuyama
- Department of Physical Therapy, Aino University, Ibaraki, Japan
- Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Japan
| | - Haruka Murakami
- Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Japan
| | - Motoyuki Iemitsu
- Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Japan
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Lopes LR, Amaral MVG, Goes RA, Tavares V, Dias F, Medeiros R, Machado DE, Perini JA. Tenascin-C-Matrix Metalloproteinase-3 Phenotype and the Risk of Tendinopathy in High-Performance Athletes: A Case-Control Study. Diagnostics (Basel) 2024; 14:2469. [PMID: 39594135 PMCID: PMC11592874 DOI: 10.3390/diagnostics14222469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 10/26/2024] [Accepted: 10/28/2024] [Indexed: 11/28/2024] Open
Abstract
Background/Objectives: Tendon structure is predominantly composed of the extracellular matrix (ECM), and genetic variants in non-collagenous ECM components may influence susceptibility to tendinopathy. We investigated the potential influence of single nucleotide polymorphisms (SNPs) in fibrillin-2 (FBN2), tenascin-C (TNC), and matrix metalloproteinase-3 (MMP3) on the tendon regeneration failure phenotype and impact on the susceptibility to tendinopathy in Brazilian high-performance athletes. Methods: This case-control study was conducted with 397 high-performance athletes from different sports modalities (197 tendinopathy cases and 200 controls), and they were analyzed by validated TaqManTM SNP genotyping assays of the SNPs FBN2 (rs331079), TNC (rs2104772), and MMP3 (rs591058). Results: Out of the 197 tendinopathy cases, 63% suffered from chronic tendon pain and 22% experienced more than three episodes of disease manifestation. The TNC-rs2104772-A allele was significantly associated with tendinopathy (OR: 1.4; 95% CI: 1.1-1.8), while athletes carrying the MMP3-rs591058-T allele were linked to an increased risk of more episodes of disease manifestation (OR: 1.7; 95% CI: 1.1-2.8). The TNC-MMP3 tendon regeneration failure phenotype (TNC-A/MMP3-T) was associated with an increased risk of tendinopathy (OR: 1.4; 95% CI: 1.1-2.0) and episodes of disease manifestation (OR: 2.0; 95% CI: 1.2-3.5). Athletes with tendinopathy who had the TNC-A/MMP3-T interaction were more prone to experiencing more than three disease exacerbations (OR: 4.3; 95% CI: 1.8-10.5) compared to TNC-A/TNC-C. Conclusions: This study suggests that rs2104772 and rs591058 SNPs could be involved in the tendon regeneration failure phenotype and may influence the molecular mechanism related to the regulation of the tendon ECM during training workload.
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Affiliation(s)
- Lucas Rafael Lopes
- Research Laboratory of Pharmaceutical Science (LAPESF), Rio de Janeiro State University (UERJ), Av. Manuel Caldeira de Alvarenga, 1203—Campo Grande, Rio de Janeiro 23070-200, RJ, Brazil; (L.R.L.); (D.E.M.)
- Program of Post-Graduation in Public Health and Environment, National School of Public Health, Oswald Cruz Foundation, Rio de Janeiro 21041-210, RJ, Brazil
| | - Marcus Vinícius Galvão Amaral
- Research Division, National Institute of Traumatology and Orthopaedics, Rio de Janeiro 20940-070, RJ, Brazil (R.A.G.)
| | - Rodrigo Araujo Goes
- Research Division, National Institute of Traumatology and Orthopaedics, Rio de Janeiro 20940-070, RJ, Brazil (R.A.G.)
| | - Valéria Tavares
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/Pathology and Laboratory Medicine Department, Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto CCC), 4200-072 Porto, Portugal; (V.T.); (R.M.)
| | - Francisca Dias
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/Pathology and Laboratory Medicine Department, Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto CCC), 4200-072 Porto, Portugal; (V.T.); (R.M.)
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/Pathology and Laboratory Medicine Department, Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto CCC), 4200-072 Porto, Portugal; (V.T.); (R.M.)
- Faculty of Medicine, University of Porto (FMUP), 4200-072 Porto, Portugal
- ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
- Research Department, Portuguese League Against Cancer (NRNorte), 4200-172 Porto, Portugal
- Faculty of Health Sciences, Fernando Pessoa University, 4200-150 Porto, Portugal
| | - Daniel Escorsim Machado
- Research Laboratory of Pharmaceutical Science (LAPESF), Rio de Janeiro State University (UERJ), Av. Manuel Caldeira de Alvarenga, 1203—Campo Grande, Rio de Janeiro 23070-200, RJ, Brazil; (L.R.L.); (D.E.M.)
| | - Jamila Alessandra Perini
- Research Laboratory of Pharmaceutical Science (LAPESF), Rio de Janeiro State University (UERJ), Av. Manuel Caldeira de Alvarenga, 1203—Campo Grande, Rio de Janeiro 23070-200, RJ, Brazil; (L.R.L.); (D.E.M.)
- Program of Post-Graduation in Public Health and Environment, National School of Public Health, Oswald Cruz Foundation, Rio de Janeiro 21041-210, RJ, Brazil
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Schmidt L, Saynisch M, Hoegsbjerg C, Schmidt A, Mackey A, Lackmann JW, Müller S, Koch M, Brachvogel B, Kjaer M, Antczak P, Krüger M. Spatial proteomics of skeletal muscle using thin cryosections reveals metabolic adaptation at the muscle-tendon transition zone. Cell Rep 2024; 43:114374. [PMID: 38900641 DOI: 10.1016/j.celrep.2024.114374] [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: 12/07/2023] [Revised: 04/05/2024] [Accepted: 05/31/2024] [Indexed: 06/22/2024] Open
Abstract
Morphological studies of skeletal muscle tissue provide insights into the architecture of muscle fibers, the surrounding cells, and the extracellular matrix (ECM). However, a spatial proteomics analysis of the skeletal muscle including the muscle-tendon transition zone is lacking. Here, we prepare cryotome muscle sections of the mouse soleus muscle and measure each slice using short liquid chromatography-mass spectrometry (LC-MS) gradients. We generate 3,000 high-resolution protein profiles that serve as the basis for a network analysis to reveal the complex architecture of the muscle-tendon junction. Among the protein profiles that increase from muscle to tendon, we find proteins related to neuronal activity, fatty acid biosynthesis, and the renin-angiotensin system (RAS). Blocking the RAS in cultured mouse tenocytes using losartan reduces the ECM synthesis. Overall, our analysis of thin cryotome sections provides a spatial proteome of skeletal muscle and reveals that the RAS acts as an additional regulator of the matrix within muscle-tendon junctions.
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Affiliation(s)
- Luisa Schmidt
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
| | - Michael Saynisch
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
| | - Christian Hoegsbjerg
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark; Part of IOC Research Center Copenhagen and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Abigail Mackey
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark; Part of IOC Research Center Copenhagen and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jan-Wilm Lackmann
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
| | - Stefan Müller
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
| | - Manuel Koch
- Institute for Dental Research and Oral Musculoskeletal Biology, Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
| | - Bent Brachvogel
- Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Medical Faculty, University of Cologne, Cologne, Germany; Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
| | - Michael Kjaer
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark; Part of IOC Research Center Copenhagen and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Philipp Antczak
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
| | - Marcus Krüger
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
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5
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Sayed RKA, Hibbert JE, Jorgenson KW, Hornberger TA. The Structural Adaptations That Mediate Disuse-Induced Atrophy of Skeletal Muscle. Cells 2023; 12:2811. [PMID: 38132132 PMCID: PMC10741885 DOI: 10.3390/cells12242811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 12/07/2023] [Accepted: 12/09/2023] [Indexed: 12/23/2023] Open
Abstract
The maintenance of skeletal muscle mass plays a fundamental role in health and issues associated with quality of life. Mechanical signals are one of the most potent regulators of muscle mass, with a decrease in mechanical loading leading to a decrease in muscle mass. This concept has been supported by a plethora of human- and animal-based studies over the past 100 years and has resulted in the commonly used term of 'disuse atrophy'. These same studies have also provided a great deal of insight into the structural adaptations that mediate disuse-induced atrophy. For instance, disuse results in radial atrophy of fascicles, and this is driven, at least in part, by radial atrophy of the muscle fibers. However, the ultrastructural adaptations that mediate these changes remain far from defined. Indeed, even the most basic questions, such as whether the radial atrophy of muscle fibers is driven by the radial atrophy of myofibrils and/or myofibril hypoplasia, have yet to be answered. In this review, we thoroughly summarize what is known about the macroscopic, microscopic, and ultrastructural adaptations that mediated disuse-induced atrophy and highlight some of the major gaps in knowledge that need to be filled.
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Affiliation(s)
- Ramy K. A. Sayed
- Department of Comparative Biosciences, University of Wisconsin—Madison, Madison, WI 53706, USA; (R.K.A.S.); (J.E.H.); (K.W.J.)
- School of Veterinary Medicine, University of Wisconsin—Madison, Madison, WI 53706, USA
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sohag University, Sohag 82524, Egypt
| | - Jamie E. Hibbert
- Department of Comparative Biosciences, University of Wisconsin—Madison, Madison, WI 53706, USA; (R.K.A.S.); (J.E.H.); (K.W.J.)
- School of Veterinary Medicine, University of Wisconsin—Madison, Madison, WI 53706, USA
| | - Kent W. Jorgenson
- Department of Comparative Biosciences, University of Wisconsin—Madison, Madison, WI 53706, USA; (R.K.A.S.); (J.E.H.); (K.W.J.)
- School of Veterinary Medicine, University of Wisconsin—Madison, Madison, WI 53706, USA
| | - Troy A. Hornberger
- Department of Comparative Biosciences, University of Wisconsin—Madison, Madison, WI 53706, USA; (R.K.A.S.); (J.E.H.); (K.W.J.)
- School of Veterinary Medicine, University of Wisconsin—Madison, Madison, WI 53706, USA
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Raja E, Clarin MTRDC, Yanagisawa H. Matricellular Proteins in the Homeostasis, Regeneration, and Aging of Skin. Int J Mol Sci 2023; 24:14274. [PMID: 37762584 PMCID: PMC10531864 DOI: 10.3390/ijms241814274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/13/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
Matricellular proteins are secreted extracellular proteins that bear no primary structural functions but play crucial roles in tissue remodeling during development, homeostasis, and aging. Despite their low expression after birth, matricellular proteins within skin compartments support the structural function of many extracellular matrix proteins, such as collagens. In this review, we summarize the function of matricellular proteins in skin stem cell niches that influence stem cells' fate and self-renewal ability. In the epidermal stem cell niche, fibulin 7 promotes epidermal stem cells' heterogeneity and fitness into old age, and the transforming growth factor-β-induced protein ig-h3 (TGFBI)-enhances epidermal stem cell growth and wound healing. In the hair follicle stem cell niche, matricellular proteins such as periostin, tenascin C, SPARC, fibulin 1, CCN2, and R-Spondin 2 and 3 modulate stem cell activity during the hair cycle and may stabilize arrector pili muscle attachment to the hair follicle during piloerections (goosebumps). In skin wound healing, matricellular proteins are upregulated, and their functions have been examined in various gain-and-loss-of-function studies. However, much remains unknown concerning whether these proteins modulate skin stem cell behavior, plasticity, or cell-cell communications during wound healing and aging, leaving a new avenue for future studies.
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Affiliation(s)
- Erna Raja
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan; (E.R.); (M.T.R.D.C.C.)
| | - Maria Thea Rane Dela Cruz Clarin
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan; (E.R.); (M.T.R.D.C.C.)
- Ph.D. Program in Humanics, School of Integrative and Global Majors (SIGMA), University of Tsukuba, Tsukuba 305-8577, Japan
| | - Hiromi Yanagisawa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan; (E.R.); (M.T.R.D.C.C.)
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Jiang N, Su Z, Sun Y, Ren R, Zhou J, Bi R, Zhu S. Spatial Heterogeneity Directs Energy Dissipation in Condylar Fibrocartilage. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2301051. [PMID: 37156747 DOI: 10.1002/smll.202301051] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/04/2023] [Indexed: 05/10/2023]
Abstract
Condylar fibrocartilage with structural and compositional heterogeneity can efficiently orchestrate load-bearing and energy dissipation, making the temporomandibular joint (TMJ) survive high occlusion loads for a prolonged lifetime. How the thin condylar fibrocartilage can achieve efficient energy dissipation to cushion enormous stresses remains an open question in biology and tissue engineering. Here, three distinct zones in the condylar fibrocartilage are identified by analyzing the components and structure from the macro-and microscale to the nanoscale. Specific proteins are highly expressed in each zone related to its mechanics. The heterogeneity of condylar fibrocartilage can direct energy dissipation through the nano-micron-macro gradient spatial scale, by atomic force microscope (AFM), nanoindentation, dynamic mechanical analyzer assay (DMA), and the corresponding energy dissipation mechanisms are exclusive for each distinct zone. This study reveals the significance of the heterogeneity of condylar fibrocartilage in mechanical behavior and provides new insights into the research methods for cartilage biomechanics and the design of energy-dissipative materials.
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Affiliation(s)
- Nan Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Zhan Su
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Yixin Sun
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Rong Ren
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Jiahao Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Ruiye Bi
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Songsong Zhu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
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8
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Lipp SN, Jacobson KR, Colling HA, Tuttle TG, Miles DT, McCreery KP, Calve S. Mechanical loading is required for initiation of extracellular matrix deposition at the developing murine myotendinous junction. Matrix Biol 2023; 116:28-48. [PMID: 36709857 PMCID: PMC10218368 DOI: 10.1016/j.matbio.2023.01.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 01/17/2023] [Accepted: 01/24/2023] [Indexed: 01/27/2023]
Abstract
The myotendinous junction (MTJ) contributes to the generation of motion by connecting muscle to tendon. At the adult MTJ, a specialized extracellular matrix (ECM) is thought to contribute to the mechanical integrity of the muscle-tendon interface, but the factors that influence MTJ formation during mammalian development are unclear. Here, we combined 3D imaging and proteomics with murine models in which muscle contractility and patterning are disrupted to resolve morphological and compositional changes in the ECM during MTJ development. We found that MTJ-specific ECM deposition can be initiated via static loading due to growth; however, it required cyclic loading to develop a mature morphology. Furthermore, the MTJ can mature without the tendon terminating into cartilage. Based on these results, we describe a model wherein MTJ development depends on mechanical loading but not insertion into an enthesis.
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Affiliation(s)
- Sarah N Lipp
- Weldon School of Biomedical Engineering, Purdue University, 206 South Martin Jischke Drive, West Lafayette, IN 47907, United States; The Indiana University Medical Scientist/Engineer Training Program, Indianapolis, IN 46202, United States
| | - Kathryn R Jacobson
- Purdue University Interdisciplinary Life Science Program, 155 S. Grant Street, West Lafayette, IN 47907, United States
| | - Haley A Colling
- Department of Integrative Physiology, University of Colorado Boulder, 354 UCB, Boulder CO, 80309, United States
| | - Tyler G Tuttle
- Paul M. Rady Department of Mechanical Engineering, University of Colorado Boulder, 1111 Engineering Dr, Boulder, CO 80309, United States
| | - Dalton T Miles
- Chemical and Biological Engineering, University of Colorado Boulder, 596 UCB, CO 80309, United States
| | - Kaitlin P McCreery
- Paul M. Rady Department of Mechanical Engineering, University of Colorado Boulder, 1111 Engineering Dr, Boulder, CO 80309, United States
| | - Sarah Calve
- Weldon School of Biomedical Engineering, Purdue University, 206 South Martin Jischke Drive, West Lafayette, IN 47907, United States; Purdue University Interdisciplinary Life Science Program, 155 S. Grant Street, West Lafayette, IN 47907, United States; Paul M. Rady Department of Mechanical Engineering, University of Colorado Boulder, 1111 Engineering Dr, Boulder, CO 80309, United States.
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9
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Inguito KL, Schofield MM, Faghri AD, Bloom ET, Heino M, West VC, Ebron KMM, Elliott DM, Parreno J. Stress deprivation of tendon explants or Tpm3.1 inhibition in tendon cells reduces F-actin to promote a tendinosis-like phenotype. Mol Biol Cell 2022; 33:ar141. [PMID: 36129771 PMCID: PMC9727789 DOI: 10.1091/mbc.e22-02-0067] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 08/29/2022] [Accepted: 09/12/2022] [Indexed: 02/04/2023] Open
Abstract
Actin is a central mediator between mechanical force and cellular phenotype. In tendons, it is speculated that mechanical stress deprivation regulates gene expression by reducing filamentous (F)-actin. However, the mechanisms regulating tenocyte F-actin remain unclear. Tropomyosins (Tpms) are master regulators of F-actin. There are more than 40 Tpm isoforms, each having the unique capability to stabilize F-actin subpopulations. We investigated F-actin polymerization in stress-deprived tendons and tested the hypothesis that stress fiber-associated Tpm(s) stabilize F-actin to regulate cellular phenotype. Stress deprivation of mouse tail tendon down-regulated tenogenic and up-regulated protease (matrix metalloproteinase-3) mRNA levels. Concomitant with mRNA modulation were increases in G/F-actin, confirming reduced F-actin by tendon stress deprivation. To investigate the molecular regulation of F-actin, we identified that tail, Achilles, and plantaris tendons express three isoforms in common: Tpm1.6, 3.1, and 4.2. Tpm3.1 associates with F-actin in native and primary tenocytes. Tpm3.1 inhibition reduces F-actin, leading to decreases in tenogenic expression, increases in chondrogenic expression, and enhancement of protease expression in mouse and human tenocytes. These expression changes by Tpm3.1 inhibition are consistent with tendinosis progression. A further understanding of F-actin regulation in musculoskeletal cells could lead to new therapeutic interventions to prevent alterations in cellular phenotype during disease progression.
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Affiliation(s)
- Kameron L. Inguito
- Departments of Biological Sciences, University of Delaware, Newark, DE 19716
| | - Mandy M. Schofield
- Departments of Biological Sciences, University of Delaware, Newark, DE 19716
| | - Arya D. Faghri
- Departments of Biological Sciences, University of Delaware, Newark, DE 19716
| | - Ellen T. Bloom
- Biomedical Engineering, University of Delaware, Newark, DE 19716
| | - Marissa Heino
- Departments of Biological Sciences, University of Delaware, Newark, DE 19716
- Biomedical Engineering, University of Delaware, Newark, DE 19716
| | - Valerie C. West
- Biomedical Engineering, University of Delaware, Newark, DE 19716
| | | | - Dawn M. Elliott
- Biomedical Engineering, University of Delaware, Newark, DE 19716
| | - Justin Parreno
- Departments of Biological Sciences, University of Delaware, Newark, DE 19716
- Biomedical Engineering, University of Delaware, Newark, DE 19716
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10
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Korntner SH, Jana A, Kinnard E, Leo E, Beane T, Li X, Sengupta R, Becker L, Kuo CK. Craniofacial tendon development-Characterization of extracellular matrix morphology and spatiotemporal protein distribution. Front Cell Dev Biol 2022; 10:944126. [PMID: 36158210 PMCID: PMC9490420 DOI: 10.3389/fcell.2022.944126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 08/10/2022] [Indexed: 11/13/2022] Open
Abstract
Craniofacial (CF) tendons are often affected by traumatic injuries and painful disorders that can severely compromise critical jaw functions, such as mastication and talking. Unfortunately, tendons lack the ability to regenerate, and there are no solutions to restore their native properties or function. An understanding of jaw tendon development could inform tendon regeneration strategies to restore jaw function, however CF tendon development has been relatively unexplored. Using the chick embryo, we identified the jaw-closing Tendon of the musculus Adductor Mandibulae Externus (TmAM) and the jaw-opening Tendon of the musculus Depressor Mandibulae (TmDM) that have similar functions to the masticatory tendons in humans. Using histological and immunohistochemical (IHC) analyses, we characterized the TmAM and TmDM on the basis of cell and extracellular matrix (ECM) morphology and spatiotemporal protein distribution from early to late embryonic development. The TmAM and TmDM were detectable as early as embryonic day (d) 9 based on histological staining and tenascin-C (TNC) protein distribution. Collagen content increased and became more organized, cell density decreased, and cell nuclei elongated over time during development in both the TmAM and TmDM. The TmAM and TmDM exhibited similar spatiotemporal patterns for collagen type III (COL3), but differential spatiotemporal patterns for TNC, lysyl oxidase (LOX), and matrix metalloproteinases (MMPs). Our results demonstrate markers that play a role in limb tendon formation are also present in jaw tendons during embryonic development, implicate COL3, TNC, LOX, MMP2, and MMP9 in jaw tendon development, and suggest TmAM and TmDM possess different developmental programs. Taken together, our study suggests the chick embryo may be used as a model with which to study CF tendon extracellular matrix development, the results of which could ultimately inform therapeutic approaches for CF tendon injuries and disorders.
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Affiliation(s)
- Stefanie H Korntner
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States
| | - Aniket Jana
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States
| | - Elizabeth Kinnard
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States
| | - Emily Leo
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States
| | - Timothy Beane
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, United States
| | - Xianmu Li
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, United States
| | - Rohit Sengupta
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States
| | - Lauren Becker
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States
| | - Catherine K Kuo
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, United States
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, United States
- Department of Orthopaedics, University of Maryland Medical Center, Baltimore, MD, United States
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11
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Chen Z, Chen P, Zheng M, Gao J, Liu D, Wang A, Zheng Q, Leys T, Tai A, Zheng M. Challenges and perspectives of tendon-derived cell therapy for tendinopathy: from bench to bedside. Stem Cell Res Ther 2022; 13:444. [PMID: 36056395 PMCID: PMC9438319 DOI: 10.1186/s13287-022-03113-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/03/2022] [Indexed: 11/18/2022] Open
Abstract
Tendon is composed of dense fibrous connective tissues, connecting muscle at the myotendinous junction (MTJ) to bone at the enthesis and allowing mechanical force to transmit from muscle to bone. Tendon diseases occur at different zones of the tendon, including enthesis, MTJ and midsubstance of the tendon, due to a variety of environmental and genetic factors which consequently result in different frequencies and recovery rates. Self-healing properties of tendons are limited, and cell therapeutic approaches in which injured tendon tissues are renewed by cell replenishment are highly sought after. Homologous use of individual’s tendon-derived cells, predominantly differentiated tenocytes and tendon-derived stem cells, is emerging as a treatment for tendinopathy through achieving minimal cell manipulation for clinical use. This is the first review summarizing the progress of tendon-derived cell therapy in clinical use and its challenges due to the structural complexity of tendons, heterogeneous composition of extracellular cell matrix and cells and unsuitable cell sources. Further to that, novel future perspectives to improve therapeutic effect in tendon-derived cell therapy based on current basic knowledge are discussed.
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Affiliation(s)
- Ziming Chen
- Division of Surgery, Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia
| | - Peilin Chen
- Division of Surgery, Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia
| | - Monica Zheng
- Department of Orthopaedic Surgery, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia
| | - Junjie Gao
- Perron Institute for Neurological and Translational Science, Nedlands, WA, 6009, Australia.,Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Shanghai Sixth People's Hospital, Shanghai, 200233, China
| | - Delin Liu
- Division of Surgery, Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia.,Perron Institute for Neurological and Translational Science, Nedlands, WA, 6009, Australia
| | - Allan Wang
- Division of Surgery, Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia
| | - Qiujian Zheng
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510000, Guangdong, China.,Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510000, Guangdong, China
| | - Toby Leys
- Department of Orthopaedic Surgery, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia
| | - Andrew Tai
- Perron Institute for Neurological and Translational Science, Nedlands, WA, 6009, Australia.
| | - Minghao Zheng
- Division of Surgery, Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia. .,Perron Institute for Neurological and Translational Science, Nedlands, WA, 6009, Australia.
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12
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Guo X, Wang X, Tang H, Ren Y, Li D, Yi B, Zhang Y. Engineering a Mechanoactive Fibrous Substrate with Enhanced Efficiency in Regulating Stem Cell Tenodifferentiation. ACS APPLIED MATERIALS & INTERFACES 2022; 14:23219-23231. [PMID: 35544769 DOI: 10.1021/acsami.2c04294] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Electrospun-aligned fibers in ultrathin fineness have previously demonstrated a limited capacity in driving stem cells to differentiate into tendon-like cells. In view of the tendon's mechanoactive nature, endowing such aligned fibrous structure with mechanoactivity to exert in situ mechanical stimulus by itself, namely, without any forces externally applied, is likely to potentiate its efficiency of tenogenic induction. To test this hypothesis, in this study, a shape-memory-capable poly(l-lactide-co-caprolactone) (PLCL) copolymer was electrospun into aligned fibrous form followed by a "stretching-recovery" shape-programming procedure to impart shape memory capability. Thereafter, in the absence of tenogenic supplements, human adipose-derived stem cells (ADSCs) were cultured on the programmed fibrous substrates for a duration of 7 days, and the effects of constrained recovery resultant stress-stiffening on cell morphology, proliferation, and tenogenic differentiation were examined. The results indicate that the in situ enacted mechanical stimulus due to shape memory effect (SME) did not have adverse influence on cell viability and proliferation, but significantly promoted cellular elongation along the direction of fiber alignment. Moreover, it revealed that tendon-specific protein markers such as tenomodulin (TNMD) and tenascin-C (TNC) and gene expression of scleraxis (SCX), TNMD, TNC, and collagen I (COL I) were significantly upregulated on the mechanoactive fibrous substrate with higher recovery stress compared to the counterparts. Mechanistically, the Rho/ROCK signaling pathway was identified to be involved in the substrate self-actuation-induced enhancement in tenodifferentiation. Together, these results suggest that constrained shape recovery stress may be employed as an innovative loading modality to regulate the stem cell tenodifferentiation by presenting the fibrous substrate with an aligned tendon-like topographical cue and an additional mechanoactivity. This newly demonstrated paradigm in modulating stem cell tenodifferentiation may improve the efficacy of tendon tissue engineering strategy for tendon healing and regeneration.
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Affiliation(s)
- Xuran Guo
- College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Donghua University, Shanghai 201620, China
| | - Xianliu Wang
- College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Donghua University, Shanghai 201620, China
| | - Han Tang
- College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Donghua University, Shanghai 201620, China
| | - Yajuan Ren
- Longhua Hospital affiliated to the Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Donghong Li
- College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Donghua University, Shanghai 201620, China
| | - Bingcheng Yi
- College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
- Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital affiliated to the Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Yanzhong Zhang
- College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Donghua University, Shanghai 201620, China
- Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital affiliated to the Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou 310058, China
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13
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Ribbans WJ, September AV, Collins M. Tendon and Ligament Genetics: How Do They Contribute to Disease and Injury? A Narrative Review. Life (Basel) 2022; 12:life12050663. [PMID: 35629331 PMCID: PMC9147569 DOI: 10.3390/life12050663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/24/2022] [Accepted: 04/26/2022] [Indexed: 12/15/2022] Open
Abstract
A significant proportion of patients requiring musculoskeletal management present with tendon and ligament pathology. Our understanding of the intrinsic and extrinsic mechanisms that lead to such disabilities is increasing. However, the complexity underpinning these interactive multifactorial elements is still not fully characterised. Evidence highlighting the genetic components, either reducing or increasing susceptibility to injury, is increasing. This review examines the present understanding of the role genetic variations contribute to tendon and ligament injury risk. It examines the different elements of tendon and ligament structure and considers our knowledge of genetic influence on form, function, ability to withstand load, and undertake repair or regeneration. The role of epigenetic factors in modifying gene expression in these structures is also explored. It considers the challenges to interpreting present knowledge, the requirements, and likely pathways for future research, and whether such information has reached the point of clinical utility.
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Affiliation(s)
- William J. Ribbans
- School of Health, The University of Northampton, Northampton NN1 5PH, UK
- The County Clinic, Northampton NN1 5DB, UK
- Correspondence: ; Tel.: +44-1604-795414
| | - Alison V. September
- Division of Physiological Sciences, Department of Human Biology, Health Sciences Faculty, University of Cape Town, Cape Town 7700, South Africa; (A.V.S.); (M.C.)
- Health Through Physical Activity, Lifestyle and Sport Research Centre (HPALS), Department of Human Biology, Health Sciences Faculty, University of Cape Town, Cape Town 7700, South Africa
- International Federation of Sports Medicine (FIMS), Collaborative Centre of Sports Medicine, Department of Human Biology, University of Cape Town, Cape Town 7700, South Africa
| | - Malcolm Collins
- Division of Physiological Sciences, Department of Human Biology, Health Sciences Faculty, University of Cape Town, Cape Town 7700, South Africa; (A.V.S.); (M.C.)
- Health Through Physical Activity, Lifestyle and Sport Research Centre (HPALS), Department of Human Biology, Health Sciences Faculty, University of Cape Town, Cape Town 7700, South Africa
- International Federation of Sports Medicine (FIMS), Collaborative Centre of Sports Medicine, Department of Human Biology, University of Cape Town, Cape Town 7700, South Africa
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14
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Colbath G, Murray A, Siatkowski S, Pate T, Krussig M, Pill S, Hawkins R, Tokish J, Mercuri J. Autograft Long Head Biceps Tendon Can Be Used as a Scaffold for Biologically Augmenting Rotator Cuff Repairs. Arthroscopy 2022; 38:38-48. [PMID: 34126215 PMCID: PMC8665938 DOI: 10.1016/j.arthro.2021.05.064] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 05/23/2021] [Accepted: 05/31/2021] [Indexed: 02/02/2023]
Abstract
PURPOSE We create a viable, mechanically expanded autograft long head biceps tendon (LHBT) scaffold for biologically augmenting the repair of torn rotator cuffs. METHODS The proximal aspect of the tenotomized LHBTs was harvested from patients during rotator cuff repair surgery and was mechanically formed into porous scaffolds using a surgical graft expander. LHBT scaffolds were evaluated for change in area, tensile properties, and tenocyte viability before and after expansion. The ability of endogenous tenocytes derived from the LHBT scaffold to promote tenogenic differentiation of human adipose-derived mesenchymal stromal cells (ADMSCs) was also determined. RESULTS Autograft LHBTs were successfully expanded using a modified surgical graft expander to create a porous scaffold containing viable resident tenoctyes from patients undergoing rotator cuff repair. LHBT scaffolds had significantly increased area (length: 24.91 mm [13.91, 35.90] × width: 22.69 mm [1.87, 34.50]; P = .011) compared with the native LHBT tendon (length: 27.16 mm [2.70, 33.62] × width: 6.68 mm [5.62, 7.74]). The structural properties of the autograft were altered, including the ultimate tensile strength (LHBT scaffold: .56 MPa [.06, 1.06] vs. native LHBT: 2.35 MPa [1.36, 3.33]; P = .002) and tensile modulus (LHBT scaffold: 4.72 MPa [-.80, 1.24] versus native LHBT: 37.17 MPa [24.56, 49.78]; P = .001). There was also a reduction in resident tenocyte percent viability (LHBT scaffold: 38.52% [17.94, 59.09] vs. native LHBT: 68.87% [63.67, 74.37]; P =.004). Tenocytes derived from the LHBT scaffold produced soluble signals that initiated ADMSC differentiation into an immature tenocyte-like phenotype, as indicated by an 8.7× increase in scleraxis (P = .040) and a 3.6× increase in collagen type III mRNA expression (P = .050) compared with undifferentiated ADMSC controls. CONCLUSIONS The ability to produce a viable autologous scaffold from the proximal biceps tendon having dimensions, porosity, mechanical characteristics, native ECM components, and viable tenocytes that produce bioactive signals conducive to supporting the biologic augmentation of rotator cuff repair surgery has been demonstrated. CLINICAL RELEVANCE This biologically active construct may help to improve the quality of healing and regeneration at the repair site of rotator cuff tears, especially those at high risk for retear.
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Affiliation(s)
- Gregory Colbath
- Medical Group of the Carolinas, Department of Orthopaedic Surgery, Spartanburg Regional, Spartanburg, SC
| | - Alison Murray
- Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Department of Bioengineering, Clemson University, Clemson, SC,Frank H. Stelling and C. Dayton Riddle Orthopaedic Education and Research Laboratory, Clemson University Biomedical Engineering Innovation Campus, Greenville, SC
| | - Sandra Siatkowski
- Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Department of Bioengineering, Clemson University, Clemson, SC,Frank H. Stelling and C. Dayton Riddle Orthopaedic Education and Research Laboratory, Clemson University Biomedical Engineering Innovation Campus, Greenville, SC
| | - Taylor Pate
- Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Department of Bioengineering, Clemson University, Clemson, SC,Frank H. Stelling and C. Dayton Riddle Orthopaedic Education and Research Laboratory, Clemson University Biomedical Engineering Innovation Campus, Greenville, SC
| | - Mario Krussig
- Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Department of Bioengineering, Clemson University, Clemson, SC,Frank H. Stelling and C. Dayton Riddle Orthopaedic Education and Research Laboratory, Clemson University Biomedical Engineering Innovation Campus, Greenville, SC
| | - Stephan Pill
- Steadman Hawkins Clinic of the Carolinas, Department of Orthopaedic Surgery, Prisma Health, Greenville, SC
| | - Richard Hawkins
- Steadman Hawkins Clinic of the Carolinas, Department of Orthopaedic Surgery, Prisma Health, Greenville, SC
| | - John Tokish
- Mayo Clinic, Department of Orthopaedic Surgery, Phoenix, AZ
| | - Jeremy Mercuri
- Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Department of Bioengineering, Clemson University, Clemson, SC,Frank H. Stelling and C. Dayton Riddle Orthopaedic Education and Research Laboratory, Clemson University Biomedical Engineering Innovation Campus, Greenville, SC
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15
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Halper J. Basic Components of Connective Tissues and Extracellular Matrix: Fibronectin, Fibrinogen, Laminin, Elastin, Fibrillins, Fibulins, Matrilins, Tenascins and Thrombospondins. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:105-126. [PMID: 34807416 DOI: 10.1007/978-3-030-80614-9_4] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Collagens are the most abundant components of the extracellular matrix (ECM) and many types of soft tissues. Elastin is another major component of certain soft tissues, such as arterial walls and ligaments. It is an insoluble polymer of the monomeric soluble precursor tropoelastin, and the main component of elastic fibers in matrix tissue where it provides elastic recoil and resilience to a variety of connective tissues, e.g., aorta and ligaments. Elastic fibers regulate activity of transforming growth factors β (TGFβ) through their association with fibrillin microfibrils. Elastin also plays a role in cell adhesion, cell migration, and has the ability to participate in cell signaling. Mutations in the elastin gene lead to cutis laxa. Many other molecules, though lower in quantity, function as essential, structural and/or functional components of the extracellular matrix in soft tissues. Some of these are reviewed in this chapter. Besides their basic structure, biochemistry and physiology, their roles in disorders of soft tissues are discussed only briefly as most chapters in this volume deal with relevant individual compounds. Fibronectin with its multidomain structure plays a role of "master organizer" in matrix assembly as it forms a bridge between cell surface receptors, e.g., integrins, and compounds such collagen, proteoglycans and other focal adhesion molecules. It also plays an essential role in the assembly of fibrillin-1 into a structured network. Though the primary role of fibrinogen is in clot formation, after conversion to fibrin by thrombin it also binds to a variety of compounds, particularly to various growth factors, and as such, fibrinogen is a player in cardiovascular and extracellular matrix physiology. Laminins contribute to the structure of the ECM and modulate cellular functions such as adhesion, differentiation, migration, stability of phenotype, and resistance towards apoptosis. Fibrillins represent the predominant core of microfibrils in elastic as well as non-elastic extracellular matrixes, and interact closely with tropoelastin and integrins. Not only do microfibrils provide structural integrity of specific organ systems, but they also provide basis for elastogenesis in elastic tissues. Fibrillin is important for the assembly of elastin into elastic fibers. Mutations in the fibrillin-1 gene are closely associated with Marfan syndrome. Latent TGFβ binding proteins (LTBPs) are included here as their structure is similar to fibrillins. Several categories of ECM components described after fibrillins are sub-classified as matricellular proteins, i.e., they are secreted into ECM, but do not provide structure. Rather they interact with cell membrane receptors, collagens, proteases, hormones and growth factors, communicating and directing cell-ECM traffic. Fibulins are tightly connected with basement membranes, elastic fibers and other components of extracellular matrix and participate in formation of elastic fibers. Matrilins have been emerging as a new group of supporting actors, and their role in connective tissue physiology and pathophysiology has not been fully characterized. Tenascins are ECM polymorphic glycoproteins found in many connective tissues in the body. Their expression is regulated by mechanical stress both during development and in adulthood. Tenascins mediate both inflammatory and fibrotic processes to enable effective tissue repair and play roles in pathogenesis of Ehlers-Danlos, heart disease, and regeneration and recovery of musculo-tendinous tissue. One of the roles of thrombospondin 1 is activation of TGFβ. Increased expression of thrombospondin and TGFβ activity was observed in fibrotic skin disorders such as keloids and scleroderma. Cartilage oligomeric matrix protein (COMP) or thrombospondin-5 is primarily present in the cartilage. High levels of COMP are present in fibrotic scars and systemic sclerosis of the skin, and in tendon, especially with physical activity, loading and post-injury. It plays a role in vascular wall remodeling and has been found in atherosclerotic plaques as well.
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Affiliation(s)
- Jaroslava Halper
- Department of Pathology, College of Veterinary Medicine, and Department of Basic Sciences, AU/UGA Medical Partnership, The University of Georgia, Athens, GA, USA.
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16
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Decellularized tendon matrix membranes prevent post-surgical tendon adhesion and promote functional repair. Acta Biomater 2021; 134:160-176. [PMID: 34303866 DOI: 10.1016/j.actbio.2021.07.038] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 06/25/2021] [Accepted: 07/19/2021] [Indexed: 12/19/2022]
Abstract
Adhesion often occurs after tendon injury, and results in sliding disorder and movement limitation with no ideal solution for it in clinic. In this study, an anti-adhesion membrane, i.e., decellularized tendon matrix (DTM) for tendon is successfully prepared by an optimized tendon decellularization method from homologous extracellular matrix. Microsection technology has been used to optimize the method of decellularization in order to better preserve the bioactive components in tissues and reduce the chemical reagent residues on the premise of effective decellularization with relatively shorter time and less reagents for decellularization. The physic-chemical properties and biological functions of DTM are evaluated, and high-throughput and high-precision tandem mass tags (TMT) labeling proteomics technology is used to analyze protein components of DTM, which may provide the scientific support for application of the innovative product. In vitro biosafety tests show that DTM not only is non-toxic but also promote cell proliferation. Subcutaneous implantation test confirms that DTM is completely degraded after 12 weeks and there is no obvious inflammatory reaction. The results of Achilles tendon repair in rabbits show that DTM can not only prevent tendon adhesion but also improve the quality of tendon repair, which demonstrates its tremendous application potential. STATEMENT OF SIGNIFICANCE: There is no ideal solution for adhesion after tendon injury. In this study, a dense tendon anti-adhesion membrane (DTM) was successfully prepared from homologous extracellular matrix (ECM). This DTM could effectively retain bioactive ingredients, and prevent adhesion as well as improve the quality of tendon repair in vivo. An optimized decellularization method was used which could effectively decellularize tendon in a short time, better preserve bioactive components, and reduce reagent residues. For the first time, high-throughput and high-precision tandem mass tags (TMT) labeling proteomics technology was used to qualitatively and quantitatively analyze the protein composition of fresh tendon, acellular tendon and DTM, which provided not only scientific support for the application of DTM, but also comprehensive and accurate data support for related research of bovine tendons and decellularization.
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17
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Zhang S, Ju W, Chen X, Zhao Y, Feng L, Yin Z, Chen X. Hierarchical ultrastructure: An overview of what is known about tendons and future perspective for tendon engineering. Bioact Mater 2021; 8:124-139. [PMID: 34541391 PMCID: PMC8424392 DOI: 10.1016/j.bioactmat.2021.06.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/07/2021] [Accepted: 06/07/2021] [Indexed: 12/27/2022] Open
Abstract
Abnormal tendons are rarely ever repaired to the natural structure and morphology of normal tendons. To better guide the repair and regeneration of injured tendons through a tissue engineering method, it is necessary to have insights into the internal morphology, organization, and composition of natural tendons. This review summarized recent researches on the structure and function of the extracellular matrix (ECM) components of tendons and highlight the application of multiple detection methodologies concerning the structure of ECMs. In addition, we look forward to the future of multi-dimensional biomaterial design methods and the potential of structural repair for tendon ECM components. In addition, focus is placed on the macro to micro detection methods for tendons, and current techniques for evaluating the extracellular matrix of tendons at the micro level are introduced in detail. Finally, emphasis is given to future extracellular matrix detection methods, as well as to how future efforts could concentrate on fabricating the biomimetic tendons.
Summarize recent research on the structure and function of the extracellular matrix (ECM) components of tendons. Comments on current research methods concerning the structure of ECMs. Perspective on the future of multi-dimensional detection techniques and structural repair of tendon ECM components.
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Affiliation(s)
- Shichen Zhang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine and Department of Orthopedic Surgery of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310052, China.,Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Wei Ju
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Xiaoyi Chen
- Guangxi Key Laboratory of Regenerative Medicine, Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Guangxi Medical University, Guangxi, 530021, China
| | - Yanyan Zhao
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine and Department of Orthopedic Surgery of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310052, China.,Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Lingchong Feng
- State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Zi Yin
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China.,Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine and Regenerative Medicine and Department of Orthopedic Surgery of Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China.,Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, 310058, China.,China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, 310058, China
| | - Xiao Chen
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine and Department of Orthopedic Surgery of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310052, China.,Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China.,Guangxi Key Laboratory of Regenerative Medicine, Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Guangxi Medical University, Guangxi, 530021, China.,Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, 310058, China.,China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, 310058, China
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18
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Ryan C, Pugliese E, Shologu N, Gaspar D, Rooney P, Islam MN, O'Riordan A, Biggs M, Griffin M, Zeugolis D. A combined physicochemical approach towards human tenocyte phenotype maintenance. Mater Today Bio 2021; 12:100130. [PMID: 34632361 PMCID: PMC8488312 DOI: 10.1016/j.mtbio.2021.100130] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/27/2021] [Accepted: 08/28/2021] [Indexed: 02/08/2023] Open
Abstract
During in vitro culture, bereft of their optimal tissue context, tenocytes lose their phenotype and function. Considering that tenocytes in their native tissue milieu are exposed simultaneously to manifold signals, combination approaches (e.g. growth factor supplementation and mechanical stimulation) are continuously gaining pace to control cell fate during in vitro expansion, albeit with limited success due to the literally infinite number of possible permutations. In this work, we assessed the potential of scalable and potent physicochemical approaches that control cell fate (substrate stiffness, anisotropic surface topography, collagen type I coating) and enhance extracellular matrix deposition (macromolecular crowding) in maintaining human tenocyte phenotype in culture. Cell morphology was primarily responsive to surface topography. The tissue culture plastic induced the largest nuclei area, the lowest aspect ratio, and the highest focal adhesion kinase. Collagen type I coating increased cell number and metabolic activity. Cell viability was not affected by any of the variables assessed. Macromolecular crowding intensely enhanced and accelerated native extracellular matrix deposition, albeit not in an aligned fashion, even on the grooved substrates. Gene analysis at day 14 revealed that the 130 kPa grooved substrate without collagen type I coating and under macromolecular crowding conditions positively regulated human tenocyte phenotype. Collectively, this work illustrates the beneficial effects of combined physicochemical approaches in controlling cell fate during in vitro expansion.
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Affiliation(s)
- C.N.M. Ryan
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - E. Pugliese
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - N. Shologu
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - D. Gaspar
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - P. Rooney
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Md N. Islam
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Regenerative Medicine Institute (REMEDI), School of Medicine, Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Discipline of Biochemistry, School of Natural Sciences, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - A. O'Riordan
- Tyndall National Institute, University College Cork (UCC), Cork, Ireland
| | - M.J. Biggs
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - M.D. Griffin
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Regenerative Medicine Institute (REMEDI), School of Medicine, Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - D.I. Zeugolis
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Charles Institute of Dermatology, Conway Institute of Biomolecular & Biomedical Research and School of Mechanical & Materials Engineering, University College Dublin (UCD), Dublin, Ireland
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19
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Maintenance of Ligament Homeostasis of Spheroid-Colonized Embroidered and Functionalized Scaffolds after 3D Stretch. Int J Mol Sci 2021; 22:ijms22158204. [PMID: 34360970 PMCID: PMC8348491 DOI: 10.3390/ijms22158204] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/18/2021] [Accepted: 07/23/2021] [Indexed: 01/12/2023] Open
Abstract
Anterior cruciate ligament (ACL) ruptures are usually treated with autograft implantation to prevent knee instability. Tissue engineered ACL reconstruction is becoming promising to circumvent autograft limitations. The aim was to evaluate the influence of cyclic stretch on lapine (L) ACL fibroblasts on embroidered scaffolds with respect to adhesion, DNA and sulphated glycosaminoglycan (sGAG) contents, gene expression of ligament-associated extracellular matrix genes, such as type I collagen, decorin, tenascin C, tenomodulin, gap junctional connexin 43 and the transcription factor Mohawk. Control scaffolds and those functionalized by gas phase fluorination and cross-linked collagen foam were either pre-cultured with a suspension or with spheroids of LACL cells before being subjected to cyclic stretch (4%, 0.11 Hz, 3 days). Stretch increased significantly the scaffold area colonized with cells but impaired sGAGs and decorin gene expression (functionalized scaffolds seeded with cell suspension). Stretching increased tenascin C, connexin 43 and Mohawk but decreased decorin gene expression (control scaffolds seeded with cell suspension). Pre-cultivation of functionalized scaffolds with spheroids might be the more suitable method for maintaining ligamentogenesis in 3D scaffolds compared to using a cell suspension due to a significantly higher sGAG content in response to stretching and type I collagen gene expression in functionalized scaffolds.
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20
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Physicochemical Properties and Biocompatibility of Electrospun Polycaprolactone/Gelatin Nanofibers. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18094764. [PMID: 33947053 PMCID: PMC8125554 DOI: 10.3390/ijerph18094764] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/23/2021] [Accepted: 04/26/2021] [Indexed: 11/17/2022]
Abstract
Tissue-engineered substitutes have shown great promise as a potential replacement for current tissue grafts to treat tendon/ligament injury. Herein, we have fabricated aligned polycaprolactone (PCL) and gelatin (GT) nanofibers and further evaluated their physicochemical properties and biocompatibility. PCL and GT were mixed at a ratio of 100:0, 70:30, 50:50, 30:70, 0:100, and electrospun to generate aligned nanofibers. The PCL/GT nanofibers were assessed to determine the diameter, alignment, water contact angle, degradation, and surface chemical analysis. The effects on cells were evaluated through Wharton's jelly-derived mesenchymal stem cell (WJ-MSC) viability, alignment and tenogenic differentiation. The PCL/GT nanofibers were aligned and had a mean fiber diameter within 200-800 nm. Increasing the GT concentration reduced the water contact angle of the nanofibers. GT nanofibers alone degraded fastest, observed only within 2 days. Chemical composition analysis confirmed the presence of PCL and GT in the nanofibers. The WJ-MSCs were aligned and remained viable after 7 days with the PCL/GT nanofibers. Additionally, the PCL/GT nanofibers supported tenogenic differentiation of WJ-MSCs. The fabricated PCL/GT nanofibers have a diameter that closely resembles the native tissue's collagen fibrils and have good biocompatibility. Thus, our study demonstrated the suitability of PCL/GT nanofibers for tendon/ligament tissue engineering applications.
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21
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Kritikaki E, Asterling R, Ward L, Padget K, Barreiro E, C. M. Simoes D. Exercise Training-Induced Extracellular Matrix Protein Adaptation in Locomotor Muscles: A Systematic Review. Cells 2021; 10:cells10051022. [PMID: 33926070 PMCID: PMC8146973 DOI: 10.3390/cells10051022] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 12/17/2022] Open
Abstract
Exercise training promotes muscle adaptation and remodelling by balancing the processes of anabolism and catabolism; however, the mechanisms by which exercise delays accelerated muscle wasting are not fully understood. Intramuscular extracellular matrix (ECM) proteins are essential to tissue structure and function, as they create a responsive environment for the survival and repair of the muscle fibres. However, their role in muscle adaptation is underappreciated and underinvestigated. The PubMed, COCHRANE, Scopus and CIHNAL databases were systematically searched from inception until February 2021. The inclusion criteria were on ECM adaptation after exercise training in healthy adult population. Evidence from 21 studies on 402 participants demonstrates that exercise training induces muscle remodelling, and this is accompanied by ECM adaptation. All types of exercise interventions promoted a widespread increase in collagens, glycoproteins and proteoglycans ECM transcriptomes in younger and older participants. The ECM controlling mechanisms highlighted here were concerned with myogenic and angiogenic processes during muscle adaptation and remodelling. Further research identifying the mechanisms underlying the link between ECMs and muscle adaptation will support the discovery of novel therapeutic targets and the development of personalised exercise training medicine.
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Affiliation(s)
- Efpraxia Kritikaki
- Faculty of Health and Life Sciences, Northumbria University Newcastle, Newcastle upon Tyne NE1 8ST, UK; (E.K.); (R.A.); (L.W.); (K.P.)
| | - Rhiannon Asterling
- Faculty of Health and Life Sciences, Northumbria University Newcastle, Newcastle upon Tyne NE1 8ST, UK; (E.K.); (R.A.); (L.W.); (K.P.)
| | - Lesley Ward
- Faculty of Health and Life Sciences, Northumbria University Newcastle, Newcastle upon Tyne NE1 8ST, UK; (E.K.); (R.A.); (L.W.); (K.P.)
| | - Kay Padget
- Faculty of Health and Life Sciences, Northumbria University Newcastle, Newcastle upon Tyne NE1 8ST, UK; (E.K.); (R.A.); (L.W.); (K.P.)
| | - Esther Barreiro
- Pulmonology Department, Lung Cancer and Muscle Research Group, Hospital del Mar-IMIM, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), CIBERES, 08002 Barcelona, Spain;
| | - Davina C. M. Simoes
- Faculty of Health and Life Sciences, Northumbria University Newcastle, Newcastle upon Tyne NE1 8ST, UK; (E.K.); (R.A.); (L.W.); (K.P.)
- Correspondence:
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22
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Zahn I, Stöbener DD, Weinhart M, Gögele C, Breier A, Hahn J, Schröpfer M, Meyer M, Schulze-Tanzil G. Cruciate Ligament Cell Sheets Can Be Rapidly Produced on Thermoresponsive poly(glycidyl ether) Coating and Successfully Used for Colonization of Embroidered Scaffolds. Cells 2021; 10:cells10040877. [PMID: 33921450 PMCID: PMC8069541 DOI: 10.3390/cells10040877] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/04/2021] [Accepted: 04/07/2021] [Indexed: 01/14/2023] Open
Abstract
Anterior cruciate ligament (ACL) cell sheets combined with biomechanically competent scaffolds might facilitate ACL tissue engineering. Since thermoresponsive polymers allow a rapid enzyme-free detachment of cell sheets, we evaluated the applicability of a thermoresponsive poly(glycidyl ether) (PGE) coating for cruciate ligamentocyte sheet formation and its influence on ligamentocyte phenotype during sheet-mediated colonization of embroidered scaffolds. Ligamentocytes were seeded on surfaces either coated with PGE or without coating. Detached ligamentocyte sheets were cultured separately or wrapped around an embroidered scaffold made of polylactide acid (PLA) and poly(lactic-co-ε-caprolactone) (P(LA-CL)) threads functionalized by gas-phase fluorination and with collagen foam. Ligamentocyte viability, protein and gene expression were determined in sheets detached from surfaces with or without PGE coating, scaffolds seeded with sheets from PGE-coated plates and the respective monolayers. Stable and vital ligamentocyte sheets could be produced within 24 h with both surfaces, but more rapidly with PGE coating. PGE did not affect ligamentocyte phenotype. Scaffolds could be colonized with sheets associated with high cell survival, stable gene expression of ligament-related type I collagen, decorin, tenascin C and Mohawk after 14 d and extracellular matrix (ECM) deposition. PGE coating facilitates ligamentocyte sheet formation, and sheets colonizing the scaffolds displayed a ligament-related phenotype.
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Affiliation(s)
- Ingrid Zahn
- Institute of Anatomy and Cell Biology, Paracelsus Medical University, Nuremberg and Salzburg, Prof. Ernst Nathan Str. 1, 90419 Nuremberg, Germany; (I.Z.); (C.G.)
- Department of Applied Chemistry, Nuremberg Institute of Technology Georg Simon Ohm, Keßlerplatz 12, 90489 Nuremberg, Germany
- Institute of Functional and Clinical Anatomy, Friedrich Alexander University, Erlangen-Nuremberg, Universitätsstr. 19, 91054 Erlangen, Germany
| | - Daniel David Stöbener
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany; (D.D.S.); (M.W.)
- Institute of Physical Chemistry and Electrochemistry, Leibniz Universität Hannover, Callinstr. 3A, 30167 Hannover, Germany
| | - Marie Weinhart
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany; (D.D.S.); (M.W.)
- Institute of Physical Chemistry and Electrochemistry, Leibniz Universität Hannover, Callinstr. 3A, 30167 Hannover, Germany
| | - Clemens Gögele
- Institute of Anatomy and Cell Biology, Paracelsus Medical University, Nuremberg and Salzburg, Prof. Ernst Nathan Str. 1, 90419 Nuremberg, Germany; (I.Z.); (C.G.)
- Department of Biosciences, Paris Lodron University Salzburg, Hellbrunnerstraße 34, 5020 Salzburg, Austria
| | - Annette Breier
- Leibniz-Institut für Polymerforschung Dresden e. V. (IPF), Hohe Straße 6, 01069 Dresden, Germany; (A.B.); (J.H.)
| | - Judith Hahn
- Leibniz-Institut für Polymerforschung Dresden e. V. (IPF), Hohe Straße 6, 01069 Dresden, Germany; (A.B.); (J.H.)
| | - Michaela Schröpfer
- FILK Freiberg Institute (FILK), Meißner Ring 1-5, 09599 Freiberg, Germany; (M.S.); (M.M.)
| | - Michael Meyer
- FILK Freiberg Institute (FILK), Meißner Ring 1-5, 09599 Freiberg, Germany; (M.S.); (M.M.)
| | - Gundula Schulze-Tanzil
- Institute of Anatomy and Cell Biology, Paracelsus Medical University, Nuremberg and Salzburg, Prof. Ernst Nathan Str. 1, 90419 Nuremberg, Germany; (I.Z.); (C.G.)
- Correspondence: ; Tel.: +49-911-398-(11)-6772
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23
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Comparative Analysis of Tenogenic Gene Expression in Tenocyte-Derived Induced Pluripotent Stem Cells and Bone Marrow-Derived Mesenchymal Stem Cells in Response to Biochemical and Biomechanical Stimuli. Stem Cells Int 2021; 2021:8835576. [PMID: 33510795 PMCID: PMC7825360 DOI: 10.1155/2021/8835576] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 11/19/2020] [Accepted: 12/22/2020] [Indexed: 12/12/2022] Open
Abstract
The tendon is highly prone to injury, overuse, or age-related degeneration in both humans and horses. Natural healing of injured tendon is poor, and cell-based therapeutic treatment is still a significant clinical challenge. In this study, we extensively investigated the expression of tenogenic genes in equine bone marrow mesenchymal stem cells (BMSCs) and tenocyte-derived induced pluripotent stem cells (teno-iPSCs) stimulated by growth factors (TGF-β3 and BMP12) combined with ectopic expression of tenogenic transcription factor MKX or cyclic uniaxial mechanical stretch. Western blotting revealed that TGF-β3 and BMP12 increased the expression of transcription factors SCX and MKX in both cells, but the tenocyte marker tenomodulin (TNMD) was detected only in BMSCs and upregulated by either inducer. On the other hand, quantitative real-time PCR showed that TGF-β3 increased the expression of EGR1, COL1A2, FMOD, and TNC in BMSCs and SCX, COL1A2, DCN, FMOD, and TNC in teno-iPSCs. BMP12 treatment elevated SCX, MKX, DCN, FMOD, and TNC in teno-iPSCs. Overexpression of MKX increased SCX, DCN, FMOD, and TNC in BMSCs and EGR1, COL1A2, DCN, FMOD, and TNC in teno-iPSCs; TGF-β3 further enhanced TNC in BMSCs. Moreover, mechanical stretch increased SCX, EGR1, DCN, ELN, and TNC in BMSCs and SCX, MKX, EGR1, COL1A2, DCN, FMOD, and TNC in teno-iPSCs; TGF-β3 tended to further elevate SCX, ELN, and TNC in BMSCs and SCX, MKX, COL1A2, DCN, and TNC in teno-iPSCs, while BMP12 further uptrended the expression of SCX and DCN in BMSCs and DCN in teno-iPSCs. Additionally, the aforementioned tenogenic inducers also affected the expression of signaling regulators SMAD7, ETV4, and SIRT1 in BMSCs and teno-iPSCs. Taken together, our data demonstrate that, in respect to the tenocyte-lineage-specific gene expression, BMSCs and teno-iPSCs respond differently to the tenogenic stimuli, which may affect the outcome of their application in tendon repair or regeneration.
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24
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Citeroni MR, Ciardulli MC, Russo V, Della Porta G, Mauro A, El Khatib M, Di Mattia M, Galesso D, Barbera C, Forsyth NR, Maffulli N, Barboni B. In Vitro Innovation of Tendon Tissue Engineering Strategies. Int J Mol Sci 2020; 21:E6726. [PMID: 32937830 PMCID: PMC7555358 DOI: 10.3390/ijms21186726] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/06/2020] [Accepted: 09/07/2020] [Indexed: 12/12/2022] Open
Abstract
Tendinopathy is the term used to refer to tendon disorders. Spontaneous adult tendon healing results in scar tissue formation and fibrosis with suboptimal biomechanical properties, often resulting in poor and painful mobility. The biomechanical properties of the tissue are negatively affected. Adult tendons have a limited natural healing capacity, and often respond poorly to current treatments that frequently are focused on exercise, drug delivery, and surgical procedures. Therefore, it is of great importance to identify key molecular and cellular processes involved in the progression of tendinopathies to develop effective therapeutic strategies and drive the tissue toward regeneration. To treat tendon diseases and support tendon regeneration, cell-based therapy as well as tissue engineering approaches are considered options, though none can yet be considered conclusive in their reproduction of a safe and successful long-term solution for full microarchitecture and biomechanical tissue recovery. In vitro differentiation techniques are not yet fully validated. This review aims to compare different available tendon in vitro differentiation strategies to clarify the state of art regarding the differentiation process.
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Affiliation(s)
- Maria Rita Citeroni
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Maria Camilla Ciardulli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy; (M.C.C.); (G.D.P.); (N.M.)
| | - Valentina Russo
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Giovanna Della Porta
- Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy; (M.C.C.); (G.D.P.); (N.M.)
- Interdepartment Centre BIONAM, Università di Salerno, via Giovanni Paolo I, 84084 Fisciano (SA), Italy
| | - Annunziata Mauro
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Mohammad El Khatib
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Miriam Di Mattia
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Devis Galesso
- Fidia Farmaceutici S.p.A., via Ponte della Fabbrica 3/A, 35031 Abano Terme (PD), Italy; (D.G.); (C.B.)
| | - Carlo Barbera
- Fidia Farmaceutici S.p.A., via Ponte della Fabbrica 3/A, 35031 Abano Terme (PD), Italy; (D.G.); (C.B.)
| | - Nicholas R. Forsyth
- Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Thornburrow Drive, Stoke on Trent ST4 7QB, UK;
| | - Nicola Maffulli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy; (M.C.C.); (G.D.P.); (N.M.)
- Department of Musculoskeletal Disorders, Faculty of Medicine and Surgery, University of Salerno, Via San Leonardo 1, 84131 Salerno, Italy
- Centre for Sports and Exercise Medicine, Barts and The London School of Medicine and Dentistry, Mile End Hospital, Queen Mary University of London, 275 Bancroft Road, London E1 4DG, UK
- School of Pharmacy and Bioengineering, Keele University School of Medicine, Thornburrow Drive, Stoke on Trent ST5 5BG, UK
| | - Barbara Barboni
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
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25
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Jacobson KR, Lipp S, Acuna A, Leng Y, Bu Y, Calve S. Comparative Analysis of the Extracellular Matrix Proteome across the Myotendinous Junction. J Proteome Res 2020; 19:3955-3967. [PMID: 32830507 DOI: 10.1021/acs.jproteome.0c00248] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The myotendinous junction is a highly interdigitated interface designed to transfer muscle-generated force to tendon. Understanding how this interface is formed and organized, as well as identifying tendon- and muscle-specific extracellular matrix (ECM), is critical for designing effective regenerative therapies to restore functionality to damaged muscle-tendon units. However, a comparative analysis of the ECM proteome across this interface has not been conducted. The goal of this study was to resolve the distribution of ECM proteins that are uniformly expressed as well as those specific to each of the muscle, tendon, and junction tissues. The soleus muscles from 5-month-old wild-type C57BL/6 mice were harvested and dissected into the central muscle (M) away from tendon, the junction between muscle and tendon (J) and the tendon (T). Tissues were processed by either homogenizing in guanidine hydrochloride or fractionating to isolate the ECM from more soluble intracellular components and then analyzed using liquid chromatography-tandem mass spectrometry. Overall, we found that both tissue processing methods generated similar ECM profiles. Many ECM were found across the muscle-tendon unit, including type I collagen and associated fibril-regulating proteins. The ECM identified exclusively in M were primarily related to the basal lamina, whereas those specific to T and J tissue included thrombospondins and other matricellular ECM. Type XXII collagen (COL22A1) was restricted to J, and we identified COL5A3 as a potential marker of the muscle-tendon interface. Immunohistochemical analysis of key proteins confirmed the restriction of some basal lamina proteins to M, tenascin-C to T, and COL22A1 to J. COL5A3, PRELP, and POSTN were visualized in the tissue surrounding the junction, suggesting that these proteins play a role in stabilizing the interface. This comparative map provides a guide for tissue-specific ECM that can facilitate the spatial visualization of M, J, and T tissues and inform musculoskeletal regenerative therapies.
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Affiliation(s)
- Kathryn R Jacobson
- Purdue University Interdisciplinary Life Science Program, 155 S. Grant Street, West Lafayette, Indiana 47907, United States
| | - Sarah Lipp
- Weldon School of Biomedical Engineering, Purdue University, 206 South Martin Jischke Drive, West Lafayette, Indiana 47907, United States
| | - Andrea Acuna
- Weldon School of Biomedical Engineering, Purdue University, 206 South Martin Jischke Drive, West Lafayette, Indiana 47907, United States
| | - Yue Leng
- Weldon School of Biomedical Engineering, Purdue University, 206 South Martin Jischke Drive, West Lafayette, Indiana 47907, United States
| | - Ye Bu
- Weldon School of Biomedical Engineering, Purdue University, 206 South Martin Jischke Drive, West Lafayette, Indiana 47907, United States
| | - Sarah Calve
- Purdue University Interdisciplinary Life Science Program, 155 S. Grant Street, West Lafayette, Indiana 47907, United States.,Weldon School of Biomedical Engineering, Purdue University, 206 South Martin Jischke Drive, West Lafayette, Indiana 47907, United States.,Paul M. Rady Department of Mechanical Engineering, University of Colorado-Boulder, 1111 Engineering Center, 427 UCB, Boulder, Colorado 80309, United States
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Gawel SH, Davis GJ, Luo M, Deutz NEP, Wolfe RR, Pereira SL. Serum biomarkers that predict lean mass loss over bed rest in older adults: An exploratory study. Clin Chim Acta 2020; 509:72-78. [PMID: 32505773 DOI: 10.1016/j.cca.2020.06.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/23/2020] [Accepted: 06/02/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND Lean mass (LM) loss during extended bed rest contributes to long term functional decline in older adults. Identifying blood biomarkers that predict a hospitalized individual's risk of losing LM could allow for timely intervention. METHODS LM from 19 healthy subjects (age 60-76 y, 4 males, 15 females), who were confined to 10 days of complete bed rest, was measured pre- and post-bed rest. One hundred eighty-seven biomarkers from pre-bed rest fasted serum samples were obtained from all evaluable subjects (n = 18), analyzed using multiplexed immunoassay array and pooled. Decision tree analysis was used to identify pre-bed rest markers that predict LM loss over bed rest. RESULTS Sixty-three markers were excluded due to being below assay detection limits. One pair of markers, Tissue inhibitor of metalloprotease-1 (TIMP1) and tenascin C (TNC), were found to correlate with percent change in total LM over bed rest: [R2 = 0.71, all subjects; R2 = 0.76, females]. Subjects with pre-bed rest TIMP1 ≥ 141 ng/ml had the highest loss of total LM over bed rest, whereas subjects with pre-bed rest TIMP1 < 141 and TNC ≥ 461 ng/ml maintained total LM over bed rest. An additional marker set was found to correlate with percent change in leg LM loss over bed rest: matrix metalloprotease-3 (MMP3) and apolipoprotein A2 (APOA2) [R2 = 0.59, females]. Females with pre-bed rest MMP3 < 6.93 ng/ml had the highest loss of leg LM over bed rest. Whereas females with pre-bed rest MMP3 ≥ 6.93 and ApoA2 < 276 ng/ml, maintained leg lean mass at the end of bed rest. CONCLUSIONS Panels of blood biomarkers associated with the muscle extracellular matrix may predict the likelihood for LM loss over extended bed rest.
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Affiliation(s)
- Susan H Gawel
- Abbott Diagnostics Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA
| | - Gerard J Davis
- Abbott Diagnostics Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA
| | - Menghua Luo
- Abbott Nutrition Division, Abbott Laboratories, 3300 Stelzer Road, Columbus, OH 43219, USA
| | - Nicolaas E P Deutz
- Texas A&M University, Department of Health & Kinesiology, 675 John Kimbrough Blvd, College Station, TX 77843-4253, USA
| | - Robert R Wolfe
- University of Arkansas Medical Sciences, UAMS Centers on Aging, 4301 West Markham Street, Little Rock, AR 72205, USA
| | - Suzette L Pereira
- Abbott Nutrition Division, Abbott Laboratories, 3300 Stelzer Road, Columbus, OH 43219, USA.
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Abstract
The morphogenesis of the mammalian secondary plate is a series of highly dynamic developmental process, including the palate shelves vertical outgrowth, elevation to the horizontal plane and complete fusion in the midline. Extracellular matrix (ECM) proteins not only form the basic infrastructure for palatal mesenchymal cells to adhere via integrins but also interact with cells to regulate their functions such as proliferation and differentiation. ECM remodeling is essential for palatal outgrowth, expansion, elevation, and fusion. Multiple signaling pathways important for palatogenesis such as FGF, TGF β, BMP, and SHH remodels ECM dynamics. Dysregulation of ECM such as HA synthesis or ECM breakdown enzymes MMPs or ADAMTS causes cleft palate in mouse models. A better understanding of ECM remodeling will contribute to revealing the pathogenesis of cleft palate.
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Affiliation(s)
- Xia Wang
- Health Science Center, Shenzhen University , Shenzhen, China
| | - Chunman Li
- Health Science Center, Shenzhen University , Shenzhen, China
| | - Zeyao Zhu
- Health Science Center, Shenzhen University , Shenzhen, China
| | - Li Yuan
- Department of Stomatology, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan University , Shenzhen, China
| | - Wood Yee Chan
- School of Biomedical Sciences, The Chinese University of Hong Kong , Hong Kong, China
| | - Ou Sha
- Health Science Center, Shenzhen University , Shenzhen, China
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Liu YC, Wang HL, Huang YZ, Weng YH, Chen RS, Tsai WC, Yeh TH, Lu CS, Chen YL, Lin YW, Chen YJ, Hsu CC, Chiu CH, Chiu CC. Alda-1, an activator of ALDH2, ameliorates Achilles tendinopathy in cellular and mouse models. Biochem Pharmacol 2020; 175:113919. [PMID: 32194057 DOI: 10.1016/j.bcp.2020.113919] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 03/13/2020] [Indexed: 12/15/2022]
Abstract
Achilles tendinopathy has a high re-injury rate and poor prognosis. Development of effective therapy for Achilles tendinopathy is important. Excessive accumulation of ROS and resulting oxidative stress are believed to cause tendinopathy. Overproduction of hydrogen peroxide (H2O2), the most common ROS, could lead to the tendinopathy by causing oxidative damage, activation of endoplasmic reticulum (ER) stress and apoptotic death of tenocytes. Activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) is expected to alleviate oxidative stress and ER stress. Alda-1 is a selective and potent activator of ALDH2. In this study, we examined the cytoprotective benefit of Alda-1, an activator of ALDH2, on H2O2-induced Achilles tendinopathy in cellular and mouse models. We prepared cellular and mouse models of Achilles tendinopathy by treating cultured Achilles tenocytes and Achilles tendons with oxidative stressor H2O2. Subsequently, we studied the protective benefit of Alda-1 on H2O2-induced Achilles tendinopathy. Alda-1 pretreatment attenuated H2O2-induced cell death of cultured Achilles tenocytes. Treatment of Alda-1 prevented H2O2-induced oxidative stress and depolarization of mitochondrial membrane potential in tenocytes. Application of Alda-1 attenuated H2O2-triggered mitochondria- and ER stress-mediated apoptotic cascades in cultured tenocytes. Alda-1 treatment ameliorated the severity of H2O2-induced Achilles tendinopathy in vivo by preventing H2O2-induced pathological histological features of Achilles tendons, apoptotic death of Achilles tenocytes and upregulated expression of inflammatory cytokines IL-1β and TNF-α. Our results provide the evidence that ALDH2 activator Alda-1 ameliorates H2O2-induced Achilles tendinopathy. Alda-1 could be used for preventing and treating Achilles tendinopathy.
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Affiliation(s)
- Yu-Chuan Liu
- Landseed Sports Medicine Center, Landseed International Hospital, Taoyuan, Taiwan
| | - Hung-Li Wang
- Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Healthy Aging Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Ying-Zu Huang
- Healthy Aging Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Institute of Cognitive Neuroscience, National Central University, Taoyuan, Taiwan
| | - Yi-Hsin Weng
- Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Rou-Shayn Chen
- Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wen-Chung Tsai
- College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Tu-Hsueh Yeh
- Department of Neurology, Taipei Medical University Hospital, Taiwan
| | - Chin-Song Lu
- Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Ying-Ling Chen
- Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan
| | - Yan-Wei Lin
- Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Yu-Jie Chen
- Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chia-Chen Hsu
- Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chi-Han Chiu
- Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Ching-Chi Chiu
- Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
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Gruber BL, Mienaltowski MJ, MacLeod JN, Schittny J, Kasper S, Flück M. Tenascin-C expression controls the maturation of articular cartilage in mice. BMC Res Notes 2020; 13:78. [PMID: 32066496 PMCID: PMC7027060 DOI: 10.1186/s13104-020-4906-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 01/14/2020] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE Expression of the de-adhesive extracellular matrix protein tenascin-C (TNC) is associated with the early postnatal development of articular cartilage which is both load-dependent and associated with chondrocyte differentiation. We assessed morphological changes in the articular cartilage of TNC deficient mice at postnatal ages of 1, 4 and 8 weeks compared to age-matched wildtype mice. RESULTS Cartilage integrity was assessed based on hematoxylin and eosin stained-sections from the tibial bone using a modified Mankin score. Chondrocyte density and cartilage thickness were assessed morphometrically. TNC expression was localized based on immunostaining. At 8 weeks of age, the formed tangential/transitional zone of the articular cartilage was 27% thicker and the density of chondrocytes in the articular cartilage was 55% lower in wildtype than the TNC-deficient mice. TNC protein expression was associated with chondrocytes. No relevant changes were found in mice at 1 and 4 weeks of age. The findings indicate a role of tenascin-C in the post-natal maturation of the extracellular matrix in articular cartilage. This might be a compensatory mechanism to strengthen resilience against mechanical stress.
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Affiliation(s)
- Bastian L Gruber
- Laboratory for Muscle Plasticity, Department of Orthopedics, University of Zurich, Balgrist Campus, Lengghalde 5, 8008, Zurich, Switzerland
| | - Michael J Mienaltowski
- Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY, USA.,Department of Animal Science, University of California Davis, Davis, CA, USA
| | - James N MacLeod
- Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY, USA
| | | | - Stephanie Kasper
- Laboratory for Muscle Plasticity, Department of Orthopedics, University of Zurich, Balgrist Campus, Lengghalde 5, 8008, Zurich, Switzerland
| | - Martin Flück
- Laboratory for Muscle Plasticity, Department of Orthopedics, University of Zurich, Balgrist Campus, Lengghalde 5, 8008, Zurich, Switzerland. .,Institute of Anatomy, University of Berne, Berne, Switzerland.
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30
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Taye N, Karoulias SZ, Hubmacher D. The "other" 15-40%: The Role of Non-Collagenous Extracellular Matrix Proteins and Minor Collagens in Tendon. J Orthop Res 2020; 38:23-35. [PMID: 31410892 PMCID: PMC6917864 DOI: 10.1002/jor.24440] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 08/02/2019] [Indexed: 02/04/2023]
Abstract
Extracellular matrix (ECM) determines the physiological function of all tissues, including musculoskeletal tissues. In tendon, ECM provides overall tissue architecture, which is tailored to match the biomechanical requirements of their physiological function, that is, force transmission from muscle to bone. Tendon ECM also constitutes the microenvironment that allows tendon-resident cells to maintain their phenotype and that transmits biomechanical forces from the macro-level to the micro-level. The structure and function of adult tendons is largely determined by the hierarchical organization of collagen type I fibrils. However, non-collagenous ECM proteins such as small leucine-rich proteoglycans (SLRPs), ADAMTS proteases, and cross-linking enzymes play critical roles in collagen fibrillogenesis and guide the hierarchical bundling of collagen fibrils into tendon fascicles. Other non-collagenous ECM proteins such as the less abundant collagens, fibrillins, or elastin, contribute to tendon formation or determine some of their biomechanical properties. The interfascicular matrix or endotenon and the outer layer of tendons, the epi- and paratenon, includes collagens and non-collagenous ECM proteins, but their function is less well understood. The ECM proteins in the epi- and paratenon may provide the appropriate microenvironment to maintain the identity of distinct tendon cell populations that are thought to play a role during repair processes after injury. The aim of this review is to provide an overview of the role of non-collagenous ECM proteins and less abundant collagens in tendon development and homeostasis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:23-35, 2020.
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Affiliation(s)
- Nandaraj Taye
- Leni & Peter W. May Department of Orthopaedics, Orthopaedic Research LaboratoriesIcahn School of Medicine at Mt. SinaiNew York New York 10029
| | - Stylianos Z. Karoulias
- Leni & Peter W. May Department of Orthopaedics, Orthopaedic Research LaboratoriesIcahn School of Medicine at Mt. SinaiNew York New York 10029
| | - Dirk Hubmacher
- Leni & Peter W. May Department of Orthopaedics, Orthopaedic Research LaboratoriesIcahn School of Medicine at Mt. SinaiNew York New York 10029
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31
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Deniz P, Guler S, Çelik E, Hosseinian P, Aydin HM. Use of cyclic strain bioreactor for the upregulation of key tenocyte gene expression on Poly(glycerol-sebacate) (PGS) sheets. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 106:110293. [PMID: 31753347 DOI: 10.1016/j.msec.2019.110293] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 09/12/2019] [Accepted: 10/07/2019] [Indexed: 01/11/2023]
Abstract
The inadequate donor source and the difficulty of using natural grafts in tendon repair and regeneration has led researchers to develop biodegradable and biocompatible synthetic based tissue equivalents. Poly(glycerol sebacate) (PGS) is a surface-erodible bioelastomer and has been increasingly investigated in a variety of biomedical applications. In this study, PGS elastomeric sheets were prepared by using a facile microwave method and used as elastomeric platform for the first time under mechanical stimulation to induct the tenocyte gene expression. It is revealed that elastomeric PGS sheets promote progenitor tendon cell structure by increasing proliferation and gene expression with regard to tendon extracellular matrix components. Human tenocytes were seeded onto poly(glycerol-sebacate) sheets and were cultured two days prior to transfer to dynamic culture in a bioreactor system. Cell culture studies were carried out for 12 days under 0%, 3% and 6% strain at 0.33 Hz. The PGS-cell constructs were examined by using Scanning Electron Microscopy (SEM), cell viability via live/dead staining using confocal microscopy, and GAG/DNA analysis. In addition, gene expression was examined using real-time polymerase chain reaction (RT-PCR). Tenocytes cultured upon PGS scaffolds under 6% cyclic strain exhibited tendon-like gene expression profile compared to 3% and 0% strain groups. The results of this study show that PGS is a suitable material in promoting tendon tissue formation under dynamic conditions.
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Affiliation(s)
- Pelin Deniz
- Bioengineering Division, Institute of Science, Hacettepe University, Ankara, Turkey
| | - Selcan Guler
- Bioengineering Division, Institute of Science, Hacettepe University, Ankara, Turkey
| | - Ekin Çelik
- Medical Biology Division, Faculty of Medicine, Kirsehir Ahi Evran University, Kirsehir, Turkey
| | - Pezhman Hosseinian
- Nanotechnology and Nanomedicine Division, Institute of Science, Hacettepe University, Ankara, Turkey
| | - Halil Murat Aydin
- Bioengineering Division, Institute of Science and Centre for Bioengineering, Hacettepe University, Ankara, Turkey.
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Wu XS, Yeh CY, Harn HIC, Jiang TX, Wu P, Widelitz RB, Baker RE, Chuong CM. Self-assembly of biological networks via adaptive patterning revealed by avian intradermal muscle network formation. Proc Natl Acad Sci U S A 2019; 116:10858-10867. [PMID: 31072931 PMCID: PMC6561168 DOI: 10.1073/pnas.1818506116] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Networked structures integrate numerous elements into one functional unit, while providing a balance between efficiency, robustness, and flexibility. Understanding how biological networks self-assemble will provide insights into how these features arise. Here, we demonstrate how nature forms exquisite muscle networks that can repair, regenerate, and adapt to external perturbations using the feather muscle network in chicken embryos as a paradigm. The self-assembled muscle networks arise through the implementation of a few simple rules. Muscle fibers extend outward from feather buds in every direction, but only those muscle fibers able to connect to neighboring buds are eventually stabilized. After forming such a nearest-neighbor configuration, the network can be reconfigured, adapting to perturbed bud arrangement or mechanical cues. Our computational model provides a bioinspired algorithm for network self-assembly, with intrinsic or extrinsic cues necessary and sufficient to guide the formation of these regenerative networks. These robust principles may serve as a useful guide for assembling adaptive networks in other contexts.
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Affiliation(s)
- Xiao-Shan Wu
- Department of Pathology, University of Southern California, Los Angeles, CA 90033
- Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, 410008 Changsha, China
- Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, 100050 Beijing, China
| | - Chao-Yuan Yeh
- Department of Pathology, University of Southern California, Los Angeles, CA 90033
- Integrative Stem Cell Center, China Medical University, 40402 Taichung, Taiwan
| | - Hans I-Chen Harn
- Department of Pathology, University of Southern California, Los Angeles, CA 90033
- International Research Center of Wound Repair and Regeneration, National Cheng Kung University, 701 Tainan, Taiwan
| | - Ting-Xing Jiang
- Department of Pathology, University of Southern California, Los Angeles, CA 90033
| | - Ping Wu
- Department of Pathology, University of Southern California, Los Angeles, CA 90033
| | - Randall B Widelitz
- Department of Pathology, University of Southern California, Los Angeles, CA 90033
| | - Ruth E Baker
- Mathematical Institute, University of Oxford, OX2 6GG Oxford, United Kingdom
| | - Cheng-Ming Chuong
- Department of Pathology, University of Southern California, Los Angeles, CA 90033;
- Integrative Stem Cell Center, China Medical University, 40402 Taichung, Taiwan
- International Research Center of Wound Repair and Regeneration, National Cheng Kung University, 701 Tainan, Taiwan
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Nakanishi Y, Okada T, Takeuchi N, Kozono N, Senju T, Nakayama K, Nakashima Y. Histological evaluation of tendon formation using a scaffold-free three-dimensional-bioprinted construct of human dermal fibroblasts under in vitro static tensile culture. Regen Ther 2019; 11:47-55. [PMID: 31193148 PMCID: PMC6517794 DOI: 10.1016/j.reth.2019.02.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 01/11/2019] [Accepted: 02/03/2019] [Indexed: 10/26/2022] Open
Abstract
Introduction Tendon tissue engineering requires scaffold-free techniques for safe and long-term clinical applications and to explore alternative cell sources to tenocytes. Therefore, we histologically assessed tendon formation in a scaffold-free Bio-three-dimensional (3D) construct developed from normal human dermal fibroblasts (NHDFs) using our Bio-3D printer system under tensile culture in vitro. Methods Scaffold-free ring-like tissues were constructed from 120 multicellular spheroids comprising NHDFs using a bio-3D printer. Ring-like tissues were cultured in vitro under static tensile-loading with or without in-house tensile devices (tension-loaded and tension-free groups), with increases in tensile strength applied weekly to the tensile-loaded group. After a 4 or 8-week culture on the device, we evaluated histological findings according to tendon-maturing score and immunohistological findings of the middle portion of the tissues for both groups (n = 4, respectively). Results Histology of the tension-loaded group revealed longitudinally aligned collagen fibers with increased collagen deposition and spindle-shaped cells with prolonged culture. By contrast, the tension-free group showed no organized cell arrangement or collagen fiber structure. Additionally, the tension-loaded group showed a significantly improved tendon-maturing score as compared with that for the tension-free group at week 8. Moreover, immunohistochemistry revealed tenascin C distribution with a parallel arrangement in the tensile-loading direction at week 8 in the tension-loaded group, which exhibited stronger scleraxis-staining intensity than that observed in the tension-free group at weeks 4 and 8. Conclusions The NHDF-generated scaffold-free Bio-3D construct underwent remodeling and formed tendon-like structures under tensile culture in vitro.
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Affiliation(s)
- Yoshitaka Nakanishi
- Department of Orthopaedic Surgery, School of Medicine, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Takamitsu Okada
- Department of Orthopaedic Surgery, School of Medicine, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Naohide Takeuchi
- Department of Orthopaedic Surgery, School of Medicine, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Naoya Kozono
- Department of Orthopaedic Surgery, School of Medicine, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Takahiro Senju
- Department of Orthopaedic Surgery, School of Medicine, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Koichi Nakayama
- Department of Regenerative Medicine and Biomedical Engineering, Faculty of Medicine, Saga University, Honjyo 1-chome, Honjyo-cho, Saga, 840-8502, Japan
| | - Yasuharu Nakashima
- Department of Orthopaedic Surgery, School of Medicine, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka-shi, Fukuoka, 812-8582, Japan
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Lulińska-Kuklik E, Laguette MJN, Moska W, Weber-Rajek M, Ficek K, Puchala R, Cięszczyk P, Sawczuk M, September AV, Maciejewska-Skrendo A. Are TNC gene variants associated with anterior cruciate ligament rupture susceptibility? J Sci Med Sport 2018; 22:408-412. [PMID: 30528246 DOI: 10.1016/j.jsams.2018.10.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 09/05/2018] [Accepted: 10/09/2018] [Indexed: 12/19/2022]
Abstract
OBJECTIVES To investigate the role of inter-individual variations in a particular glycoprotein, TNC, and its potential contribution to anterior cruciate ligament (ACL) injury susceptibility in Polish Caucasian participants. ACL rupture is one of the most prevalent and severe knee injury that predominantly occurs during sports participation, primarily via a non-contact mechanism. Several polymorphisms in genes encoding glycoproteins either independently or as allelic combinations, modulate the risk of musculoskeletal soft tissue injuries. Specifically, the TNC rs1330363 (C>T), rs2104772 (T>A) and rs13321 (G>C) variants, independently or in haplotype combinations, were analysed in this context. DESIGN Case-control genetic association study. METHODS A group of 421 physically active, unrelated participants were recruited where 229 individuals with surgically diagnosed primary ACL rupture and 192 apparently healthy participants without any history of ACL injuries. Participants were genotyped for the above variants. RESULTS Genotype and allele frequencies of TNC variants did not differ between cases and controls. Haplotype analysis revealed no association between TNC and predisposition to ACL rupture. CONCLUSIONS Our analyses did not reveal a significant association between these TNC variants and risk of ACL rupture in Polish Caucasian participants.
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Affiliation(s)
- Ewelina Lulińska-Kuklik
- Faculty of Tourism and Recreation, Gdansk University of Physical Education and Sport, Poland
| | - Mary-Jessica Nancy Laguette
- UCT Research Centre for Health through Physical Activity, Lifestyle and Sport (HPALS), University of Cape Town, South Africa.
| | - Waldemar Moska
- Faculty of Tourism and Recreation, Gdansk University of Physical Education and Sport, Poland
| | - Magdalena Weber-Rajek
- Department of Physiotherapy, Collegium Medicum Nicolaus Copernicus University, Poland
| | - Krzysztof Ficek
- Department of Medicine and Sport Physiotherapy, Academy of Sport Education in Katowice, Poland
| | - Ryszard Puchala
- Department of Applied Physiology, Military Institute of Hygiene and Epidemiology, Poland
| | - Paweł Cięszczyk
- Faculty of Physical Education, Gdansk University of Physical Education and Sport, Poland; Faculty of Physical Education, Academy of Sport Education in Katowice, Poland
| | - Marek Sawczuk
- Faculty of Tourism and Recreation, Gdansk University of Physical Education and Sport, Poland
| | - Alison Victoria September
- UCT Research Centre for Health through Physical Activity, Lifestyle and Sport (HPALS), University of Cape Town, South Africa
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Rittweger J, Albracht K, Flück M, Ruoss S, Brocca L, Longa E, Moriggi M, Seynnes O, Di Giulio I, Tenori L, Vignoli A, Capri M, Gelfi C, Luchinat C, Francheschi C, Bottinelli R, Cerretelli P, Narici M. Sarcolab pilot study into skeletal muscle's adaptation to long-term spaceflight. NPJ Microgravity 2018; 4:18. [PMID: 30246141 PMCID: PMC6141586 DOI: 10.1038/s41526-018-0052-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 07/04/2018] [Accepted: 07/10/2018] [Indexed: 12/31/2022] Open
Abstract
Spaceflight causes muscle wasting. The Sarcolab pilot study investigated two astronauts with regards to plantar flexor muscle size, architecture, and function, and to the underlying molecular adaptations in order to further the understanding of muscular responses to spaceflight and exercise countermeasures. Two crew members (A and B) spent 6 months in space. Crew member A trained less vigorously than B. Postflight, A showed substantial decrements in plantar flexor volume, muscle architecture, in strength and in fiber contractility, which was strongly mitigated in B. The difference between these crew members closely reflected FAK-Y397 abundance, a molecular marker of muscle's loading history. Moreover, crew member A showed downregulation of contractile proteins and enzymes of anaerobic metabolism, as well as of systemic markers of energy and protein metabolism. However, both crew members exhibited decrements in muscular aerobic metabolism and phosphate high energy transfer. We conclude that countermeasures can be effective, particularly when resistive forces are of sufficient magnitude. However, to fully prevent space-related muscular deterioration, intersubject variability must be understood, and intensive exercise countermeasures programs seem mandatory. Finally, proteomic and metabolomic analyses suggest that exercise benefits in space may go beyond mere maintenance of muscle mass, but rather extend to the level of organismic metabolism.
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Affiliation(s)
- Jörn Rittweger
- 1Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany.,2Department of Pediatrics and Adolescent Medicine, University of Cologne, Cologne, Germany
| | - Kirsten Albracht
- 3Faculty of Medical Engineering and Technomathematics, FH Aachen University of Applied Science Aachen, Aachen, Germany.,4Institute of Biomechanics and Orthopaedics, German Sport University, Cologne, Germany
| | - Martin Flück
- 5Department of Orthopaedics, University of Zürich, Zürich, Switzerland
| | - Severin Ruoss
- 5Department of Orthopaedics, University of Zürich, Zürich, Switzerland
| | - Lorenza Brocca
- 6Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Emanuela Longa
- 6Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | | | - Olivier Seynnes
- 8Department of Physical Performance, Norwegian School of Sport Sciences, Oslo, Norway
| | - Irene Di Giulio
- 9Centre for Human and Applied Physiological Sciences, King's College London, London, UK
| | - Leonardo Tenori
- 10Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Alessia Vignoli
- CERM Centro di Ricerca di Risonanze Magnetiche, Florence, Italy
| | - Miriam Capri
- 12Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Cecilia Gelfi
- 13Department of Biomedical Sciences for Health, University of Milan, Milano, Italy
| | | | - Claudio Francheschi
- 12Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Roberto Bottinelli
- 6Department of Molecular Medicine, University of Pavia, Pavia, Italy.,14Fondazione Salvatore Maugeri (IRCSS), Scientific Institute of Pavia, Pavia, Italy
| | | | - Marco Narici
- 15Department of Biomedical Sciences, University of Padova, Padova, Italy
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Liu X, Laurent C, Du Q, Targa L, Cauchois G, Chen Y, Wang X, de Isla N. Mesenchymal stem cell interacted with PLCL braided scaffold coated with poly-l-lysine/hyaluronic acid for ligament tissue engineering. J Biomed Mater Res A 2018; 106:3042-3052. [PMID: 30194699 DOI: 10.1002/jbm.a.36494] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 06/19/2018] [Accepted: 06/22/2018] [Indexed: 01/07/2023]
Abstract
The challenge of finding an adapted scaffold for ligament tissue engineering remains unsolved after years of researches. A technology to fabricate a multilayer braided scaffold with flexible and elastic poly (l-lactide-co-caprolactone) (PLCL 85/15) has been recently pioneered by our team. In this study, polyelectrolyte multilayer films (PEM) with poly-l-lysine (PLL)/ hyaluronic acid (HA) were deposited on this scaffold. After PEM modification, polygonal (PLL) and particle-like (HA) structures were present on the braided scaffold with no significant variation of fibers Young's modulus. Wharton's jelly mesenchymal stem cells (WJ-MSC) and bone marrow mesenchymal stem cells (BM-MSC) showed good metabolic activity on scaffolds. They presented a spindled shape along the fiber longitudinal direction, and crossed the fibers to form cell bridges. Collagen type I, collagen type III, and tenascin-C secreted by MSCs were detected on day 14. Moreover, one-layer modified scaffold presented increased chemotaxis. As a conclusion, our results indicate that this braided PLCL scaffold with one-layer PEM modification shows inspiring potential with satisfying mechanical properties and biocompatibility. It opens new perspectives to incorporate growth factors within PEM-modified braided PLCL scaffold for ligament tissue engineering and to recruit endogenous cells after implantation. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3042-3052, 2018.
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Affiliation(s)
- Xing Liu
- CNRS UMR 7365 -Université de Lorraine, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Vandœuvre-lès-Nancy, France
| | - Cédric Laurent
- CNRS UMR 7239 LEM3 - Université de Lorraine, Vandoeuvre-lès-Nancy, France
| | - Qiaoyue Du
- Department of Biomedical Engineering, School of Basic Medical Science, Wuhan University, Wuhan, China
| | - Laurie Targa
- CNRS UMR 7365 -Université de Lorraine, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Vandœuvre-lès-Nancy, France
| | - Ghislaine Cauchois
- CNRS UMR 7365 -Université de Lorraine, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Vandœuvre-lès-Nancy, France
| | - Yun Chen
- Department of Biomedical Engineering, School of Basic Medical Science, Wuhan University, Wuhan, China
| | - Xiong Wang
- CNRS UMR 7365 -Université de Lorraine, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Vandœuvre-lès-Nancy, France
| | - Natalia de Isla
- CNRS UMR 7365 -Université de Lorraine, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Vandœuvre-lès-Nancy, France
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Bayer ML, Hoegberget-Kalisz M, Jensen MH, Olesen JL, Svensson RB, Couppé C, Boesen M, Nybing JD, Kurt EY, Magnusson SP, Kjaer M. Role of tissue perfusion, muscle strength recovery, and pain in rehabilitation after acute muscle strain injury: A randomized controlled trial comparing early and delayed rehabilitation. Scand J Med Sci Sports 2018; 28:2579-2591. [DOI: 10.1111/sms.13269] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 07/17/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Monika L. Bayer
- Department of Orthopedic Surgery M; Faculty of Health and Medical Sciences; Institute of Sports Medicine Copenhagen; Bispebjerg Hospital and Center for Healthy Aging; University of Copenhagen; Copenhagen Denmark
| | - Maren Hoegberget-Kalisz
- Department of Orthopedic Surgery M; Faculty of Health and Medical Sciences; Institute of Sports Medicine Copenhagen; Bispebjerg Hospital and Center for Healthy Aging; University of Copenhagen; Copenhagen Denmark
| | - Mikkel H. Jensen
- Department of Orthopedic Surgery M; Faculty of Health and Medical Sciences; Institute of Sports Medicine Copenhagen; Bispebjerg Hospital and Center for Healthy Aging; University of Copenhagen; Copenhagen Denmark
| | - Jens L. Olesen
- Department of Orthopedic Surgery M; Faculty of Health and Medical Sciences; Institute of Sports Medicine Copenhagen; Bispebjerg Hospital and Center for Healthy Aging; University of Copenhagen; Copenhagen Denmark
- Research Unit for General Practice in Aalborg; Department of Clinical Medicine; Aalborg University; Aalborg Denmark
| | - Rene B. Svensson
- Department of Orthopedic Surgery M; Faculty of Health and Medical Sciences; Institute of Sports Medicine Copenhagen; Bispebjerg Hospital and Center for Healthy Aging; University of Copenhagen; Copenhagen Denmark
| | - Christian Couppé
- Department of Orthopedic Surgery M; Faculty of Health and Medical Sciences; Institute of Sports Medicine Copenhagen; Bispebjerg Hospital and Center for Healthy Aging; University of Copenhagen; Copenhagen Denmark
- Department of Physical Therapy; Bispebjerg Hospital; Copenhagen Denmark
| | - Mikael Boesen
- Radiology; Bispebjerg Frederiksberg Hospital; University of Copenhagen; Copenhagen Denmark
| | - Janus D. Nybing
- Radiology; Bispebjerg Frederiksberg Hospital; University of Copenhagen; Copenhagen Denmark
| | - Engin Y. Kurt
- Radiology; Bispebjerg Frederiksberg Hospital; University of Copenhagen; Copenhagen Denmark
| | - S. Peter Magnusson
- Department of Orthopedic Surgery M; Faculty of Health and Medical Sciences; Institute of Sports Medicine Copenhagen; Bispebjerg Hospital and Center for Healthy Aging; University of Copenhagen; Copenhagen Denmark
- Department of Physical Therapy; Bispebjerg Hospital; Copenhagen Denmark
| | - Michael Kjaer
- Department of Orthopedic Surgery M; Faculty of Health and Medical Sciences; Institute of Sports Medicine Copenhagen; Bispebjerg Hospital and Center for Healthy Aging; University of Copenhagen; Copenhagen Denmark
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Abstract
Achilles tendinopathy is a common cause of disability. Despite the economic and social relevance of the problem, the causes and mechanisms of Achilles tendinopathy remain unclear. Tendon vascularity, gastrocnemius-soleus dysfunction, age, sex, body weight and height, pes cavus, and lateral ankle instability are considered common intrinsic factors. The essence of Achilles tendinopathy is a failed healing response, with haphazard proliferation of tenocytes, some evidence of degeneration in tendon cells and disruption of collagen fibers, and subsequent increase in noncollagenous matrix. Tendinopathic tendons have an increased rate of matrix remodeling, leading to a mechanically less stable tendon which is more susceptible to damage. The diagnosis of Achilles tendinopathy is mainly based on a careful history and detailed clinical examination. The latter remains the best diagnostic tool. Over the past few years, various new therapeutic options have been proposed for the management of Achilles tendinopathy. Despite the morbidity associated with Achilles tendinopathy, many of the therapeutic options described and in common use are far from scientifically based. New minimally invasive techniques of stripping of neovessels from the Kager's triangle of the tendo Achillis have been described, and seem to allow faster recovery and accelerated return to sports, rather than open surgery. A genetic component has been implicated in tendinopathies of the Achilles tendon, but these studies are still at their infancy.
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Engebretson B, Mussett ZR, Sikavitsas VI. The effects of varying frequency and duration of mechanical stimulation on a tissue-engineered tendon construct. Connect Tissue Res 2018; 59:167-177. [PMID: 28459287 DOI: 10.1080/03008207.2017.1324431] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Decellularized, discarded human tissues, such as the human umbilical vein, have been widely utilized for tissue engineering applications, including tendon grafts. When recellularized, such natural scaffolds are cultured in 3D dynamic culture environments (bioreactor systems). For tendon tissue-engineered grafts, such systems often employ oscillatory mechanical stimulation in the form uniaxial tensile strain. The three main parameters of such stimulation are frequency, duration, and force. In this study we investigated the effects of changing the duration (0.5, 1, and 2 h/day) and frequency (0.5, 1, 2 cycles/min) of stimulation of a human umbilical vein seeded with mesenchymal stem cells cultured for up to 7 days. Strain of the construct was held constant at 2%. The highest proliferation rates were observed in the 0.5 h/day duration and 1 cycle/min frequency (203% increase) with a close second being 1 h/day and 1 cycle/min frequency (170% increase). Static cultures along with a 2 cycles/min frequency and a 2 h/day duration of stretching did not increase cellular proliferation significantly. Extracellular matrix quality and alignment of the construct fibers had a direct relation to cellularity and those groups with the highest cellularity improved the most. Gene expression indicated cellular activity consistent with tendon-like tissue remodeling. In addition, scleraxis, tenascin-C, and tenomodulin were upregulated in certain groups after 7 days, with osteoblast, chondrocyte, and adipocyte phenotypes depressed. The stimulation parameters investigated in this study indicated that slower frequencies and shorter durations were best for construct quality in early stage cultures.
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Affiliation(s)
- Brandon Engebretson
- a School of Chemical , Biological and Materials Engineering, University of Oklahoma , Norman , OK , USA
| | - Zachary R Mussett
- b Stephenson School of Biomedical Engineering , University of Oklahoma , Norman , OK , USA
| | - Vassilios I Sikavitsas
- a School of Chemical , Biological and Materials Engineering, University of Oklahoma , Norman , OK , USA.,b Stephenson School of Biomedical Engineering , University of Oklahoma , Norman , OK , USA
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40
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Abstract
Tenascin-C (TN-C) is a glycoprotein component of the extracellular matrix (ECM). TN-C consists of four distinct domains, including the tenascin assembly domain, epidermal growth factor-like repeats, fibronectin type III-like repeats, and the fibrinogen-like globe (FBG) domain. This review summarizes the role of TN-C in articular cartilage. Expression of TN-C is associated with the development of articular cartilage but markedly decreases during maturation of chondrocytes and disappears almost completely in adult articular cartilage. Increased expression of TN-C has been found at diseased cartilage and synovial sites in osteoarthritis (OA) and rheumatoid arthritis (RA). TN-C is increased in the synovial fluid in patients with OA and RA. In addition, serum TN-C is elevated in RA patients. TN-C could be a useful biochemical marker for joint disease. The addition of TN-C results in different effects among TN-C domains. TN-C fragments might be endogenous inducers of cartilage matrix degradation; however, full-length TN-C could promote cartilage repair and prevent cartilage degeneration. The deficiency of TN-C enhanced cartilage degeneration in the spontaneous OA in aged joints and surgical OA model. The clinical significance of TN-C effects on cartilage is not straightforward.
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Affiliation(s)
- Masahiro Hasegawa
- a Department of Orthopaedic Surgery , Mie University Graduate School of Medicine , Mie , Japan
| | - Toshimichi Yoshida
- b Department of Pathology & Matrix Biology , Mie University Graduate School of Medicine , Mie , Japan
| | - Akihiro Sudo
- a Department of Orthopaedic Surgery , Mie University Graduate School of Medicine , Mie , Japan
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41
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Stamenkovic V, Milenkovic I, Galjak N, Todorovic V, Andjus P. Enriched environment alters the behavioral profile of tenascin-C deficient mice. Behav Brain Res 2017; 331:241-253. [DOI: 10.1016/j.bbr.2017.05.047] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2017] [Revised: 05/13/2017] [Accepted: 05/17/2017] [Indexed: 12/01/2022]
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42
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Fang F, Lake SP. Experimental evaluation of multiscale tendon mechanics. J Orthop Res 2017; 35:1353-1365. [PMID: 27878999 DOI: 10.1002/jor.23488] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 11/16/2016] [Indexed: 02/04/2023]
Abstract
Tendon's primary function is a mechanical link between muscle and bone. The hierarchical structure of tendon and specific compositional constituents are believed to be critical for proper mechanical function. With increased appreciation for tendon importance and the development of various technological advances, this review paper summarizes recent experimental approaches that have been used to study multiscale tendon mechanics, includes an overview of studies that have evaluated the role of specific tissue constituents, and also proposes challenges/opportunities facing tendon study. Tendon has been demonstrated to have specific structural characteristics (e.g., multi-level hierarchy, crimp pattern, helix) and complex mechanical properties (e.g., non-linearity, anisotropy, viscoelasticity). Physical mechanisms including uncrimping, fiber sliding, and collagen reorganization have been shown to govern tendon mechanical responses under both static and dynamic loading. Several tendon constituents with relatively small quantities have been suggested to play a role in its mechanics, although some results are conflicting. Further research should be performed to understand the interplay and communication of tendon mechanical properties across levels of the hierarchical structure, and further show how each of these components contribute to tendon mechanics. The studies summarized and discussed in this review have helped elucidate important aspects of multiscale tendon mechanics, which is a prerequisite for analyzing stress/strain transfer between multiple scales and identifying key principles of mechanotransduction. This information could further facilitate interpreting the functional diversity of tendons from different species, different locations, and even different developmental stages, and then better understand and identify fundamental concepts related to tendon degeneration, disease, and healing. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1353-1365, 2017.
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Affiliation(s)
- Fei Fang
- Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, 1 Brookings Drive, Campus Box 1185, St. Louis, Missouri, 63130
| | - Spencer P Lake
- Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, 1 Brookings Drive, Campus Box 1185, St. Louis, Missouri, 63130.,Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, Campus Box 1185, St. Louis, Missouri, 63130.,Department of Orthopaedic Surgery, Washington University in St. Louis, 1 Brookings Drive, Campus Box 1185, St. Louis, Missouri, 63130
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43
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Nielsen JL, Aagaard P, Prokhorova TA, Nygaard T, Bech RD, Suetta C, Frandsen U. Blood flow restricted training leads to myocellular macrophage infiltration and upregulation of heat shock proteins, but no apparent muscle damage. J Physiol 2017; 595:4857-4873. [PMID: 28481416 DOI: 10.1113/jp273907] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 05/02/2017] [Indexed: 12/27/2022] Open
Abstract
KEY POINTS Muscular contractions performed using a combination of low external loads and partial restriction of limb blood flow appear to induce substantial gains in muscle strength and muscle mass. This exercise regime may initially induce muscular stress and damage; however, the effects of a period of blood flow restricted training on these parameters remain largely unknown. The present study shows that short-term, high-frequency, low-load muscle training performed with partial blood flow restriction does not induce significant muscular damage. However, signs of myocellular stress and inflammation that were observed in the early phase of training and after the training intervention, respectively, may be facilitating the previously reported gains in myogenic satellite cell content and muscle hypertrophy. The present results improve our current knowledge about the physiological effects of low-load muscular contractions performed under blood flow restriction and may provide important information of relevance for future therapeutic treatment of muscular atrophy. ABSTRACT Previous studies indicate that low-load muscle contractions performed under local blood flow restriction (BFR) may initially induce muscle damage and stress. However, whether these factors are evoked with longitudinal BFR training remains unexplored at the myocellular level. Two distinct study protocols were conducted, covering 3 weeks (3 wk) or one week (1 wk). Subjects performed BFR exercise (100 mmHg, 20% 1RM) to concentric failure (BFRE) (3 wk/1 wk), while controls performed work-matched (LLE) (3 wk) or high-load (HLE; 70% 1RM) (1 wk) free-flow exercise. Muscle biopsies (3 wk) were obtained at baseline (Pre), 8 days into the intervention (Mid8), and 3 and 10 days after training cessation (Post3, Post10) to examine macrophage (M1/M2) content as well as heat shock protein (HSP27/70) and tenascin-C expression. Blood samples (1 wk) were collected before and after (0.1-24 h) the first and last training session to examine markers of muscle damage (creatine kinase), oxidative stress (total antibody capacity, glutathione) and inflammation (monocyte chemotactic protein-1, interleukin-6, tumour necrosis factor α). M1-macrophage content increased 108-165% with BFRE and LLE at Post3 (P < 0.05), while M2-macrophages increased (163%) with BFRE only (P < 0.01). Membrane and intracellular HSP27 expression increased 60-132% at Mid8 with BFRE (P < 0.05-0.01). No or only minor changes were observed in circulating markers of muscle damage, oxidative stress and inflammation. The amplitude, timing and localization of the above changes indicate that only limited muscle damage was evoked with BFRE. This study is the first to show that a period of high-frequency, low-load BFR training does not appear to induce general myocellular damage. However, signs of tissue inflammation and focal myocellular membrane stress and/or reorganization were observed that may be involved in the adaptation processes evoked by BFR muscle exercise.
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Affiliation(s)
- Jakob L Nielsen
- Department of Sports Science and Clinical Biomechanics, and SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense, Denmark
| | - Per Aagaard
- Department of Sports Science and Clinical Biomechanics, and SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense, Denmark
| | - Tatyana A Prokhorova
- Department of Sports Science and Clinical Biomechanics, and SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense, Denmark
| | - Tobias Nygaard
- Department of Orthopaedic Surgery, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Rune D Bech
- Department of Orthopaedic Surgery, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Charlotte Suetta
- Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet Glostrup, University of Copenhagen, Copenhagen, Denmark
| | - Ulrik Frandsen
- Department of Sports Science and Clinical Biomechanics, and SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense, Denmark
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Abstract
Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease. © 2017 American Physiological Society. Compr Physiol 7:891-944, 2017.
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Affiliation(s)
- Christine A Henderson
- Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, Arizona, USA.,Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, USA
| | - Christopher G Gomez
- Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, Arizona, USA.,Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, USA
| | - Stefanie M Novak
- Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, Arizona, USA.,Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, USA
| | - Lei Mi-Mi
- Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, Arizona, USA.,Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, USA
| | - Carol C Gregorio
- Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, Arizona, USA.,Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, USA
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Govoni M, Berardi AC, Muscari C, Campardelli R, Bonafè F, Guarnieri C, Reverchon E, Giordano E, Maffulli N, Della Porta G. * An Engineered Multiphase Three-Dimensional Microenvironment to Ensure the Controlled Delivery of Cyclic Strain and Human Growth Differentiation Factor 5 for the Tenogenic Commitment of Human Bone Marrow Mesenchymal Stem Cells. Tissue Eng Part A 2017; 23:811-822. [PMID: 28401805 DOI: 10.1089/ten.tea.2016.0407] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
At present, injuries or rupture of tendons are treated by surgical repair or conservative approaches with unpredictable clinical outcome. Alternative strategies to repair tendon defects without the undesirable side effects associated with the current options are needed. With this in mind, a tissue engineering approach has gained considerable attention as a promising strategy. Here we investigated a synthetic three-dimensional (3D) microenvironment able to interact with stem cells and inducing, via coupled biochemical and physical signals, their early commitment toward the tenogenic lineage. This multiphase 3D construct consisted of a braided hyaluronate elastic band merged with human bone marrow mesenchymal stem cells (hBMSCs) and poly-lactic-co-glycolic acid microcarriers loaded with human growth differentiation factor 5 (hGDF-5) by means of fibrin hydrogel. The multiphase structure allowed hBMSC culture under cyclic strain within a microenvironment where a controlled amount of hGDF-5 was regularly delivered. The cooperative biochemical and physical stimuli induced significantly increased expression of tenogenic markers, such as collagen type I and III, decorin, scleraxis, and tenascin-C, within only 3 days of dynamic hBMSC culture. This approach opens exciting perspectives for future development of engineered tendon tissue substitutes.
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Affiliation(s)
- Marco Govoni
- 1 Health Sciences and Technologies-Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna , Bologna, Italy
| | - Anna Concetta Berardi
- 2 Laboratory "Stem Cells" U.O.C. Laboratory of Immunohematology and Transfusion Center , "Spirito Santo" Hospital, Pescara, Italy
| | - Claudio Muscari
- 1 Health Sciences and Technologies-Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna , Bologna, Italy .,3 Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna , Bologna, Italy
| | - Roberta Campardelli
- 4 Department of Industrial Engineering, University of Salerno , Fisciano, Italy
| | - Francesca Bonafè
- 3 Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna , Bologna, Italy
| | - Carlo Guarnieri
- 1 Health Sciences and Technologies-Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna , Bologna, Italy .,3 Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna , Bologna, Italy
| | - Ernesto Reverchon
- 4 Department of Industrial Engineering, University of Salerno , Fisciano, Italy
| | - Emanuele Giordano
- 1 Health Sciences and Technologies-Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna , Bologna, Italy .,5 Department of Electrical, Electronic and Information Engineering "Guglielmo Marconi" (DEI), University of Bologna , Cesena, Italy .,6 Advanced Research Center on Electronic Systems (ARCES), University of Bologna , Bologna, Italy
| | - Nicola Maffulli
- 7 Department of Medicine, Surgery and Dentistry, University of Salerno , Baronissi, Italy
| | - Giovanna Della Porta
- 4 Department of Industrial Engineering, University of Salerno , Fisciano, Italy .,7 Department of Medicine, Surgery and Dentistry, University of Salerno , Baronissi, Italy
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Valdivieso P, Toigo M, Hoppeler H, Flück M. T/T homozygosity of the tenascin-C gene polymorphism rs2104772 negatively influences exercise-induced angiogenesis. PLoS One 2017; 12:e0174864. [PMID: 28384286 PMCID: PMC5383042 DOI: 10.1371/journal.pone.0174864] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 03/16/2017] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Mechanical stress, including blood pressure related factors, up-regulate expression of the pro-angiogenic extracellular matrix protein tenascin-C in skeletal muscle. We hypothesized that increased capillarization of skeletal muscle with the repeated augmentation in perfusion during endurance training is associated with blood vessel-related expression of tenascin-C and would be affected by the single-nucleotide polymorphism (SNP) rs2104772, which characterizes the non-synonymous exchange of thymidine (T)-to-adenosine (A) in the amino acid codon 1677 of tenascin-C. METHODS Sixty-one healthy, untrained, male white participants of Swiss descent performed thirty 30-min bouts of endurance exercise on consecutive weekdays using a cycling ergometer. Genotype and training interactions were called significant at Bonferroni-corrected p-value of 5% (repeated measures ANOVA). RESULTS Endurance training increased capillary-to-fiber-ratio (+11%), capillary density (+7%), and mitochondrial volume density (+30%) in m. vastus lateralis. Tenascin-C protein expression in this muscle was confined to arterioles and venules (80% of cases) and increased after training in A-allele carriers. Prior to training, volume densities of subsarcolemmal and myofibrillar mitochondria in m. vastus lateralis muscle were 49% and 18%, respectively, higher in A/A homozygotes relative to T-nucleotide carriers (A/T and T/T). Training specifically increased capillary-to-fiber ratio in A-nucleotide carriers but not in T/T homozygotes. Genotype specific regulation of angiogenesis was reflected by the expression response of 8 angiogenesis-associated transcripts after exercise, and confirmed by training-induced alterations of the shear stress related factors, vimentin and VEGF A. CONCLUSION Our findings provide evidence for a negative influence of T/T homozygosity in rs2104772 on capillary remodeling with endurance exercise.
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Affiliation(s)
- Paola Valdivieso
- Laboratory for Muscle Plasticity, Department of Orthopedics, University of Zurich, Balgrist Campus, Zurich, Switzerland
| | - Marco Toigo
- Laboratory for Muscle Plasticity, Department of Orthopedics, University of Zurich, Balgrist Campus, Zurich, Switzerland
| | - Hans Hoppeler
- Institute of Anatomy, University of Berne, Berne, Switzerland
| | - Martin Flück
- Laboratory for Muscle Plasticity, Department of Orthopedics, University of Zurich, Balgrist Campus, Zurich, Switzerland
- Institute of Anatomy, University of Berne, Berne, Switzerland
- * E-mail:
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Abstract
BACKGROUND Posterior tibial tendinopathy (PTT) is the most common cause of acquired (progressive) flatfoot deformity in adults. To date, PTT research has mainly focused on management rather than on causal mechanisms. The etiology of PTT is likely to be multifactorial because both intrinsic and extrinsic risk factors have been reported. We sought to critically evaluate reported etiologic factors for PTT and consider the concept of genetic risk factors. METHODS A detailed review of the literature published after 1936 was undertaken using English-language medical databases. RESULTS No clear consensus exists as to the relative importance of the risk factors reported, and neither has any consideration been given to a possible genetic basis for PTT. CONCLUSIONS To date, studies have examined various intrinsic and extrinsic risk factors implicated in the etiology of PTT. The interaction of these factors with an individual's genetic background may provide valuable data and help offer a more complete risk profile for PTT. A properly constructed genetic association study to determine the genetic basis of PTT would provide a novel and alternative approach to understanding this condition.
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Affiliation(s)
- Paul Beeson
- Division of Podiatry, The University of Northampton, Park Campus, Boughton Green Road, Northampton, Northamptonshire, NN2 7AL, England. (E-mail: )
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Jung MC, Kim SJ, Rhee JJ, Lee DH. Electromyographic activities of the subscapularis, supraspinatus and infraspinatus muscles during passive shoulder and active elbow exercises. Knee Surg Sports Traumatol Arthrosc 2016; 24:2238-43. [PMID: 25813676 DOI: 10.1007/s00167-015-3586-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 03/18/2015] [Indexed: 11/25/2022]
Abstract
PURPOSE Postoperative exercises may increase load on repaired tendons. Differences in the activity of the rotator cuff muscles were assessed during several different types of passive shoulder and active elbow exercises. METHODS In 15 healthy subjects, passive forward flexion of the shoulder was performed using a table, pulley and rope, and a cane, and external rotation was performed using a cane and a wall. The active elbow flexion-extension exercise was also performed while holding the upper arm with the contralateral hand. Activation amplitudes of the supraspinatus, infraspinatus and subscapularis muscles were evaluated using electromyography with fine wires. RESULTS During passive forward flexion, the supraspinatus and infraspinatus muscles exhibited lower activity when using a table compared with a cane (both P < 0.01) and a pulley and rope (both P < 0.05). Flexion of <90° decreased supraspinatus activation compared with 170° (P = 0.047). During external rotation of the shoulder while using the cane and wall, there was no difference in the activity of any muscles. Electromyographic activity during the active elbow exercise was lower in the supraspinatus while holding the upper arm (P = 0.018). CONCLUSION The table sliding exercise may reduce stress on the rotator cuff during passive forward flexion more than the other exercises do. Decreasing the range of motion to less than 90° in forward flexion activated the supraspinatus less. Moreover, movement of the elbow can be performed holding the upper arm to activate the rotator cuff to a lesser extent. LEVEL OF EVIDENCE Prognostic study, Level II.
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Affiliation(s)
- Myung-Chul Jung
- Department of Industrial Engineering, Ajou University, Suwon, Korea
| | - Sung-Jae Kim
- Department of Orthopaedic Surgery, Yonsei University Health System, Yonsei University Arthroscopy and Joint Research Institute, Seoul, Korea
- Department of Orthopaedic Surgery, Graduated School of Medicine, Yonsei University, Seoul, Korea
| | - Jae-Jun Rhee
- Department of Orthopaedic Surgery, School of Medicine, Ajou University, San 5, Woncheon-dong, Yeongtong-gu, Suwon, 443-721, Korea
| | - Doo-Hyung Lee
- Department of Orthopaedic Surgery, Graduated School of Medicine, Yonsei University, Seoul, Korea.
- Department of Orthopaedic Surgery, School of Medicine, Ajou University, San 5, Woncheon-dong, Yeongtong-gu, Suwon, 443-721, Korea.
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Comparative Transcriptomic Analyses by RNA-seq to Elucidate Differentially Expressed Genes in the Muscle of Korean Thoroughbred Horses. Appl Biochem Biotechnol 2016; 180:588-608. [DOI: 10.1007/s12010-016-2118-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 05/05/2016] [Indexed: 12/27/2022]
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Maqbool A, Spary EJ, Manfield IW, Ruhmann M, Zuliani-Alvarez L, Gamboa-Esteves FO, Porter KE, Drinkhill MJ, Midwood KS, Turner NA. Tenascin C upregulates interleukin-6 expression in human cardiac myofibroblasts via toll-like receptor 4. World J Cardiol 2016; 8:340-350. [PMID: 27231521 PMCID: PMC4877363 DOI: 10.4330/wjc.v8.i5.340] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 04/04/2016] [Accepted: 04/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of Tenascin C (TNC) on the expression of pro-inflammatory cytokines and matrix metalloproteinases in human cardiac myofibroblasts (CMF).
METHODS: CMF were isolated and cultured from patients undergoing coronary artery bypass grafting. Cultured cells were treated with either TNC (0.1 μmol/L, 24 h) or a recombinant protein corresponding to different domains of the TNC protein; fibrinogen-like globe (FBG) and fibronectin type III-like repeats (TNIII 5-7) (both 1 μmol/L, 24 h). The expression of the pro-inflammatory cytokines; interleukin (IL)-6, IL-1β, TNFα and the matrix metalloproteinases; MMPs (MMP1, 2, 3, 9, 10, MT1-MMP) was assessed using real time RT-PCR and western blot analysis.
RESULTS: TNC increased both IL-6 and MMP3 (P < 0.01) mRNA levels in cultured human CMF but had no significant effect on the other markers studied. The increase in IL-6 mRNA expression was mirrored by an increase in protein secretion as assessed by enzyme-linked immunosorbant assay (P < 0.01). Treating CMF with the recombinant protein FBG increased IL-6 mRNA and protein (P < 0.01) whereas the recombinant protein TNIII 5-7 had no effect. Neither FBG nor TNIII 5-7 had any significant effect on MMP3 expression. The expression of toll-like receptor 4 (TLR4) in human CMF was confirmed by real time RT-PCR, western blot and immunohistochemistry. Pre-incubation of cells with TLR4 neutralising antisera attenuated the effect of both TNC and FBG on IL-6 mRNA and protein expression.
CONCLUSION: TNC up-regulates IL-6 expression in human CMF, an effect mediated through the FBG domain of TNC and via the TLR4 receptor.
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