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Gray AJ, Krupenevich RL, Batsis JA, Sawicki GS, Franz JR. Reduced Achilles tendon stiffness in aging associates with higher metabolic cost of walking. J Appl Physiol (1985) 2024; 137:1541-1548. [PMID: 39508895 PMCID: PMC11687843 DOI: 10.1152/japplphysiol.00377.2024] [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: 05/21/2024] [Revised: 09/24/2024] [Accepted: 10/20/2024] [Indexed: 11/15/2024] Open
Abstract
The mechanisms responsible for increased metabolic cost of walking in older adults are poorly understood. We recently proposed a theoretical premise by which age-related reductions in Achilles tendon stiffness (kAT) can disrupt the neuromechanics of calf muscle force production and contribute to faster rates of oxygen consumption during walking. The purpose of this study was to objectively evaluate this premise. We quantified kAT at a range of matched relative activations prescribed using electromyographic biofeedback and walking metabolic cost and ankle joint biomechanics in a group of 15 younger (age: 23 ± 4 yr) and 15 older (age: 72 ± 5 yr) adults. Older adults averaged 44% lower kAT than younger adults at matched triceps surae activations during isokinetic dorsiflexion tasks on a dynamometer (P = 0.046). Older adults also walked with a 17% higher net metabolic power (P = 0.017) but indistinguishable peak Achilles tendon forces than younger adults. Thus, data implicate altered tendon length-tension relations with age more than differences in the operating region of those length-tension relations between younger and older adults. In addition, we discovered empirical evidence that lesser kAT-likely due to the shorter muscle lengths and thus higher relative activations it imposes-was positively correlated with higher net metabolic power during walking (r = -0.365, P = 0.048). These results pave the way for interventions focused on restoring ankle muscle-tendon unit structural stiffness to improve walking energetics in aging.NEW & NOTEWORTHY This study provides the first empirical evidence to our knowledge that age-related decreases in kAT exact a potentially significant metabolic penalty during walking. These results pave the way for interventions focused on restoring ankle muscle-tendon unit structural stiffness to improve walking energetics in aging.
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Affiliation(s)
- Aubrey J Gray
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, United States
| | - Rebecca L Krupenevich
- Division of Behavioral and Social Research, National Institute on Aging, Bethesda, Maryland, United States
| | - John A Batsis
- Division of Geriatric Medicine, Center for Aging and Health, University of North Carolina, Chapel Hill, North Carolina, United States
- Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States
| | - Gregory S Sawicki
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States
| | - Jason R Franz
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, United States
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Wang S, Liu H, Li T, Zhang D. Role of the Medial Canthus Fibrous Band in Forming Moderate and Severe Epicanthal Folds in Asians and Its Clinical Application. Plast Reconstr Surg 2024; 153:1092e-1100e. [PMID: 37220334 DOI: 10.1097/prs.0000000000010724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
BACKGROUND Epicanthal folds (EFs) are skin folds located at the medial canthus in Asians. However, the anatomical structure of EFs remains unclear. The authors discovered a fibrous band connected to the medial canthal tendon (MCT) and referred to it as the medial canthal fibrous band (MCFB). This study aimed to verify whether the MCFB is different from the MCT and whether its unique anatomical relationship with the MCT plays an important role in EF formation. METHODS Forty patients who underwent epicanthoplasty from February of 2020 to October of 2021 were included. EFs from 11 patients underwent biopsy and were stained with hematoxylin and eosin, Masson trichrome, and Weigert stains to reveal their composition. Expression of collagens I and III and elastin was determined through immunohistochemical staining, and their mean optical density was measured. Preoperative and immediate exposed lacrimal caruncle area (ELCA) was measured after removing the MCFB. RESULTS The MCFB is a fibrous tissue located in the EF and above the MCT. The orientation and composition of collagen fibers of the MCFB are different from those of the MCT ( P < 0.001). The MCFB also has more elastin fibers than the MCT ( P < 0.05). Immediate ELCA was significantly higher than before ELCA ( P < 0.001) once the MCFB was removed. CONCLUSIONS The MCFB is composed of collagen fibers different from those in the MCT and plays a role in EF formation. Removing the MCFB during epicanthoplasty can result in a more attractive appearance postoperatively. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, IV.
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Affiliation(s)
- Shimeng Wang
- From the Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University
| | - Haipeng Liu
- From the Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University
| | - Tian Li
- From the Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University
| | - Duo Zhang
- From the Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University
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Farach-Carson MC, Wu D, França CM. Proteoglycans in Mechanobiology of Tissues and Organs: Normal Functions and Mechanopathology. PROTEOGLYCAN RESEARCH 2024; 2:e21. [PMID: 39584146 PMCID: PMC11584024 DOI: 10.1002/pgr2.21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 05/03/2024] [Indexed: 11/26/2024]
Abstract
Proteoglycans (PGs) are a diverse class of glycoconjugates that serve critical functions in normal mechanobiology and mechanopathology. Both the protein cores and attached glycosaminoglycan (GAG) chains function in mechanically-sensitive processes, and loss of either can contribute to development of pathological conditions. PGs function as key components of the extracellular matrix (ECM) where they can serve as mechanosensors in mechanosensitive tissues including bone, cartilage, tendon, blood vessels and soft organs. The mechanical properties of these tissues depend on the presence and function of PGs, which play important roles in tissue elasticity, osmolarity and pressure sensing, and response to physical activity. Tissue responses depend on cell surface mechanoreceptors that include integrins, CD44, voltage sensitive ion channels, transient receptor potential (TRP) and piezo channels. PGs contribute to cell and molecular interplay in wound healing, fibrosis, and cancer, where they transduce the mechanical properties of the ECM and influence the progression of various context-specific conditions and diseases. The PGs that are most important in mechanobiology vary depending on the tissue and its functions and functional needs. Perlecan, for example, is important in the mechanobiology of basement membranes, cardiac and skeletal muscle, while aggrecan plays a primary role in the mechanical properties of cartilage and joints. A variety of techniques have been used to study the mechanobiology of PGs, including atomic force microscopy, mouse knockout models, and in vitro cell culture experiments with 3D organoid models. These studies have helped to elucidate the tissue-specific roles that PGs play in cell-level mechanosensing and tissue mechanics. Overall, the study of PGs in mechanobiology is yielding fundamental new concepts in the molecular basis of mechanosensing that can open the door to the development of new treatments for a host of conditions related to mechanopathology.
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Affiliation(s)
- Mary C Farach-Carson
- Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX 77054
- Departments of BioSciences and Bioengineering, Rice University, Houston, TX 77005
| | - Danielle Wu
- Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX 77054
- Departments of BioSciences and Bioengineering, Rice University, Houston, TX 77005
| | - Cristiane Miranda França
- Department of Oral Rehabilitation and Biosciences, School of Dentistry, Oregon Health & Science University, Portland, OR, 97201
- Knight Cancer Precision Biofabrication Hub, Cancer Early Detection Advanced Research Center (CEDAR), Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97201
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Wang N, Wang H, Shen L, Liu X, Ma Y, Wang C. Aging-Related Rotator Cuff Tears: Molecular Mechanisms and Implications for Clinical Management. Adv Biol (Weinh) 2024; 8:e2300331. [PMID: 38295015 DOI: 10.1002/adbi.202300331] [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: 07/12/2023] [Revised: 11/15/2023] [Indexed: 02/02/2024]
Abstract
Shoulder pain and disabilities are prevalent issues among the elderly population, with rotator cuff tear (RCT) being one of the leading causes. Although surgical treatment has shown some success, high postoperative retear rates remain a great challenge, particularly in elderly patients. Aging-related degeneration of muscle, tendon, tendon-to-bone enthesis, and bone plays a critical role in the development and prognosis of RCT. Studies have demonstrated that aging worsens muscle atrophy and fatty infiltration, alters tendon structure and biomechanical properties, exacerbates enthesis degeneration, and reduces bone density. Although recent researches have contributed to understanding the pathophysiological mechanisms of aging-related RCT, a comprehensive systematic review of this topic is still lacking. Therefore, this article aims to present a review of the pathophysiological changes and their clinical significance, as well as the molecular mechanisms underlying aging-related RCT, with the goal of shedding light on new therapeutic approaches to reduce the occurrence of aging-related RCT and improve postoperative prognosis in elderly patients.
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Affiliation(s)
- Ni Wang
- Department of Rehabilitation Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Haoyuan Wang
- Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Longxiang Shen
- Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Xudong Liu
- Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yanhong Ma
- Department of Rehabilitation Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Chongyang Wang
- Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
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Kwan KYC, Ng KWK, Rao Y, Zhu C, Qi S, Tuan RS, Ker DFE, Wang DM. Effect of Aging on Tendon Biology, Biomechanics and Implications for Treatment Approaches. Int J Mol Sci 2023; 24:15183. [PMID: 37894875 PMCID: PMC10607611 DOI: 10.3390/ijms242015183] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/07/2023] [Accepted: 09/20/2023] [Indexed: 10/29/2023] Open
Abstract
Tendon aging is associated with an increasing prevalence of tendon injuries and/or chronic tendon diseases, such as tendinopathy, which affects approximately 25% of the adult population. Aged tendons are often characterized by a reduction in the number and functionality of tendon stem/progenitor cells (TSPCs), fragmented or disorganized collagen bundles, and an increased deposition of glycosaminoglycans (GAGs), leading to pain, inflammation, and impaired mobility. Although the exact pathology is unknown, overuse and microtrauma from aging are thought to be major causative factors. Due to the hypovascular and hypocellular nature of the tendon microenvironment, healing of aged tendons and related injuries is difficult using current pain/inflammation and surgical management techniques. Therefore, there is a need for novel therapies, specifically cellular therapy such as cell rejuvenation, due to the decreased regenerative capacity during aging. To augment the therapeutic strategies for treating tendon-aging-associated diseases and injuries, a comprehensive understanding of tendon aging pathology is needed. This review summarizes age-related tendon changes, including cell behaviors, extracellular matrix (ECM) composition, biomechanical properties and healing capacity. Additionally, the impact of conventional treatments (diet, exercise, and surgery) is discussed, and recent advanced strategies (cell rejuvenation) are highlighted to address aged tendon healing. This review underscores the molecular and cellular linkages between aged tendon biomechanical properties and the healing response, and provides an overview of current and novel strategies for treating aged tendons. Understanding the underlying rationale for future basic and translational studies of tendon aging is crucial to the development of advanced therapeutics for tendon regeneration.
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Affiliation(s)
- Ka Yu Carissa Kwan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; (K.Y.C.K.); (K.W.K.N.); (Y.R.); (C.Z.); (R.S.T.); (D.F.E.K.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ka Wai Kerry Ng
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; (K.Y.C.K.); (K.W.K.N.); (Y.R.); (C.Z.); (R.S.T.); (D.F.E.K.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ying Rao
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; (K.Y.C.K.); (K.W.K.N.); (Y.R.); (C.Z.); (R.S.T.); (D.F.E.K.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Chenxian Zhu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; (K.Y.C.K.); (K.W.K.N.); (Y.R.); (C.Z.); (R.S.T.); (D.F.E.K.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Shengcai Qi
- Department of Prosthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200040, China;
| | - Rocky S. Tuan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; (K.Y.C.K.); (K.W.K.N.); (Y.R.); (C.Z.); (R.S.T.); (D.F.E.K.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, China
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Dai Fei Elmer Ker
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; (K.Y.C.K.); (K.W.K.N.); (Y.R.); (C.Z.); (R.S.T.); (D.F.E.K.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, China
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Ministry of Education Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Dan Michelle Wang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; (K.Y.C.K.); (K.W.K.N.); (Y.R.); (C.Z.); (R.S.T.); (D.F.E.K.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, China
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Ministry of Education Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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Pechanec MY, Mienaltowski MJ. Decoding the transcriptomic expression and genomic methylation patterns in the tendon proper and its peritenon region in the aging horse. BMC Res Notes 2023; 16:267. [PMID: 37821884 PMCID: PMC10566085 DOI: 10.1186/s13104-023-06562-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 10/10/2023] [Indexed: 10/13/2023] Open
Abstract
OBJECTIVES Equine tendinopathies are challenging because of the poor healing capacity of tendons commonly resulting in high re-injury rates. Within the tendon, different regions - tendon proper (TP) and peritenon (PERI) - contribute to the tendon matrix in differing capacities during injury and aging. Aged tendons have decreased repair potential; the underlying transcriptional and epigenetic changes that occur in the TP and PERI regions are not well understood. The objective of this study was to assess TP and PERI regional differences in adolescent, midlife, and geriatric horses using RNA sequencing and DNA methylation techniques. RESULTS Differences existed between TP and PERI regions of equine superficial digital flexor tendons by age as evidenced by RNASeq and DNA methylation. Cluster analysis indicated that regional distinctions existed regardless of age. Genes such as DCN, COMP, FN1, and LOX maintained elevated TP expression while genes such as GSN and AHNAK were abundant in PERI. Increased gene activity was present in adolescent and geriatric populations but decreased during midlife. Regional differences in DNA methylation were also noted. Notably, when evaluating all ages of TP against PERI, five genes (HAND2, CHD9, RASL11B, ADGRD1, and COL14A1) had regions of differential methylation as well as differential gene expression.
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Affiliation(s)
- Monica Y Pechanec
- Department of Animal Science, University of California Davis, 2251 Meyer Hall, One Shields Ave, Davis, CA, 95616, USA
| | - Michael J Mienaltowski
- Department of Animal Science, University of California Davis, 2251 Meyer Hall, One Shields Ave, Davis, CA, 95616, USA.
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Mebratu YA, Soni S, Rosas L, Rojas M, Horowitz JC, Nho R. The aged extracellular matrix and the profibrotic role of senescence-associated secretory phenotype. Am J Physiol Cell Physiol 2023; 325:C565-C579. [PMID: 37486065 PMCID: PMC10511170 DOI: 10.1152/ajpcell.00124.2023] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 07/13/2023] [Accepted: 07/13/2023] [Indexed: 07/25/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is an irreversible and fatal lung disease that is primarily found in the elderly population, and several studies have demonstrated that aging is the major risk factor for IPF. IPF is characterized by the presence of apoptosis-resistant, senescent fibroblasts that generate an excessively stiff extracellular matrix (ECM). The ECM profoundly affects cellular functions and tissue homeostasis, and an aberrant ECM is closely associated with the development of lung fibrosis. Aging progressively alters ECM components and is associated with the accumulation of senescent cells that promote age-related tissue dysfunction through the expression of factors linked to a senescence-associated secretary phenotype (SASP). There is growing evidence that SASP factors affect various cell behaviors and influence ECM turnover in lung tissue through autocrine and/or paracrine signaling mechanisms. Since life expectancy is increasing worldwide, it is important to elucidate how aging affects ECM dynamics and turnover via SASP and thereby promotes lung fibrosis. In this review, we will focus on the molecular properties of SASP and its regulatory mechanisms. Furthermore, the pathophysiological process of ECM remodeling by SASP factors and the influence of an altered ECM from aged lungs on the development of lung fibrosis will be highlighted. Finally, recent attempts to target ECM alteration and senescent cells to modulate fibrosis will be introduced.NEW & NOTEWORTHY Aging is the most prominent nonmodifiable risk factor for various human diseases including Idiopathic pulmonary fibrosis. Aging progressively alters extracellular matrix components and is associated with the accumulation of senescent cells that promote age-related tissue dysfunction. In this review, we will discuss the pathological impact of aging and senescence on lung fibrosis via senescence-associated secretary phenotype factors and potential therapeutic approaches to limit the progression of lung fibrosis.
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Affiliation(s)
- Yohannes A Mebratu
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States
| | - Sourabh Soni
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States
| | - Lorena Rosas
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States
| | - Mauricio Rojas
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States
| | - Jeffrey C Horowitz
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States
| | - Richard Nho
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States
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Wang H, Dai GC, Li YJ, Chen MH, Lu PP, Zhang YW, -Zhang M, Cao MM, Rui YF. Targeting Senescent Tendon Stem/Progenitor Cells to Prevent or Treat Age-Related Tendon Disorders. Stem Cell Rev Rep 2023; 19:680-693. [PMID: 36520409 DOI: 10.1007/s12015-022-10488-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 11/01/2022] [Accepted: 12/04/2022] [Indexed: 12/23/2022]
Abstract
Age-related tendon disorder, a primary motor system disease, is characterized by biological changes in the tendon tissue due to senescence and seriously affects the quality of life of the elderly. The pathogenesis of this disease is not well-understood. Tendon stem/progenitor cells (TSPCs) exhibit multi-differentiation capacity. These cells are important cellular components of the tendon because of their roles in tendon tissue homeostasis, remodeling, and repair. Previous studies revealed alterations in the biological characteristics and tenogenic differentiation potential of TSPCs in senescent tendon tissue, in turn contributing to insufficient differentiation of TSPCs into tenocytes. Poor tendon repair can result in age-related tendinopathies. Therefore, targeting of senescent TSPCs may restore the tenogenic differentiation potential of these cells and achieve homeostasis of the tendon tissue to prevent or treat age-related tendinopathy. In this review, we summarize the biological characteristics of TSPCs and histopathological changes in age-related tendinopathy, as well as the potential mechanisms through which TSPCs contribute to senescence. This information may promote further exploration of innovative treatment strategies to rescue TSPCs from senescence.
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Affiliation(s)
- Hao Wang
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Trauma Center, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
| | - Guang-Chun Dai
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Trauma Center, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
| | - Ying-Juan Li
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Trauma Center, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
| | - Min-Hao Chen
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Trauma Center, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
| | - Pan-Pan Lu
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Trauma Center, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
| | - Yuan-Wei Zhang
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Trauma Center, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
| | - Ming -Zhang
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
| | - Mu-Min Cao
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Trauma Center, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
| | - Yun-Feng Rui
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China.
- Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China.
- Trauma Center, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China.
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9
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Korcari A, Nichols AEC, Buckley MR, Loiselle AE. Scleraxis-lineage cells are required for tendon homeostasis and their depletion induces an accelerated extracellular matrix aging phenotype. eLife 2023; 12:e84194. [PMID: 36656751 PMCID: PMC9908079 DOI: 10.7554/elife.84194] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 01/18/2023] [Indexed: 01/20/2023] Open
Abstract
Aged tendons have disrupted homeostasis, increased injury risk, and impaired healing capacity. Understanding mechanisms of homeostatic disruption is crucial for developing therapeutics to retain tendon health through the lifespan. Here, we developed a novel model of accelerated tendon extracellular matrix (ECM) aging via depletion of Scleraxis-lineage cells in young mice (Scx-DTR). Scx-DTR recapitulates many aspects of tendon aging including comparable declines in cellularity, alterations in ECM structure, organization, and composition. Single-cell RNA sequencing demonstrated a conserved decline in tenocytes associated with ECM biosynthesis in aged and Scx-DTR tendons, identifying the requirement for Scleraxis-lineage cells during homeostasis. However, the remaining cells in aged and Scx-DTR tendons demonstrate functional divergence. Aged tenocytes become pro-inflammatory and lose proteostasis. In contrast, tenocytes from Scx-DTR tendons demonstrate enhanced remodeling capacity. Collectively, this study defines Scx-DTR as a novel model of accelerated tendon ECM aging and identifies novel biological intervention points to maintain tendon function through the lifespan.
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Affiliation(s)
- Antonion Korcari
- Center for Musculoskeletal Research, Department of Orthopaedics & Rehabilitation, University of Rochester Medical CenterRochesterUnited States
- Department of Biomedical Engineering, University of RochesterRochesterUnited States
| | - Anne EC Nichols
- Center for Musculoskeletal Research, Department of Orthopaedics & Rehabilitation, University of Rochester Medical CenterRochesterUnited States
| | - Mark R Buckley
- Center for Musculoskeletal Research, Department of Orthopaedics & Rehabilitation, University of Rochester Medical CenterRochesterUnited States
- Department of Biomedical Engineering, University of RochesterRochesterUnited States
| | - Alayna E Loiselle
- Center for Musculoskeletal Research, Department of Orthopaedics & Rehabilitation, University of Rochester Medical CenterRochesterUnited States
- Department of Biomedical Engineering, University of RochesterRochesterUnited States
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10
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Korcari A, Przybelski SJ, Gingery A, Loiselle AE. Impact of aging on tendon homeostasis, tendinopathy development, and impaired healing. Connect Tissue Res 2023; 64:1-13. [PMID: 35903886 PMCID: PMC9851966 DOI: 10.1080/03008207.2022.2102004] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 07/11/2022] [Indexed: 02/03/2023]
Abstract
Aging is a complex and progressive process where the tissues of the body demonstrate a decreased ability to maintain homeostasis. During aging, there are substantial cellular and molecular changes, with a subsequent increase in susceptibility to pathological degeneration of normal tissue function. In tendon, aging results in well characterized alterations in extracellular matrix (ECM) structure and composition. In addition, the cellular environment of aged tendons is altered, including a marked decrease in cell density and metabolic activity, as well as an increase in cellular senescence. Collectively, these degenerative changes make aging a key risk factor for the development of tendinopathies and can increase the frequency of tendon injuries. However, inconsistencies in the extent of age-related degenerative impairments in tendons have been reported, likely due to differences in how "old" and "young" age-groups have been defined, differences between anatomically distinct tendons, and differences between animal models that have been utilized to study the impact of aging on tendon homeostasis. In this review, we address these issues by summarizing data by well-defined age categories (young adults, middle-aged, and aged) and from anatomically distinct tendon types. We then summarize in detail how aging affects tendon mechanics, structure, composition, and the cellular environment based on current data and underscore what is currently not known. Finally, we discuss gaps in the current understanding of tendon aging and propose key avenues for future research that can shed light on the specific mechanisms of tendon pathogenesis due to aging.
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Affiliation(s)
- Antonion Korcari
- Department of Orthopaedics & Rehabilitation, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA
| | | | - Anne Gingery
- Division of Orthopedic Surgery Research, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Alayna E Loiselle
- Department of Orthopaedics & Rehabilitation, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA
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11
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Graça AL, Gomez-Florit M, Gomes ME, Docheva D. Tendon Aging. Subcell Biochem 2023; 103:121-147. [PMID: 37120467 DOI: 10.1007/978-3-031-26576-1_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2023]
Abstract
Tendons are mechanosensitive connective tissues responsible for the connection between muscles and bones by transmitting forces that allow the movement of the body, yet, with advancing age, tendons become more prone to degeneration followed by injuries. Tendon diseases are one of the main causes of incapacity worldwide, leading to changes in tendon composition, structure, and biomechanical properties, as well as a decline in regenerative potential. There is still a great lack of knowledge regarding tendon cellular and molecular biology, interplay between biochemistry and biomechanics, and the complex pathomechanisms involved in tendon diseases. Consequently, this reflects a huge need for basic and clinical research to better elucidate the nature of healthy tendon tissue and also tendon aging process and associated diseases. This chapter concisely describes the effects that the aging process has on tendons at the tissue, cellular, and molecular levels and briefly reviews potential biological predictors of tendon aging. Recent research findings that are herein reviewed and discussed might contribute to the development of precision tendon therapies targeting the elderly population.
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Affiliation(s)
- Ana Luísa Graça
- 3B's Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Manuel Gomez-Florit
- Health Research Institute of the Balearic Islands (IdISBa), Palma de Mallorca, Spain
| | - Manuela Estima Gomes
- 3B's Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Denitsa Docheva
- Department of Musculoskeletal Tissue Regeneration, Orthopaedic Hospital König-Ludwig-Haus, University of Würzburg, Würzburg, Germany.
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12
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Furuta H, Yamada M, Nagashima T, Matsuda S, Nagayasu K, Shirakawa H, Kaneko S. Increased expression of glutathione peroxidase 3 prevents tendinopathy by suppressing oxidative stress. Front Pharmacol 2023; 14:1137952. [PMID: 37021050 PMCID: PMC10067742 DOI: 10.3389/fphar.2023.1137952] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 03/07/2023] [Indexed: 04/07/2023] Open
Abstract
Tendinopathy, a degenerative disease, is characterized by pain, loss of tendon strength, or rupture. Previous studies have identified multiple risk factors for tendinopathy, including aging and fluoroquinolone use; however, its therapeutic target remains unclear. We analyzed self-reported adverse events and the US commercial claims data and found that the short-term use of dexamethasone prevented both fluoroquinolone-induced and age-related tendinopathy. Rat tendons treated systemically with fluoroquinolone exhibited mechanical fragility, histological change, and DNA damage; co-treatment with dexamethasone attenuated these effects and increased the expression of the antioxidant enzyme glutathione peroxidase 3 (GPX3), as revealed via RNA-sequencing. The primary role of GPX3 was validated in primary cultured rat tenocytes treated with fluoroquinolone or H2O2, which accelerates senescence, in combination with dexamethasone or viral overexpression of GPX3. These results suggest that dexamethasone prevents tendinopathy by suppressing oxidative stress through the upregulation of GPX3. This steroid-free approach for upregulation or activation of GPX3 can serve as a novel therapeutic strategy for tendinopathy.
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Affiliation(s)
- Haruka Furuta
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Mari Yamada
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Takuya Nagashima
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Shuichi Matsuda
- Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kazuki Nagayasu
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Hisashi Shirakawa
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Shuji Kaneko
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
- *Correspondence: Shuji Kaneko,
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13
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Kayser F, Bori E, Fourny S, Hontoir F, Clegg P, Dugdale A, Vandeweerd JM, Innocenti B. Ex vivo study correlating the stiffness of the ovine patellar tendon to age and weight. Int Biomech 2022; 9:1-9. [PMID: 35929916 PMCID: PMC9359184 DOI: 10.1080/23335432.2022.2108899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Tendons play a crucial role in the musculoskeletal system. In humans, tendon injuries, especially chronic tendinopathy, are very common and the patellar tendon is a frequent location for tendinopathy or injuries. The biomechanical characteristics of the patellar tendon, such as elasticity and stiffness, are of paramount importance and constitute major outcome measures in research studies. We aimed to assess whether the stiffness of the healthy ovine patellar tendon changes with age and weight in a population of normal animals. Sixty-eight 'patella-patellar tendon-tibial tuberosity' units from thirty-four Ile-de-France ewes of body mass 65 to 95 kg, euthanized for reasons other than musculoskeletal diseases, underwent a tensile test providing a measure of the tendon stiffness. Animals were sorted into three categories of age (1-2 yo, 3-5 yo, 6-10 yo). We found a positive but not significant correlation between age category and stiffness (r = 0.22, p = 0.27). There was a significantly positive correlation between weight and stiffness (r = 0.39, p = 0.04). In conclusion, the study characterized biomechanical properties of healthy tendons, provided useful reference values, and established the basis for future biomechanical tests on healing tendons in sheep. The most appropriate sheep population for those future studies would be non-overweight young adults presenting with no lameness.
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Affiliation(s)
- Françoise Kayser
- Department of Medical Imaging, CHU UCL NAMUR (Centre Hospitalier Universitaire-Université Catholique de Louvain-NAMUR) site Godinne, Yvoir, Belgium
| | - Edoardo Bori
- BEAMS Department (Bio-Electro and Mechanical System), ULB (Université Libre de Bruxelles)-Ecole Polytechnique de Bruxelles, Bruxelles, Belgium
| | - Sophie Fourny
- Department of Veterinary Medicine, University of Namur, Namur, Belgium
| | - Fanny Hontoir
- NaRILiS (Namur Research Institute for Life Sciences)-IRVU (Integrated Veterinary Research Unit), Department of Veterinary Medicine, University of Namur, Namur, Belgium
| | - Peter Clegg
- Faculty of Health and Life Sciences, Department of Musculoskeletal Biology, University of Liverpool, Neston, UK
| | - Alexandra Dugdale
- Units E & F, Telford Court, Dunkirk Trading Estate, Gates Lane, Chester Gates Veterinary Specialists CVS (UK) Ltd, Chester, UK
| | - Jean-Michel Vandeweerd
- NaRILiS (Namur Research Institute for Life Sciences)-IRVU (Integrated Veterinary Research Unit), Department of Veterinary Medicine, University of Namur, Namur, Belgium
| | - Bernardo Innocenti
- BEAMS Department (Bio-Electro and Mechanical System), ULB (Université Libre de Bruxelles), Bruxelles, Belgium
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14
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Crossland H, Brook MS, Quinlan JI, Franchi MV, Phillips BE, Wilkinson DJ, Maganaris CN, Greenhaff PL, Szewczyk NJ, Smith K, Narici MV, Atherton PJ. Metabolic and molecular responses of human patellar tendon to concentric- and eccentric-type exercise in youth and older age. GeroScience 2022; 45:331-344. [PMID: 35948859 PMCID: PMC9886711 DOI: 10.1007/s11357-022-00636-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 07/28/2022] [Indexed: 02/03/2023] Open
Abstract
Exercise training can induce adaptive changes to tendon tissue both structurally and mechanically; however, the underlying compositional changes that contribute to these alterations remain uncertain in humans, particularly in the context of the ageing tendon. The aims of the present study were to determine the molecular changes with ageing in patellar tendons in humans, as well as the responses to exercise and exercise type (eccentric (ECC) and concentric (CON)) in young and old patellar tendon. Healthy younger males (age 23.5 ± 6.1 years; n = 27) and older males (age 68.5 ± 1.9 years; n = 27) undertook 8 weeks of CON or ECC training (3 times per week; at 60% of 1 repetition maximum (1RM)) or no training. Subjects consumed D2O throughout the protocol and tendon biopsies were collected after 4 and 8 weeks for measurement of fractional synthetic rates (FSR) of tendon protein synthesis and gene expression. There were increases in tendon protein synthesis following 4 weeks of CON and ECC training (P < 0.01; main effect by ANOVA), with no differences observed between young and old males, or training type. At the transcriptional level however, ECC in young adults generally induced greater responses of collagen and extracellular matrix-related genes than CON, while older individuals had reduced gene expression responses to training. Different training types did not appear to induce differential tendon responses in terms of protein synthesis, and while tendons from older adults exhibited different transcriptional responses to younger individuals, protein turnover changes with training were similar for both age groups.
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Affiliation(s)
- Hannah Crossland
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Royal Derby Hospital Centre, Derby, DE22 3DT, UK
| | - Matthew S Brook
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Royal Derby Hospital Centre, Derby, DE22 3DT, UK
| | - Jonathan I Quinlan
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Royal Derby Hospital Centre, Derby, DE22 3DT, UK
- School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK
- 3National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Martino V Franchi
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Royal Derby Hospital Centre, Derby, DE22 3DT, UK
- Department of Biomedical Sciences, University of Padova, Padua, Italy
| | - Bethan E Phillips
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Royal Derby Hospital Centre, Derby, DE22 3DT, UK
| | - Daniel J Wilkinson
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Royal Derby Hospital Centre, Derby, DE22 3DT, UK
| | | | - Paul L Greenhaff
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Royal Derby Hospital Centre, Derby, DE22 3DT, UK
| | - Nathaniel J Szewczyk
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Royal Derby Hospital Centre, Derby, DE22 3DT, UK
- Ohio Musculoskeletal and Neurological Institute (OMNI) and Department of Biomedical Sciences, Ohio University, Athens, OH, 45701, USA
| | - Kenneth Smith
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Royal Derby Hospital Centre, Derby, DE22 3DT, UK
| | - Marco V Narici
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Royal Derby Hospital Centre, Derby, DE22 3DT, UK
- Department of Biomedical Sciences, University of Padova, Padua, Italy
- CIR-MYO Myology Center, University of Padova, Padua, Italy
| | - Philip J Atherton
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Royal Derby Hospital Centre, Derby, DE22 3DT, UK.
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15
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Ibelli AMG, Peixoto JDO, Zanella R, Gouveia JJDS, Cantão ME, Coutinho LL, Marchesi JAP, Pizzol MSD, Marcelino DEP, Ledur MC. Downregulation of growth plate genes involved with the onset of femoral head separation in young broilers. Front Physiol 2022; 13:941134. [PMID: 36003650 PMCID: PMC9393217 DOI: 10.3389/fphys.2022.941134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Femoral head separation (FHS) is characterized by the detachment of growth plate (GP) and articular cartilage, occurring in tibia and femur. However, the molecular mechanisms involved with this condition are not completely understood. Therefore, genes and biological processes (BP) involved with FHS were identified in 21-day-old broilers through RNA sequencing of the femoral GP. 13,487 genes were expressed in the chicken femoral head transcriptome of normal and FHS-affected broilers. From those, 34 were differentially expressed (DE; FDR ≤0.05) between groups, where all of them were downregulated in FHS-affected broilers. The main BP were enriched in receptor signaling pathways, ossification, bone mineralization and formation, skeletal morphogenesis, and vascularization. RNA-Seq datasets comparison of normal and FHS-affected broilers with 21, 35 and 42 days of age has shown three shared DE genes (FBN2, C1QTNF8, and XYLT1) in GP among ages. Twelve genes were exclusively DE at 21 days, where 10 have already been characterized (SHISA3, FNDC1, ANGPTL7, LEPR, ENSGALG00000049529, OXTR, ENSGALG00000045154, COL16A1, RASD2, BOC, GDF10, and THSD7B). Twelve SNPs were associated with FHS (p < 0.0001). Out of those, 5 were novel and 7 were existing variants located in 7 genes (RARS, TFPI2, TTI1, MAP4K3, LINK54, and AREL1). We have shown that genes related to chondrogenesis and bone differentiation were downregulated in the GP of FHS-affected young broilers. Therefore, these findings evince that candidate genes pointed out in our study are probably related to the onset of FHS in broilers.
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Affiliation(s)
- Adriana Mércia Guaratini Ibelli
- Embrapa Suínos e Aves, Concórdia, Brazil
- Programa de Pós-Graduação em Ciências Veterinárias, Universidade Estadual do Centro-Oeste, Guarapuava, Brazil
| | - Jane de Oliveira Peixoto
- Embrapa Suínos e Aves, Concórdia, Brazil
- Programa de Pós-Graduação em Ciências Veterinárias, Universidade Estadual do Centro-Oeste, Guarapuava, Brazil
| | | | | | | | - Luiz Lehmann Coutinho
- Laboratório de Biotecnologia Animal, Escola Superior de Agricultura “Luiz de Queiroz”, Universidade de SP, Piracicaba, Brazil
| | | | | | | | - Mônica Corrêa Ledur
- Embrapa Suínos e Aves, Concórdia, Brazil
- Programa de Pós-Graduação Em Zootecnia, Universidade do Estado de SC, UDESC-Oeste, Chapecó, Brazil
- *Correspondence: Mônica Corrêa Ledur,
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16
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Lai F, Wang J, Tang H, Huang P, Liu J, He G, Zhou M, Tao X, Tang K. VEGF promotes tendon regeneration of aged rats by inhibiting adipogenic differentiation of tendon stem/progenitor cells and promoting vascularization. FASEB J 2022; 36:e22433. [PMID: 35867348 DOI: 10.1096/fj.202200213r] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/23/2022] [Accepted: 06/13/2022] [Indexed: 11/11/2022]
Abstract
Studies have shown that the stem cell microenvironment is a key factor for stem cell maintenance or differentiation. In this study, we compared the expression of 23 cytokines such as IL-6, IL-10, and TNFα between young and aged rats during patellar tendon repair by cytokine microarray, and found that significant difference between IL-10, G-CSF, and VEGF at 3, 7, or 14 days post-operatively. The effects of these factors on adipogenic differentiation of TPSCs were examined through western blot and oil red O experiments. It was shown that VEGF had an inhibitive effect on the adipogenic differentiation of TPSCs. SPP-1 was figured out as our target by RNA sequencing and confirmed by western blot in vitro. Further in vivo studies showed that adipocyte accumulation was also decreased in the tendons of aged rats after injection of VEGF and the histological score and biomechanical property were also improved via targeting SPP-1. Furthermore, histochemical results showed that vascularization of the injury sites was significantly elevated. In conclusion, VEGF not only plays an important role in decreasing adipocyte accumulation but also improves vascularization of the tendon during aged tendon healing. We believe active regulation of VEGF may improve the treatment of age-related tendon diseases and tendon injuries.
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Affiliation(s)
- Fan Lai
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
| | - Jingjing Wang
- Department of Blood Transfusion, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Hong Tang
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
| | - Pan Huang
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
| | - Juan Liu
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
| | - Gang He
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
| | - Mei Zhou
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
| | - Xu Tao
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
| | - Kanglai Tang
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
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17
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Schulze-Tanzil GG, Delgado-Calcares M, Stange R, Wildemann B, Docheva D. Tendon healing: a concise review on cellular and molecular mechanisms with a particular focus on the Achilles tendon. Bone Joint Res 2022; 11:561-574. [PMID: 35920195 PMCID: PMC9396922 DOI: 10.1302/2046-3758.118.bjr-2021-0576.r1] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Tendon is a bradytrophic and hypovascular tissue, hence, healing remains a major challenge. The molecular key events involved in successful repair have to be unravelled to develop novel strategies that reduce the risk of unfavourable outcomes such as non-healing, adhesion formation, and scarring. This review will consider the diverse pathophysiological features of tendon-derived cells that lead to failed healing, including misrouted differentiation (e.g. de- or transdifferentiation) and premature cell senescence, as well as the loss of functional progenitors. Many of these features can be attributed to disturbed cell-extracellular matrix (ECM) or unbalanced soluble mediators involving not only resident tendon cells, but also the cross-talk with immigrating immune cell populations. Unrestrained post-traumatic inflammation could hinder successful healing. Pro-angiogenic mediators trigger hypervascularization and lead to persistence of an immature repair tissue, which does not provide sufficient mechano-competence. Tendon repair tissue needs to achieve an ECM composition, structure, strength, and stiffness that resembles the undamaged highly hierarchically ordered tendon ECM. Adequate mechano-sensation and -transduction by tendon cells orchestrate ECM synthesis, stabilization by cross-linking, and remodelling as a prerequisite for the adaptation to the increased mechanical challenges during healing. Lastly, this review will discuss, from the cell biological point of view, possible optimization strategies for augmenting Achilles tendon (AT) healing outcomes, including adapted mechanostimulation and novel approaches by restraining neoangiogenesis, modifying stem cell niche parameters, tissue engineering, the modulation of the inflammatory cells, and the application of stimulatory factors.Cite this article: Bone Joint Res 2022;11(8):561-574.
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Affiliation(s)
| | - Manuel Delgado-Calcares
- Experimental Trauma Surgery, Department of Trauma Surgery, University Regensburg Medical Centre, Regensburg, Germany
| | - Richard Stange
- Department of Regenerative Musculoskeletal Medicine, Institute for Musculoskeletal Medicine (IMM), University Hospital Münster, Münster, Germany
| | - Britt Wildemann
- Department of Experimental Trauma Surgery, University Hospital Jena, Jena, Germany
| | - Denitsa Docheva
- Department of Musculoskeletal Tissue Regeneration, Orthopaedic Hospital König-Ludwig-Haus, University of Würzburg, Würzburg, Germany
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18
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Mudigonda S, Shah S, Das N, Corpuz JM, Ninkovic N, Al-Jezani N, Underhill TM, Salo PT, Mitha AP, Lyons FG, Cho R, Schmidt TA, Dufour A, Krawetz RJ. Proteoglycan 4 is present within the dura mater and produced by mesenchymal progenitor cells. Cell Tissue Res 2022; 389:483-499. [PMID: 35704103 DOI: 10.1007/s00441-022-03647-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 06/02/2022] [Indexed: 11/25/2022]
Abstract
Mesenchymal progenitor cells (MPCs) have been recently identified in human and murine epidural fat and have been hypothesized to contribute to the maintenance/repair/regeneration of the dura mater. MPCs can secrete proteoglycan 4 (PRG4/lubricin), and this protein can regulate tissue homeostasis through bio-lubrication and immunomodulatory functions. MPC lineage tracing reporter mice (Hic1) and human epidural fat MPCs were used to determine if PRG4 is expressed by these cells in vivo. PRG4 expression co-localized with Hic1+ MPCs in the dura throughout skeletal maturity and was localized adjacent to sites of dural injury. When Hic1+ MPCs were ablated, PRG4 expression was retained in the dura, yet when Prx1+ MPCs were ablated, PRG4 expression was completely lost. A number of cellular processes were impacted in human epidural fat MPCs treated with rhPRG4, and human MPCs contributed to the formation of epidural fat, and dura tissues were xenotransplanted into mouse dural injuries. We have shown that human and mouse MPCs in the epidural/dura microenvironment produce PRG4 and can contribute to dura homeostasis/repair/regeneration. Overall, these results suggest that these MPCs have biological significance within the dural microenvironment and that the role of PRG4 needs to be further elucidated.
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Affiliation(s)
- Sathvika Mudigonda
- McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada
| | - Sophia Shah
- McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada.,Biomedical Engineering Graduate Program, University of Calgary, Calgary, AB, Canada
| | - Nabangshu Das
- McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada
| | - Jessica May Corpuz
- McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada.,Biomedical Engineering Graduate Program, University of Calgary, Calgary, AB, Canada
| | - Nicoletta Ninkovic
- McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada
| | - Nedaa Al-Jezani
- McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada
| | - T Michael Underhill
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Paul T Salo
- McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada.,Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Alim P Mitha
- Biomedical Engineering Graduate Program, University of Calgary, Calgary, AB, Canada.,Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Frank G Lyons
- Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Roger Cho
- Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Tannin A Schmidt
- Biomedical Engineering Department, University of Connecticut Health Center, Farmington, CT, USA
| | - Antoine Dufour
- McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada.,Biomedical Engineering Graduate Program, University of Calgary, Calgary, AB, Canada.,Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Roman J Krawetz
- McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada. .,Biomedical Engineering Graduate Program, University of Calgary, Calgary, AB, Canada. .,Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. .,Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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19
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Increasing Vascular Response to Injury Improves Tendon Early Healing Outcome in Aged Rats. Ann Biomed Eng 2022; 50:587-600. [PMID: 35303172 PMCID: PMC9107615 DOI: 10.1007/s10439-022-02948-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 03/09/2022] [Indexed: 11/01/2022]
Abstract
Tendon injuries positively correlate with patient age, as aging has significant effects on tendon homeostatic maintenance and healing potential after injury. Vascularity is also influenced by age, with both clinical and animal studies demonstrating reduced blood flow in aged tissues. However, it is unknown how aging effects vascularity following tendon injury, and if this vascular response can be modulated through the delivery of angiogenic factors. Therefore, the objective of this study is to evaluate the vascular response following Achilles tendon injury in adult and aged rats, and to define the alterations to tendon healing in an aged model following injection of angiogenic factors. It was determined that aged rat Achilles tendons have a reduced angiogenesis following injury. Further, the delivery of vascular endothelial growth factor, VEGF, caused an increase in vascular response to tendon injury and improved mechanical outcome in this aged population. This work suggests that reduced angiogenic potential with aging may be contributing to impaired tendon healing response and that the delivery of angiogenic factors can rescue this impaired response. This study was also the first to relate changes in vascular response in an aged model using in vivo measures of blood perfusion to alterations in healing properties.
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20
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The Effect of Age and Intrinsic Aerobic Exercise Capacity on the Expression of Inflammation and Remodeling Markers in Rat Achilles Tendons. Int J Mol Sci 2021; 23:ijms23010079. [PMID: 35008516 PMCID: PMC8744822 DOI: 10.3390/ijms23010079] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 12/19/2022] Open
Abstract
Old age, adiposity, and metabolic disorders are known as risk factors for chronic tendinopathy, which is a common problem in both athletes and the general population. However, the importance of these influencing factors has not yet been well understood. This study investigated alterations in gene expression and histology of Achilles tendons of young (10 weeks) and old (100 weeks) rats bred for low (low capacity runners, LCR) and high (high capacity runners, HCR) intrinsic aerobic exercise capacity. In this rat model, LCR displayed a phenotype of reduced exercise capacity, higher body weight, and metabolic dysfunctions compared to HCR. We hypothesized that the risk factors for tendinopathy in old LCR could lead to more pronounced impairments in Achilles tendon tissue. In quantitative real-time PCR (qPCR), age-related downregulation of tenocyte markers e.g., tenomodulin, genes related to matrix modeling and remodeling (e.g., collagens, elastin, biglycan, fibronectin, tenascin C) as well as transforming growth factor beta 3 (Tgfb3) have been detected. Inflammation marker cyclooxygenase 2 (Cox2) was downregulated in old rats, while microsomal prostaglandin E synthase 2 (Ptges2) was upregulated in old HCR and old LCR. In all groups, interleukin 6 (Il6), interleukin 1 beta (Il1b), and tumor necrosis factor alpha (Tnfa) showed no significant alteration. In histological evaluation, tendons of old rats had fewer and more elongated tenocyte nuclei than young rats. Even though a higher content of glycosaminoglycans, a sign of degeneration, was found in old HCR and LCR, no further signs of tendinopathy were detectable in tendons of old rats by histological evaluation. Low intrinsic aerobic exercise capacity and the associated phenotype did not show significant effects on gene expression and tendon histology. These findings indicate that aging seems to play a prominent role in molecular and structural alterations of Achilles tendon tissue and suggests that other risk factors associated with intrinsic aerobic exercise capacity are less influential in this rat model.
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21
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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: 30] [Impact Index Per Article: 7.5] [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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22
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Mienaltowski MJ, Gonzales NL, Beall JM, Pechanec MY. Basic Structure, Physiology, and Biochemistry of Connective Tissues and Extracellular Matrix Collagens. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:5-43. [PMID: 34807414 DOI: 10.1007/978-3-030-80614-9_2] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The physiology of connective tissues like tendons and ligaments is highly dependent upon the collagens and other such extracellular matrix molecules hierarchically organized within the tissues. By dry weight, connective tissues are mostly composed of fibrillar collagens. However, several other forms of collagens play essential roles in the regulation of fibrillar collagen organization and assembly, in the establishment of basement membrane networks that provide support for vasculature for connective tissues, and in the formation of extensive filamentous networks that allow for cell-extracellular matrix interactions as well as maintain connective tissue integrity. The structures and functions of these collagens are discussed in this chapter. Furthermore, collagen synthesis is a multi-step process that includes gene transcription, translation, post-translational modifications within the cell, triple helix formation, extracellular secretion, extracellular modifications, and then fibril assembly, fibril modifications, and fiber formation. Each step of collagen synthesis and fibril assembly is highly dependent upon the biochemical structure of the collagen molecules created and how they are modified in the cases of development and maturation. Likewise, when the biochemical structures of collagens or are compromised or these molecules are deficient in the tissues - in developmental diseases, degenerative conditions, or injuries - then the ultimate form and function of the connective tissues are impaired. In this chapter, we also review how biochemistry plays a role in each of the processes involved in collagen synthesis and assembly, and we describe differences seen by anatomical location and region within tendons. Moreover, we discuss how the structures of the molecules, fibrils, and fibers contribute to connective tissue physiology in health, and in pathology with injury and repair.
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Affiliation(s)
| | - Nicole L Gonzales
- Department of Animal Science, University of California Davis, Davis, CA, USA
| | - Jessica M Beall
- Department of Animal Science, University of California Davis, Davis, CA, USA
| | - Monica Y Pechanec
- Department of Animal Science, University of California Davis, Davis, CA, USA
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23
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Hettinger ZR, Hamagata K, Confides AL, Lawrence MM, Miller BF, Butterfield TA, Dupont-Versteegden EE. Age-Related Susceptibility to Muscle Damage Following Mechanotherapy in Rats Recovering From Disuse Atrophy. J Gerontol A Biol Sci Med Sci 2021; 76:2132-2140. [PMID: 34181006 PMCID: PMC8599051 DOI: 10.1093/gerona/glab186] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Indexed: 12/13/2022] Open
Abstract
The inability to fully recover lost muscle mass following periods of disuse atrophy predisposes older adults to lost independence and poor quality of life. We have previously shown that mechanotherapy at a moderate load (4.5 N) enhances muscle mass recovery following atrophy in adult, but not older adult rats. We propose that elevated transverse stiffness in aged muscle inhibits the growth response to mechanotherapy and hypothesize that a higher load (7.6 N) will overcome this resistance to mechanical stimuli. F344/BN adult and older adult male rats underwent 14 days of hindlimb suspension, followed by 7 days of recovery with (RE + M) or without (RE) mechanotherapy at 7.6 N on gastrocnemius muscle. The 7.6 N load was determined by measuring transverse passive stiffness and linearly scaling up from 4.5 N. No differences in protein turnover or mean fiber cross-sectional area were observed between RE and RE + M for older adult rats or adult rats at 7.6 N. However, there was a higher number of small muscle fibers present in older adult, but not adult rats, which was explained by a 16-fold increase in the frequency of small fibers expressing embryonic myosin heavy chain. Elevated central nucleation, satellite cell abundance, and dystrophin-/laminin+ fibers were present in older adult rats only following 7.6 N, while 4.5 N did not induce damage at either age. We conclude that age is an important variable when considering load used during mechanotherapy and age-related transverse stiffness may predispose older adults to damage during the recovery period following disuse atrophy.
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Affiliation(s)
- Zachary R Hettinger
- Department of Physical Therapy, College of Health Sciences, University of Kentucky, Lexington, USA
- Center for Muscle Biology, University of Kentucky, Lexington, USA
| | - Kyoko Hamagata
- Center for Muscle Biology, University of Kentucky, Lexington, USA
| | - Amy L Confides
- Department of Physical Therapy, College of Health Sciences, University of Kentucky, Lexington, USA
- Center for Muscle Biology, University of Kentucky, Lexington, USA
| | - Marcus M Lawrence
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, USA
| | - Benjamin F Miller
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, USA
| | - Timothy A Butterfield
- Center for Muscle Biology, University of Kentucky, Lexington, USA
- Department of Athletic Training and Clinical Nutrition, College of Health Sciences, University of Kentucky, Lexington, USA
| | - Esther E Dupont-Versteegden
- Department of Physical Therapy, College of Health Sciences, University of Kentucky, Lexington, USA
- Center for Muscle Biology, University of Kentucky, Lexington, USA
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24
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Hart DA, Nakamura N, Shrive NG. Perspective: Challenges Presented for Regeneration of Heterogeneous Musculoskeletal Tissues that Normally Develop in Unique Biomechanical Environments. Front Bioeng Biotechnol 2021; 9:760273. [PMID: 34650964 PMCID: PMC8505961 DOI: 10.3389/fbioe.2021.760273] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 09/13/2021] [Indexed: 11/30/2022] Open
Abstract
Perspective: Musculoskeletal (MSK) tissues such as articular cartilage, menisci, tendons, and ligaments are often injured throughout life as a consequence of accidents. Joints can also become compromised due to the presence of inflammatory diseases such as rheumatoid arthritis. Thus, there is a need to develop regenerative approaches to address such injuries to heterogeneous tissues and ones that occur in heterogeneous environments. Such injuries can compromise both the biomechanical integrity and functional capability of these tissues. Thus, there are several challenges to overcome in order to enhance success of efforts to repair and regenerate damaged MSK tissues. Challenges: 1. MSK tissues arise during development in very different biological and biomechanical environments. These early tissues serve as a template to address the biomechanical requirements evolving during growth and maturation towards skeletal maturity. Many of these tissues are heterogeneous and have transition points in their matrix. The heterogeneity of environments thus presents a challenge to replicate with regard to both the cells and the ECM. 2. Growth and maturation of musculoskeletal tissues occurs in the presence of anabolic mediators such as growth hormone and the IGF-1 family of proteins which decline with age and are low when there is a greater need for the repair and regeneration of injured or damaged tissues with advancing age. Thus, there is the challenge of re-creating an anabolic environment to enhance incorporation of implanted constructs. 3. The environments associated with injury or chronic degeneration of tissues are often catabolic or inflammatory. Thus, there is the challenge of creating a more favorable in vivo environment to facilitate the successful implantation of in vitro engineered constructs to regenerate damaged tissues. Conclusions: The goal of regenerating MSK tissues has to be to meet not only the biological requirements (components and structure) but also the heterogeneity of function (biomechanics) in vivo. Furthermore, for many of these tissues, the regenerative approach has to overcome the site of injury being influenced by catabolism/inflammation. Attempts to date using both endogenous cells, exogenous cells and scaffolds of various types have been limited in achieving long term outcomes, but progress is being made.
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Affiliation(s)
- David A Hart
- Department of Surgery, Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada.,Bone and Joint Health Strategic Clinical Network, Alberta Health Services, Edmonton, AB, Canada.,McCaig Institute for Bone & Joint Health, University of Calgary, Calgary, AB, Canada
| | - Norimasa Nakamura
- Institute for Medical Science in Sport, Osaka Health Science University, Osaka, Japan
| | - Nigel G Shrive
- McCaig Institute for Bone & Joint Health, University of Calgary, Calgary, AB, Canada.,Biomedical Engineering Graduate Program, Department of Civil Engineering, University of Calgary, Calgary, AB, Canada
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25
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Employing Extracellular Matrix-Based Tissue Engineering Strategies for Age-Dependent Tissue Degenerations. Int J Mol Sci 2021; 22:ijms22179367. [PMID: 34502277 PMCID: PMC8431718 DOI: 10.3390/ijms22179367] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/25/2021] [Accepted: 08/26/2021] [Indexed: 01/10/2023] Open
Abstract
Tissues and organs are not composed of solely cellular components; instead, they converge with an extracellular matrix (ECM). The composition and function of the ECM differ depending on tissue types. The ECM provides a microenvironment that is essential for cellular functionality and regulation. However, during aging, the ECM undergoes significant changes along with the cellular components. The ECM constituents are over- or down-expressed, degraded, and deformed in senescence cells. ECM aging contributes to tissue dysfunction and failure of stem cell maintenance. Aging is the primary risk factor for prevalent diseases, and ECM aging is directly or indirectly correlated to it. Hence, rejuvenation strategies are necessitated to treat various age-associated symptoms. Recent rejuvenation strategies focus on the ECM as the basic biomaterial for regenerative therapies, such as tissue engineering. Modified and decellularized ECMs can be used to substitute aged ECMs and cell niches for culturing engineered tissues. Various tissue engineering approaches, including three-dimensional bioprinting, enable cell delivery and the fabrication of transplantable engineered tissues by employing ECM-based biomaterials.
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26
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Abstract
In organisms from flies to mammals, the initial formation of a functional tendon is completely dependent on chemical signals from muscle (myokines). However, how myokines affect the maturation, maintenance, and regeneration of tendons as a function of age is completely unstudied. Here we discuss the role of four myokines - fibroblast growth factors (FGF), myostatin, the secreted protein acidic and rich in cysteine (SPARC), and miR-29 - in tendon development and hypothesize a role for these factors in the progressive changes in tendon structure and function as a result of muscle wasting (disuse, aging and disease). Because of the close relationship between mechanical loading and muscle and tendon regulation, disentangling muscle-tendon crosstalk from simple mechanical loading is experimentally quite difficult. Therefore, we propose an experimental framework that hopefully will be useful in demonstrating muscle-tendon crosstalk in vivo. Though understudied, the promise of a better understanding of muscle-tendon crosstalk is the development of new interventions that will improve tendon development, regeneration, and function throughout the lifespan.
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Affiliation(s)
- Alec M Avey
- Functional Molecular Biology Laboratory, University of California, Davis, CA, United States.,Molecular, Cellular and Integrative Physiology, University of California Davis, Davis, CA, United States
| | - Keith Baar
- Functional Molecular Biology Laboratory, University of California, Davis, CA, United States.,Neurobiology, Physiology and Behavior, University of California Davis, Davis, CA, United States.,Physiology and Membrane Biology, University of California Davis Health, Sacramento, CA, United States.,VA Northern California Health Care System, Mather, CA, United States
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27
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O'Brien C, Marr N, Thorpe C. Microdamage in the equine superficial digital flexor tendon. Equine Vet J 2021; 53:417-430. [PMID: 32772396 DOI: 10.1111/evj.13331] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 06/02/2020] [Accepted: 07/30/2020] [Indexed: 12/24/2022]
Abstract
The forelimb superficial digital flexor tendon (SDFT) is an energy-storing tendon that is highly susceptible to injury during activities such as galloping and jumping, such that it is one of the most commonly reported causes of lameness in the performance horse. This review outlines the biomechanical and biothermal effects of strain on the SDFT and how these contribute to the accumulation of microdamage. The effect of age-related alterations on strain response and subsequent injury risk is also considered. Given that tendon is a slowly healing and poorly regenerative tissue, prompt detection of early stages of pathology in vivo and timely adaptations to training protocols are likely to have a greater outcome than advances in treatment. Early screening tools and detection protocols could subsequently be of benefit in identifying subclinical signs of degeneration during the training programme. This provides an opportunity for preventative strategies to be implemented to minimise incidences of SDFT injury and reduce recovery periods in elite performance horses. Therefore, this review will focus on the modalities available to implement early screening and prevention protocols as opposed to methods to diagnose and treat injuries.
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Affiliation(s)
| | - Neil Marr
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
| | - Chavaunne Thorpe
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
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28
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Tomlinson DJ, Erskine RM, Morse CI, Pappachan JM, Sanderson-Gillard E, Onambélé-Pearson GL. The combined effects of obesity and ageing on skeletal muscle function and tendon properties in vivo in men. Endocrine 2021; 72:411-422. [PMID: 33484409 PMCID: PMC8128745 DOI: 10.1007/s12020-020-02601-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 12/24/2020] [Indexed: 02/08/2023]
Abstract
PURPOSE We investigated the combined impact of ageing and obesity on Achilles tendon (AT) properties in vivo in men, utilizing three classification methods of obesity. METHOD Forty healthy, untrained men were categorised by age (young (18-49 years); older (50-80 years)), body mass index (BMI; normal weight (≥18.5-<25); overweight (≥25-<30); obese (≥30)), body fat% (normal adipose (<28%); high adiposity (≥28%)) and fat mass index (FMI; normal (3-6); excess fat (>6-9); high fat (>9). Assessment of body composition used dual-energy X-ray absorptiometry, gastrocnemius medialis (GM)/AT properties used dynamometry and ultrasonography and endocrine profiling used multiplex luminometry. RESULTS Older men had lower total range of motion (ROM; -11%; P = 0.020), GM AT force (-29%; P < 0.001), stiffness (-18%; P = 0.041), Young's modulus (-22%; P = 0.011) and AT stress (-28%; P < 0.001). All three methods of classifying obesity revealed obesity to be associated with lower total ROM (P = 0.014-0.039). AT cross sectional area (CSA) was larger with higher BMI (P = 0.030). However, after controlling for age, higher BMI only tended to be associated with greater tendon stiffness (P = 0.074). Interestingly, both AT CSA and stiffness were positively correlated with body mass (r = 0.644 and r = 0.520) and BMI (r = 0.541 and r = 0.493) in the young but not older adults. Finally, negative relationships were observed between AT CSA and pro-inflammatory cytokines TNF-α, IL-6 and IL-1β. CONCLUSIONS This is the first study to provide evidence of positive adaptations in tendon stiffness and size in vivo resulting from increased mass and BMI in young but not older men, irrespective of obesity classification.
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Affiliation(s)
- David J Tomlinson
- Musculoskeletal Science and Sports Medicine Research Centre, Manchester Metropolitan University, Manchester, UK.
| | - Robert M Erskine
- Research Institute for Sport & Exercise Sciences, Liverpool John Moores University, Liverpool, UK
- Institute of Sport, Exercise & Health, University College London, London, UK
| | - Christopher I Morse
- Musculoskeletal Science and Sports Medicine Research Centre, Manchester Metropolitan University, Manchester, UK
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Royal Preston Hospital, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
| | - Emmanuel Sanderson-Gillard
- Musculoskeletal Science and Sports Medicine Research Centre, Manchester Metropolitan University, Manchester, UK
| | - Gladys L Onambélé-Pearson
- Musculoskeletal Science and Sports Medicine Research Centre, Manchester Metropolitan University, Manchester, UK
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29
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Narayanan N, Calve S. Extracellular matrix at the muscle - tendon interface: functional roles, techniques to explore and implications for regenerative medicine. Connect Tissue Res 2021; 62:53-71. [PMID: 32856502 PMCID: PMC7718290 DOI: 10.1080/03008207.2020.1814263] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The muscle-tendon interface is an anatomically specialized region that is involved in the efficient transmission of force from muscle to tendon. Due to constant exposure to loading, the interface is susceptible to injury. Current treatment methods do not meet the socioeconomic demands of reduced recovery time without compromising the risk of reinjury, requiring the need for developing alternative strategies. The extracellular matrix (ECM) present in muscle, tendon, and at the interface of these tissues consists of unique molecules that play significant roles in homeostasis and repair. Better, understanding the function of the ECM during development, injury, and aging has the potential to unearth critical missing information that is essential for accelerating the repair at the muscle-tendon interface. Recently, advanced techniques have emerged to explore the ECM for identifying specific roles in musculoskeletal biology. Simultaneously, there is a tremendous increase in the scope for regenerative medicine strategies to address the current clinical deficiencies. Advancements in ECM research can be coupled with the latest regenerative medicine techniques to develop next generation therapies that harness ECM for treating defects at the muscle-tendon interface. The current work provides a comprehensive review on the role of muscle and tendon ECM to provide insights about the role of ECM in the muscle-tendon interface and discusses the latest research techniques to explore the ECM to gathered information for developing regenerative medicine strategies.
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Affiliation(s)
- Naagarajan Narayanan
- Paul M. Rady Department of Mechanical Engineering, University of Colorado – Boulder, 1111 Engineering Drive, Boulder, Colorado 80309 – 0427
| | - Sarah Calve
- Paul M. Rady Department of Mechanical Engineering, University of Colorado – Boulder, 1111 Engineering Drive, Boulder, Colorado 80309 – 0427
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30
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Siadat SM, Zamboulis DE, Thorpe CT, Ruberti JW, Connizzo BK. Tendon Extracellular Matrix Assembly, Maintenance and Dysregulation Throughout Life. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:45-103. [PMID: 34807415 DOI: 10.1007/978-3-030-80614-9_3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
In his Lissner Award medal lecture in 2000, Stephen Cowin asked the question: "How is a tissue built?" It is not a new question, but it remains as relevant today as it did when it was asked 20 years ago. In fact, research on the organization and development of tissue structure has been a primary focus of tendon and ligament research for over two centuries. The tendon extracellular matrix (ECM) is critical to overall tissue function; it gives the tissue its unique mechanical properties, exhibiting complex non-linear responses, viscoelasticity and flow mechanisms, excellent energy storage and fatigue resistance. This matrix also creates a unique microenvironment for resident cells, allowing cells to maintain their phenotype and translate mechanical and chemical signals into biological responses. Importantly, this architecture is constantly remodeled by local cell populations in response to changing biochemical (systemic and local disease or injury) and mechanical (exercise, disuse, and overuse) stimuli. Here, we review the current understanding of matrix remodeling throughout life, focusing on formation and assembly during the postnatal period, maintenance and homeostasis during adulthood, and changes to homeostasis in natural aging. We also discuss advances in model systems and novel tools for studying collagen and non-collagenous matrix remodeling throughout life, and finally conclude by identifying key questions that have yet to be answered.
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Affiliation(s)
| | - Danae E Zamboulis
- Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Chavaunne T Thorpe
- Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, UK
| | - Jeffrey W Ruberti
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Brianne K Connizzo
- Department of Biomedical Engineering, Boston University, Boston, MA, USA.
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31
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Zellers JA, Eekhoff JD, Tang SY, Hastings MK, Lake SP. Clinical complications of tendon tissue mechanics due to collagen cross-linking in diabetes. THE SCIENCE, ETIOLOGY AND MECHANOBIOLOGY OF DIABETES AND ITS COMPLICATIONS 2021:201-226. [DOI: 10.1016/b978-0-12-821070-3.00009-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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32
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Hill JR, Eekhoff JD, Brophy RH, Lake SP. Elastic fibers in orthopedics: Form and function in tendons and ligaments, clinical implications, and future directions. J Orthop Res 2020; 38:2305-2317. [PMID: 32293749 PMCID: PMC7572591 DOI: 10.1002/jor.24695] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 03/21/2020] [Accepted: 04/11/2020] [Indexed: 02/04/2023]
Abstract
Elastic fibers are an essential component of the extracellular matrix of connective tissues. The focus of both clinical management and scientific investigation of elastic fiber disorders has centered on the cardiovascular manifestations due to their significant impact on morbidity and mortality. As such, the current understanding of the orthopedic conditions experienced by these patients is limited. The musculoskeletal implications of more subtle elastic fiber abnormalities, whether due to allelic variants or age-related tissue degeneration, are also not well understood. Recent advances have begun to uncover the effects of elastic fiber deficiency on tendon and ligament biomechanics; future research must further elucidate mechanisms governing the role of elastic fibers in these tissues. The identification of population-based genetic variations in elastic fibers will also be essential. Minoxidil administration, modulation of protein expression with micro-RNA molecules, and direct injection of recombinant elastic fiber precursors have demonstrated promise for therapeutic intervention, but further work is required prior to consideration for orthopedic clinical application. This review provides an overview of the role of elastic fibers in musculoskeletal tissue, summarizes current knowledge of the orthopedic manifestations of elastic fiber abnormalities, and identifies opportunities for future investigation and clinical application.
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Affiliation(s)
- J. Ryan Hill
- Department of Orthopaedic Surgery, Washington University in St. Louis, 425 S. Euclid Avenue, Suite 5505, St. Louis, MO 63110
| | - Jeremy D. Eekhoff
- Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130
| | - Robert H. Brophy
- Department of Orthopaedic Surgery, Washington University in St. Louis, 425 S. Euclid Avenue, Suite 5505, St. Louis, MO 63110
| | - Spencer P. Lake
- Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130,Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130
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Lindemann I, Coombes BK, Tucker K, Hug F, Dick TJ. Age-related differences in gastrocnemii muscles and Achilles tendon mechanical properties in vivo. J Biomech 2020; 112:110067. [DOI: 10.1016/j.jbiomech.2020.110067] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 08/30/2020] [Accepted: 09/23/2020] [Indexed: 01/30/2023]
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Zamboulis DE, Thorpe CT, Ashraf Kharaz Y, Birch HL, Screen HR, Clegg PD. Postnatal mechanical loading drives adaptation of tissues primarily through modulation of the non-collagenous matrix. eLife 2020; 9:58075. [PMID: 33063662 PMCID: PMC7593091 DOI: 10.7554/elife.58075] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 10/12/2020] [Indexed: 02/06/2023] Open
Abstract
Mature connective tissues demonstrate highly specialised properties, remarkably adapted to meet their functional requirements. Tissue adaptation to environmental cues can occur throughout life and poor adaptation commonly results in injury. However, the temporal nature and drivers of functional adaptation remain undefined. Here, we explore functional adaptation and specialisation of mechanically loaded tissues using tendon; a simple aligned biological composite, in which the collagen (fascicle) and surrounding predominantly non-collagenous matrix (interfascicular matrix) can be interrogated independently. Using an equine model of late development, we report the first phase-specific analysis of biomechanical, structural, and compositional changes seen in functional adaptation, demonstrating adaptation occurs postnatally, following mechanical loading, and is almost exclusively localised to the non-collagenous interfascicular matrix. These novel data redefine adaptation in connective tissue, highlighting the fundamental importance of non-collagenous matrix and suggesting that regenerative medicine strategies should change focus from the fibrous to the non-collagenous matrix of tissue.
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Affiliation(s)
- Danae E Zamboulis
- Institute of Ageing and Chronic Disease, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Chavaunne T Thorpe
- Comparative Biomedical Sciences, The Royal Veterinary College, Royal College Street, London, United Kingdom
| | - Yalda Ashraf Kharaz
- Institute of Ageing and Chronic Disease, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Helen L Birch
- University College London, Department of Orthopaedics and Musculoskeletal Science, Stanmore Campus, Royal National Orthopaedic Hospital, Stanmore, United Kingdom
| | - Hazel Rc Screen
- Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom
| | - Peter D Clegg
- Institute of Ageing and Chronic Disease, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
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Terzi A, Gallo N, Bettini S, Sibillano T, Altamura D, Madaghiele M, De Caro L, Valli L, Salvatore L, Sannino A, Giannini C. Sub‐ and Supramolecular X‐Ray Characterization of Engineered Tissues from Equine Tendon, Bovine Dermis, and Fish Skin Type‐I Collagen. Macromol Biosci 2020; 20:e2000017. [DOI: 10.1002/mabi.202000017] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 01/23/2020] [Indexed: 12/20/2022]
Affiliation(s)
- Alberta Terzi
- Institute of Crystallography (IC)National Research Council Bari 70126 Italy
| | - Nunzia Gallo
- Department of Engineering for InnovationUniversity of Salento Lecce 73100 Italy
| | - Simona Bettini
- Department of Engineering for InnovationUniversity of Salento Lecce 73100 Italy
| | - Teresa Sibillano
- Institute of Crystallography (IC)National Research Council Bari 70126 Italy
| | - Davide Altamura
- Institute of Crystallography (IC)National Research Council Bari 70126 Italy
| | - Marta Madaghiele
- Department of Engineering for InnovationUniversity of Salento Lecce 73100 Italy
| | - Liberato De Caro
- Institute of Crystallography (IC)National Research Council Bari 70126 Italy
| | - Ludovico Valli
- Department of Biological and Environmental Sciences and TechnologiesUniversity of Salento Lecce 73100 Italy
| | - Luca Salvatore
- Department of Engineering for InnovationUniversity of Salento Lecce 73100 Italy
| | - Alessandro Sannino
- Department of Engineering for InnovationUniversity of Salento Lecce 73100 Italy
| | - Cinzia Giannini
- Institute of Crystallography (IC)National Research Council Bari 70126 Italy
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Abate M, Di Carlo L, Belluati A, Salini V. Factors associated with positive outcomes of platelet-rich plasma therapy in Achilles tendinopathy. EUROPEAN JOURNAL OF ORTHOPAEDIC SURGERY AND TRAUMATOLOGY 2020; 30:859-867. [PMID: 32112184 DOI: 10.1007/s00590-020-02642-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 02/22/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND The efficacy of platelet-rich plasma in the treatment for Achilles tendinopathy is debated. Therefore, it is important to know which factors, related to the subjects and/or the disease, are associated with positive or negative outcomes. Aim of this study was to evaluate in a large cohort of patients with Achilles mid-portion tendinopathy which variables were independently associated with a positive outcome after platelet-rich plasma treatment. MATERIAL AND METHODS Eighty-four subjects with Achilles tendinopathy were evaluated by means of VISA-A score and ultrasound and treated with a single platelet-rich plasma injection once a week for 3 weeks. Afterward, a rehabilitation program, based on eccentric training, was implemented. At 3 and 6 months, the relationship between the mean VISA-A score and the following putative predictors was evaluated: sex, age, physical activity, sport, smoking, metabolic risk factors, BMI, symptoms duration, tendon damage, neovessels, adherence to eccentric training. Finally, the percentage of clinically evident positive outcomes (defined as an increase in VISA-A score ≥ 20 points) related to each variable was computed. RESULTS At final follow-up, using the General Linear Model for Repeated Measures procedure, male sex (0.02), age ≤ 40 (0.05) and adequate eccentric training (0.02) were found to be independently associated with a significant increase in the mean VISA-A score. Moreover, the clinically evident positive outcomes, as previously defined, were significantly associated with male sex (0.01), age ≤ 40 (0.000), BMI ≤ 25 (0.001), symptoms duration ≤ 12 months (0.02) and good adherence to eccentric training (0.004). CONCLUSION Younger age, male sex and good adherence to eccentric training can be considered predictors of better results after platelet-rich plasma therapy in Achilles tendinopathy.
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Affiliation(s)
- Michele Abate
- Department of Medicine and Science of Aging, University G. D'Annunzio, Chieti-Pescara, Via dei Vestini 31, 66013, Chieti Scalo, CH, Italy.
| | - Luigi Di Carlo
- Department of Medicine and Science of Aging, University G. D'Annunzio, Chieti-Pescara, Via dei Vestini 31, 66013, Chieti Scalo, CH, Italy
| | - Alberto Belluati
- Division of Orthopedics and Traumatology, Santa Maria Delle Croci Hospital, Ravenna, Italy
| | - Vincenzo Salini
- Division of Orthopedics and Traumatology, San Raffaele Hospital, Milan, Italy
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Tsiapalis D, De Pieri A, Spanoudes K, Sallent I, Kearns S, Kelly JL, Raghunath M, Zeugolis DI. The synergistic effect of low oxygen tension and macromolecular crowding in the development of extracellular matrix-rich tendon equivalents. Biofabrication 2020; 12:025018. [PMID: 31855856 DOI: 10.1088/1758-5090/ab6412] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cellular therapies play an important role in tendon tissue engineering, with tenocytes being the most prominent and potent cell population available. However, for the development of a rich extracellular matrix tenocyte-assembled tendon equivalent, prolonged in vitro culture is required, which is associated with phenotypic drift. Recapitulation of tendon tissue microenvironment in vitro with cues that enhance and accelerate extracellular matrix synthesis and deposition, whilst maintaining tenocyte phenotype, may lead to functional cell therapies. Herein, we assessed the synergistic effect of low oxygen tension (enhances extracellular matrix synthesis) and macromolecular crowding (enhances extracellular matrix deposition) in human tenocyte culture. Protein analysis demonstrated that human tenocytes at 2% oxygen tension and with 50 μg ml-1 carrageenan (macromolecular crowder used) significantly increased synthesis and deposition of collagen types I, III, V and VI. Gene analysis at day 7 illustrated that human tenocytes at 2% oxygen tension and with 50 μg ml-1 carrageenan significantly increased the expression of prolyl 4-hydroxylase subunit alpha 1, procollagen-lysine 2- oxoglutarate 5-dioxygenase 2, scleraxis, tenomodulin and elastin, whilst chondrogenic (e.g. runt-related transcription factor 2, cartilage oligomeric matrix protein, aggrecan) and osteogenic (e.g. secreted phosphoprotein 1, bone gamma-carboxyglutamate protein) trans-differentiation markers were significantly down-regulated or remained unchanged. Collectively, our data clearly illustrates the beneficial synergistic effect of low oxygen tension and macromolecular crowding in the accelerated development of tissue equivalents.
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Affiliation(s)
- Dimitrios Tsiapalis
- 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
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Lui PPY, Wong CM. Biology of Tendon Stem Cells and Tendon in Aging. Front Genet 2020; 10:1338. [PMID: 32010194 PMCID: PMC6976534 DOI: 10.3389/fgene.2019.01338] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 12/09/2019] [Indexed: 12/22/2022] Open
Abstract
Both tendon injuries and tendinopathies, particularly rotator cuff tears, increase with tendon aging. Tendon stem cells play important roles in promoting tendon growth, maintenance, and repair. Aged tendons show a decline in regenerative potential coupled with a loss of stem cell function. Recent studies draw attention to aging primarily a disorder of stem cells. The micro-environment (“niche”) where stem cells resided in vivo provides signals that direct them to metabolize, self-renew, differentiate, or remain quiescent. These signals include receptors and secreted soluble factors for cell-cell communication, extracellular matrix, oxidative stress, and vascularity. Both intrinsic cellular deficits and aged niche, coupled with age-associated systemic changes of hormonal and metabolic signals can inhibit or alter the functions of tendon stem cells, resulting in reduced fitness of these primitive cells and hence more frequent injuries and poor outcomes of tendon repair. This review aims to summarize the biological changes of aged tendons. The biological changes of tendon stem cells in aging are reviewed after a systematic search of the PubMed. Relevant factors of stem cell aging including cell-intrinsic factors, changes of microenvironment, and age-associated systemic changes of hormonal and metabolic signals are examined, with findings related to tendon stem cells highlighted when literature is available. Future research directions on the aging mechanisms of tendon stem cells are discussed. Better understanding of the molecular mechanisms underlying the functional decline of aged tendon stem cells would provide insight for the rational design of rejuvenating therapies.
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Affiliation(s)
| | - Chi Ming Wong
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, Hong Kong
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Connizzo BK, Piet JM, Shefelbine SJ, Grodzinsky AJ. Age-associated changes in the response of tendon explants to stress deprivation is sex-dependent. Connect Tissue Res 2020; 61:48-62. [PMID: 31411079 PMCID: PMC6884684 DOI: 10.1080/03008207.2019.1648444] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Purpose of the Study: The incidence of tendon injuries increases dramatically with age, which presents a major clinical burden. While previous studies have sought to identify age-related changes in extracellular matrix structure and function, few have been able to explain fully why aged tissues are more prone to degeneration and injury. In addition, recent studies have also demonstrated that age-related processes in humans may be sex-dependent, which could be responsible for muddled conclusions in changes with age. In this study, we investigate short-term responses through an ex vivo explant culture model of stress deprivation that specifically questions how age and sex differentially affect the ability of tendons to respond to altered mechanical stimulus.Materials and Methods: We subjected murine flexor explants from young (4 months of age) and aged (22-24 months of age) male and female mice to stress-deprived culture conditions for up to 1 week and investigated changes in viability, cell metabolism and proliferation, matrix biosynthesis and composition, gene expression, and inflammatory responses throughout the culture period.Results and Conclusions: We found that aging did have a significant influence on the response to stress deprivation, demonstrating that aged explants have a less robust response overall with reduced metabolic activity, viability, proliferation, and biosynthesis. However, age-related changes appeared to be sex-dependent. Together, this work demonstrates that the aging process and the subsequent effect of age on the ability of tendons to respond to stress-deprivation are inherently different based on sex, where male explants favor increased activity, apoptosis, and matrix remodeling while female explants favor reduced activity and tissue preservation.
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Affiliation(s)
- Brianne K. Connizzo
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States,Correspondence: Brianne K. Connizzo, 70 Massachusetts Avenue, NE47-377, Cambridge, MA 02139, T: 617-253-2469,
| | - Judith M. Piet
- Department of Bioengineering, Northeastern University, Boston, MA 02115, United States
| | - Sandra J. Shefelbine
- Department of Bioengineering, Northeastern University, Boston, MA 02115, United States,Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, United States
| | - Alan J. Grodzinsky
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States,Center for Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States,Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, United States,Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States
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Dai GC, Li YJ, Chen MH, Lu PP, Rui YF. Tendon stem/progenitor cell ageing: Modulation and rejuvenation. World J Stem Cells 2019; 11:677-692. [PMID: 31616543 PMCID: PMC6789185 DOI: 10.4252/wjsc.v11.i9.677] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 08/15/2019] [Accepted: 09/04/2019] [Indexed: 02/06/2023] Open
Abstract
Tendon ageing is a complicated process caused by multifaceted pathways and ageing plays a critical role in the occurrence and severity of tendon injury. The role of tendon stem/progenitor cells (TSPCs) in tendon maintenance and regeneration has received increasing attention in recent years. The decreased capacity of TSPCs in seniors contributes to impaired tendon functions and raises questions as to what extent these cells either affect, or cause ageing, and whether these age-related cellular alterations are caused by intrinsic factors or the cellular environment. In this review, recent discoveries concerning the biological characteristics of TSPCs and age-related changes in TSPCs, including the effects of cellular epigenetic alterations and the mechanisms involved in the ageing process, are analyzed. During the ageing process, TSPCs ageing might occur as a natural part of the tendon ageing, but could also result from decreased levels of growth factor, hormone deficits and changes in other related factors. Here, we discuss methods that might induce the rejuvenation of TSPC functions that are impaired during ageing, including moderate exercise, cell extracellular matrix condition, growth factors and hormones; these methods aim to rejuvenate the features of youthfulness with the ultimate goal of improving human health during ageing.
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Affiliation(s)
- Guang-Chun Dai
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing210009, Jiangsu Province, China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- Orthopaedic Trauma Institute, Southeast University, Nanjing 210009, Jiangsu Province, China
- School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ying-Juan Li
- Department of Geriatrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- China Orthopedic Regenerative Medicine Group, Hangzhou 310000, Zhejiang Province, China
| | - Min-Hao Chen
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing210009, Jiangsu Province, China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- Orthopaedic Trauma Institute, Southeast University, Nanjing 210009, Jiangsu Province, China
- School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Pan-Pan Lu
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing210009, Jiangsu Province, China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- Orthopaedic Trauma Institute, Southeast University, Nanjing 210009, Jiangsu Province, China
- School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Yun-Feng Rui
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing210009, Jiangsu Province, China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- Orthopaedic Trauma Institute, Southeast University, Nanjing 210009, Jiangsu Province, China
- School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- China Orthopedic Regenerative Medicine Group, Hangzhou 310000, Zhejiang Province, China.
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Kim YI, Kim KS, Ahn HJ, Kang IH, Shin MK. Reduced matrix metalloproteinase and collagen transcription mediated by the TGF-β/Smad pathway in passaged normal human dermal fibroblasts. J Cosmet Dermatol 2019; 19:1211-1218. [PMID: 31509335 DOI: 10.1111/jocd.13114] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 07/24/2019] [Accepted: 08/01/2019] [Indexed: 12/01/2022]
Abstract
BACKGROUND Transforming growth factor-β (TGF-β) is a major regulator of extracellular matrix (ECM) events, particularly collagen production. AIM We explored whether the expression of matrix metalloproteinases (MMPs) and collagen are transcriptionally regulated by the TGF-β and Smad signaling pathways, and the roles played by NF-κB and mitogen-activated protein kinase (MAPK) signaling in normal, aged, human dermal fibroblasts. METHODS We quantified mRNA and protein expression using real-time PCR and immunoblotting of proteins from cells in passage 5-15. RESULTS The levels of mRNAs encoding TGF-β1, TGF-β3, and TGF-β receptor type I (TGFβ RI) decreased with increasing passage number. The levels of mRNAs encoding TGF-β2, TGFβ RII, and TGFβ RIII increased to passage 10 but decreased by passage 15. The levels of mRNAs encoding Smad-2, -3, -4, and -7 decreased with increasing passage number. The level of mRNA encoding MMP-1 increased with increasing passage number, and the levels of mRNAs encoding MMP-2, TIMP-1, and TIMP-2 increased to passage 10 but decreased by passage 15. The levels of mRNAs encoding collagen types I and II decreased with increasing passage number. At the protein level, NF-κB, IκBα, p38, ERK, Akt, and JNK became increasingly phosphorylated at higher passage numbers. CONCLUSION Our results suggest that reductions in the expression levels of MMPs and collagen types I and III in aging human dermal fibroblasts reflect reduced expression of TGF-β/Smad and TGF-β receptors, thus compromising the TGF-β receptor-binding capacity of fibroblasts; the NF-κB and Akt-JNK/MAPK signaling pathways may play active roles in this process.
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Affiliation(s)
- Young Il Kim
- Medical Science Research Institute, Kyung Hee University Medical Center, Seoul, Korea
| | - Kyung Sook Kim
- Department of Biomedical Engineering, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Hye-Jin Ahn
- Department of Dermatology, School of Medicine, Kyung Hee University, Seoul, Korea
| | - In-Hye Kang
- Department of Dermatology, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Min Kyung Shin
- Department of Dermatology, School of Medicine, Kyung Hee University, Seoul, Korea
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Sugiyama Y, Naito K, Goto K, Kojima Y, Furuhata A, Igarashi M, Nagaoka I, Kaneko K. Effect of aging on the tendon structure and tendon-associated gene expression in mouse foot flexor tendon. Biomed Rep 2019; 10:238-244. [PMID: 30972219 DOI: 10.3892/br.2019.1200] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 03/07/2019] [Indexed: 01/23/2023] Open
Abstract
To evaluate the biological changes in tendons during the aging process, the present study examined the effect of aging on the tendon structure, distribution of collagen types I and III, and expression of tendon-associated genes, using flexor tendons in a mouse model. Histological assessment of the tendon structure and distribution of collagen types I and III were performed, and the expression of tendon-associated genes was evaluated in flexor digitorium longus tendons of young (8 weeks) and aged (78 weeks) female C57BL/6 mice. The results indicated that the Soslowsky score, based on the analysis of cellularity, fibroblastic changes, and collagen fiber orientation and disruption, was significantly increased, or worsened, in the tendons of the aged group compared with those in the young group. Furthermore, in the aged group, the distribution of type I collagen was decreased and the distribution of type III collagen was relatively increased compared with the young group. Finally, the mRNA expression levels of collagen (type I and type III) and tenogenic markers (Mohawk homeobox, tenomodulin and scleraxis BHLH transcription factor) were significantly decreased in the aged group compared with the young group. The present observations demonstrated that the structure of the tendons, distribution of types I and III collagen and the expression of tendon-associated genes were modulated by aging in the flexor tendon, and that these changes may contribute to the degeneration of tendons in tendinopathy.
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Affiliation(s)
- Yoichi Sugiyama
- Department of Medicine for Motor Organs, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Kiyohito Naito
- Department of Medicine for Motor Organs, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Kenji Goto
- Department of Medicine for Motor Organs, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Yuko Kojima
- Laboratory of Morphology and Image Analysis, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Atsushi Furuhata
- Laboratory of Morphology and Image Analysis, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Mamoru Igarashi
- Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Isao Nagaoka
- Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Kazuo Kaneko
- Department of Medicine for Motor Organs, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
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Li Y, Dai G, Shi L, Lin Y, Chen M, Li G, Rui Y. The Potential Roles of Tendon Stem/Progenitor Cells in Tendon Aging. Curr Stem Cell Res Ther 2019; 14:34-42. [PMID: 30332976 DOI: 10.2174/1574888x13666181017112233] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 09/15/2018] [Accepted: 10/02/2018] [Indexed: 12/15/2022]
Abstract
Aging is a key dangerous factor for the occurrence and severity of tendon injury, but the exact cognition of the relationship is elusive at present. More previous studies suggest age-related changes occur at tendon mechanical properties, structure and composition, but the pathological alternations may be overlooked, which might be a cause for the structure and function variations, and even speed up the progress of age-related disorders. Recently, the presence of tendon stem/progenitor cells (TSPCs) would provide new insights for the pathogenesis of tendon aging. In this review, the tendon mechanical properties, structure and composition are presented in brief, then, the pathological changes of the aging tendon are described firstly, and the latest researches on alterations of TSPCs in the pathogenesis of tendon aging have also been analyzed. At a cellular level, the hypothetical model of altered TSPCs fate for tendon aging is also proposed. Moreover, the regulation of TSPCs as a potential way of the therapies for age-related tendon diseases is discussed. Therefore, reversing the impaired function of TSPCs and promoting the tenogenic differentiation of TSPCs could become hot spots for further study and give the opportunity to establish new treatment strategies for age-related tendon injuries.
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Affiliation(s)
- Yingjuan Li
- Department of Geriatrics, Zhongda Hospital, School of Medicine, Southeast University, 87 Ding Jia Qiao, Nanjing 210009, China
- School of Medicine, Southeast University, N0.87 Ding Jia Qiao, Nanjing 210009, China
- China Orthopedic Regenerative Medicine Group, Hangzhou, Zhejiang 310000, China
| | - Guangchun Dai
- School of Medicine, Southeast University, N0.87 Ding Jia Qiao, Nanjing 210009, China
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, NO.87 Ding Jia Qiao, Nanjing, Jiangsu 210009, China
- Orthopaedic Trauma Institute, Southeast University, Nanjing, Jiangsu 210009, China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, China
| | - Liu Shi
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, NO.87 Ding Jia Qiao, Nanjing, Jiangsu 210009, China
- Orthopaedic Trauma Institute, Southeast University, Nanjing, Jiangsu 210009, China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, China
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
- Program of Stem Cell and Regeneration, School of Biomedical Science, and Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Yucheng Lin
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, NO.87 Ding Jia Qiao, Nanjing, Jiangsu 210009, China
- Orthopaedic Trauma Institute, Southeast University, Nanjing, Jiangsu 210009, China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, China
| | - Minhao Chen
- School of Medicine, Southeast University, N0.87 Ding Jia Qiao, Nanjing 210009, China
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, NO.87 Ding Jia Qiao, Nanjing, Jiangsu 210009, China
- Orthopaedic Trauma Institute, Southeast University, Nanjing, Jiangsu 210009, China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, China
| | - Gang Li
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
- Program of Stem Cell and Regeneration, School of Biomedical Science, and Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Yunfeng Rui
- School of Medicine, Southeast University, N0.87 Ding Jia Qiao, Nanjing 210009, China
- China Orthopedic Regenerative Medicine Group, Hangzhou, Zhejiang 310000, China
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, NO.87 Ding Jia Qiao, Nanjing, Jiangsu 210009, China
- Orthopaedic Trauma Institute, Southeast University, Nanjing, Jiangsu 210009, China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, China
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Abstract
We begin this chapter by describing normal characteristics of several pertinent connective tissue components, and some of the basic changes they undergo with ageing. These alterations are not necessarily tied to any specific disease or disorders, but rather an essential part of the normal ageing process. The general features of age-induced changes, such as skin wrinkles, in selected organs with high content of connective or soft tissues are discussed in the next part of the chapter. This is followed by a section dealing with age-related changes in specific diseases that fall into at least two categories. The first category encompasses common diseases with high prevalence among mostly ageing populations where both genetic and environmental factors play roles. They include but may not be limited to atherosclerosis and coronary heart disease, type II diabetes, osteopenia and osteoporosis, osteoarthritis, tendon dysfunction and injury, age-related disorders of spine and joints. Disorders where genetics plays the primary role in pathogenesis and progression include certain types of progeria, such as Werner syndrome and Hutchinson-Gilford progeria belong to the second category discussed in this chapter. These disorders are characterized by accelerated signs and symptoms of ageing. Other hereditary diseases or syndromes that arise from mutations of genes encoding for components of connective tissue and are less common than diseases included in the first group will be discussed briefly as well, though they may not be directly associated with ageing, but their connective tissue undergoes some changes compatible with ageing. Marfan and Ehlers-Danlos syndromes are primary examples of such disorders. We will probe the role of specific components of connective tissue and extracellular matrix if not in each of the diseases, then at least in the main representatives of these disorders.
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Affiliation(s)
- Carolyn Ann Sarbacher
- Department of Pathology, College of Veterinary Medicine, The University of Georgia and AU/UGA Medical Partnership, Athens, GA, USA
| | - Jaroslava T Halper
- Department of Pathology, College of Veterinary Medicine, The University of Georgia and AU/UGA Medical Partnership, Athens, GA, USA.
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Fêo HB, Biancalana A, Romero Nakagaki W, Aparecida de Aro A, Gomes L. Morphological Alterations and Increased Gelatinase Activity in the Superficial Digital Flexor Tendon of Chickens During Growth and Maturation. Anat Rec (Hoboken) 2018; 302:964-972. [DOI: 10.1002/ar.24027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 07/30/2018] [Accepted: 08/28/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Haline Ballestero Fêo
- Department of Structural and Functional BiologyInstitute of Biology, State University of Campinas – UNICAMP Campinas Brazil
| | - Adriano Biancalana
- Department of Structural and Functional BiologyInstitute of Biology, State University of Campinas – UNICAMP Campinas Brazil
- Laboratory of Cellular and Molecular BiologyFederal University of Pará – UFPA Soure Brazil
| | - Wilson Romero Nakagaki
- Department of Structural and Functional BiologyInstitute of Biology, State University of Campinas – UNICAMP Campinas Brazil
- Master's Program in Health SciencesUniversity of Western São Paulo – UNOESTE Presidente Prudente Brazil
| | - Andrea Aparecida de Aro
- Department of Structural and Functional BiologyInstitute of Biology, State University of Campinas – UNICAMP Campinas Brazil
- Biomedical Sciences Graduate ProgramHerminio Ometto University Center –UNIARARAS Araras Brazil
| | - Laurecir Gomes
- Department of Structural and Functional BiologyInstitute of Biology, State University of Campinas – UNICAMP Campinas Brazil
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Relationship between ultrasound detected tendon abnormalities, and sensory and clinical characteristics in people with chronic lateral epicondylalgia. PLoS One 2018; 13:e0205171. [PMID: 30356266 PMCID: PMC6200215 DOI: 10.1371/journal.pone.0205171] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 09/20/2018] [Indexed: 12/22/2022] Open
Abstract
Objective To investigate the relationship between tendon structural changes determined by static ultrasound images (US) and sensory changes using quantitative sensory testing (QST), and clinical measures in lateral epicondylalgia. Materials and methods Both elbows of 66 adult participants with a clinical diagnosis of lateral epicondylalgia were investigated. Using a standardised ultrasound image rating scale, common extensor hypoechogenicity, heterogenicity, neovascularity, and bony abnormalities at the enthesis were scored, and tendon thickness (longitudinal and transverse plane) was measured by a trained assessor. Sensory measures of pressure, heat and cold pain thresholds and vibration detection threshold were recorded. Pain and function were assessed using the patient-rated tennis elbow (PRTEE), pain-free grip strength, pain visual analog scale (PVAS) and quality of life (EuroQoL EQ -5D). Univariate and multivariate linear regression analyses were used to explore the association between tendon structural, sensory and clinical variables which were adjusted for age, gender and duration of symptoms. Results A negative correlation was identified between the presence of neovascularity and cold pain threshold (P = 0.015). Multiple regression analyses revealed that a combination of female gender (P = 0.044) and transverse tendon thickness (P = 0.010) were significantly associated with vibration detection threshold in affected elbows, while gender (P = 0.012) and total ultrasound scale score (P = 0.024) were significantly associated with heat pain threshold and vibration detection threshold in unaffected elbows. Heat pain threshold and gender were significantly associated with pain and disability (PRTEE; P < 0.001), and pain-free grip strength (P < 0.001) respectively, in the affected elbows. Conclusion Generally, structural and sensory measures were weakly correlated. However, neovascularity and transverse tendon thickness may be related to sensory system changes in LE.
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Titan A, Andarawis-Puri N. Tendinopathy: Investigating the Intersection of Clinical and Animal Research to Identify Progress and Hurdles in the Field. JBJS Rev 2018; 4:01874474-201610000-00002. [PMID: 27792676 DOI: 10.2106/jbjs.rvw.15.00088] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Biological treatments, surgical interventions, and rehabilitation exercises have been successfully used to treat tendinopathy, but the development of effective treatments has been hindered by the lack of mechanistic data regarding the pathogenesis of the disease. While insightful, clinical studies are limited in their capacity to provide data regarding the pathogenesis of tendinopathies, emphasizing the value of animal models and cell culture studies to fill this essential gap in knowledge. Clinical pathological findings from imaging studies or histological analysis are not universal across patients with tendinopathy and have not been clearly associated with the onset of symptoms. There are several unresolved controversies, including the cellular changes that accompany the tendinopathic disease state and the role of inflammation. Additional research is needed to correlate the manifestations of the disease with its pathogenesis, with the goal of reaching a field-wide consensus on the pathology of the disease state. Such a consensus will allow standardized clinical practices to more effectively diagnose and treat tendinopathy.
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Affiliation(s)
- Ashley Titan
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY
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Magnusson SP, Kjaer M. The impact of loading, unloading, ageing and injury on the human tendon. J Physiol 2018; 597:1283-1298. [PMID: 29920664 DOI: 10.1113/jp275450] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 05/30/2018] [Indexed: 12/28/2022] Open
Abstract
A tendon transfers force from the contracting muscle to the skeletal system to produce movement and is therefore a crucial component of the entire muscle-tendon complex and its function. However, tendon research has for some time focused on mechanical properties without any major appreciation of potential cellular and molecular changes. At the same time, methodological developments have permitted determination of the mechanical properties of human tendons in vivo, which was previously not possible. Here we review the current understanding of how tendons respond to loading, unloading, ageing and injury from cellular, molecular and mechanical points of view. A mechanistic understanding of tendon tissue adaptation will be vital for development of adequate guidelines in physical training and rehabilitation, as well as for optimal injury treatment.
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Affiliation(s)
- S Peter Magnusson
- Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, Copenhagen, NV.,Department of Physical and Occupational Therapy Bispebjerg Hospital, Copenhagen, NV.,Center for Healthy Aging, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
| | - Michael Kjaer
- Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, Copenhagen, NV.,Center for Healthy Aging, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
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49
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Gan JY, Li QS, Zhou HM, Zhang W, Lian LZ, Yu Z, Zhang ZY. A preliminary study on the establishment of an animal model of conjunctivochalasis. Int J Ophthalmol 2018; 11:899-904. [PMID: 29977798 DOI: 10.18240/ijo.2018.06.01] [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: 02/26/2018] [Accepted: 04/08/2018] [Indexed: 11/23/2022] Open
Abstract
AIM To explore a feasible method on the establishment of an animal model of conjunctivochalasis (CCH). METHODS Twelve clean-grade New Zealand white rabbits were divided into four groups (n=3/group): the control group (one received no interventions, and the others underwent subconjunctival injection of sterile water), the matrix metalloproteinases (MMPs) group (administered subconjunctival injection of MMP-3), the aging group (administered subcutaneous injection of D-galactose), the tumor necrosis factor-α (TNF-α) solution group (administered eye drops of TNF-α). Anterior segment photography, conjunctival tissue light microscopy and transmission electron microscopy (TEM) were performed after 12wk. RESULTS Among all groups, the MMPs group had the following changes: the looser connection between the inferior bulbar conjunctiva and sclera; the more disordered collagen fibers (Trichrome staining) and the broken elastic fibers (Aldehyde-fuchsin staining); the focal necrosis of fibroblasts (TEM). CONCLUSION Administration of MMPs may be a feasible method for the establishment of an animal model of CCH.
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Affiliation(s)
- Jing-Yun Gan
- Department of Ophthalmology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Qing-Song Li
- Department of Ophthalmology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Huan-Ming Zhou
- Department of Ophthalmology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Wei Zhang
- Department of Ophthalmology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Ling-Zhi Lian
- Department of Pathology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Zhang Yu
- Department of Electron Microscopy, Shanghai Medical College, Fudan University, Shanghai 200062, China
| | - Zhen-Yong Zhang
- Department of Pathology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
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50
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Eekhoff JD, Fang F, Kahan LG, Espinosa G, Cocciolone AJ, Wagenseil JE, Mecham RP, Lake SP. Functionally Distinct Tendons From Elastin Haploinsufficient Mice Exhibit Mild Stiffening and Tendon-Specific Structural Alteration. J Biomech Eng 2018; 139:2654667. [PMID: 28916838 DOI: 10.1115/1.4037932] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Indexed: 12/23/2022]
Abstract
Elastic fibers are present in low quantities in tendon, where they are located both within fascicles near tenocytes and more broadly in the interfascicular matrix (IFM). While elastic fibers have long been known to be significant in the mechanics of elastin-rich tissue (i.e., vasculature, skin, lungs), recent studies have suggested a mechanical role for elastic fibers in tendons that is dependent on specific tendon function. However, the exact contribution of elastin to properties of different types of tendons (e.g., positional, energy-storing) remains unknown. Therefore, this study purposed to evaluate the role of elastin in the mechanical properties and collagen alignment of functionally distinct supraspinatus tendons (SSTs) and Achilles tendons (ATs) from elastin haploinsufficient (HET) and wild type (WT) mice. Despite the significant decrease in elastin in HET tendons, a slight increase in linear stiffness of both tendons was the only significant mechanical effect of elastin haploinsufficiency. Additionally, there were significant changes in collagen nanostructure and subtle alteration to collagen alignment in the AT but not the SST. Hence, elastin may play only a minor role in tendon mechanical properties. Alternatively, larger changes to tendon mechanics may have been mitigated by developmental compensation of HET tendons and/or the role of elastic fibers may be less prominent in smaller mouse tendons compared to the larger bovine and human tendons evaluated in previous studies. Further research will be necessary to fully elucidate the influence of various elastic fiber components on structure-function relationships in functionally distinct tendons.
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Affiliation(s)
- Jeremy D Eekhoff
- Department of Biomedical Engineering, Washington University in St. Louis One Brookings Drive, St. Louis, MO 63130
| | - Fei Fang
- Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130
| | - Lindsey G Kahan
- Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130
| | - Gabriela Espinosa
- Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130
| | - Austin J Cocciolone
- Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130
| | - Jessica E Wagenseil
- Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130
| | - Robert P Mecham
- Department of Cell Biology and Physiology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO 63110
| | - Spencer P Lake
- Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130.,Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130.,Department of Orthopaedic Surgery, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130 e-mail:
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