Special Issue "Extracellular Matrix Remodeling"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: 15 December 2018

Special Issue Editor

Guest Editor
Prof. Nicoletta Gagliano

Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
Website | E-Mail
Interests: tumor invasion; tendon biology; fibrosis; gingival overgrowth; epithelial-to-mesenchymal transition; collagen turnover; matrix metalloproteinases

Special Issue Information

Dear Colleagues,

The extracellular matrix (ECM) is where cells live. It is composed of collagen and elastic fibers, glycosaminoglycans and proteoglycans, and by several glycoproteins. In most tissues, fibril-forming collagen type I is the major constituent of ECM.

The function of the ECM goes beyond providing mechanical support to cells and tissues. In fact, cells are embedded into ECM and interact with its components through their surface receptors, such as integrins, so cell-ECM interaction plays a key role in influencing different cell activities such as cell proliferation and migration. Moreover, the ECM sequesters and releases growth factors affecting important cellular pathways. Overall, the ECM strongly influences and affects cell behavior and tissue homeostasis.

Cell-matrix and cell-cell interactions are modulated by matricellular proteins, such as SPARC, tenascin and thrombospondin, characterized as non-structural extracellular modulators of cellular functions. Their activity is primarily related to their de-adhesive properties, but they are also able to interact with intracellular compartments.

ECM is a highly dynamic structural network that continuously undergoes controlled remodeling mediated by matrix-degrading enzymes, the matrix metalloproteinases (MMPs) under normal conditions.

Quantitative and qualitative deregulation of ECM remodeling and, especially, of collagen turnover, is responsible of the alteration of ECM composition and structure, associated with the development and progression of several pathologic conditions. For example, organ fibrosis is determined by the abnormal accumulation of ECM components, and an increased ECM remodeling is observed in tumor invasion.

The understanding of the diverse biological roles and properties of the ECM components will be helpful to develop new therapeutic tools for disease treatment.

Prof. Nicoletta Gagliano
Guest Editor

Manuscript Submission Information

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Keywords

  • fibrosis
  • tumor invasion
  • collagen turnover
  • matrix metalloproteinases
  • matricellular proteins
  • cell-extracellular matrix interaction

Published Papers (9 papers)

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Research

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Open AccessArticle Injured Achilles Tendons Treated with Adipose-Derived Stem Cells Transplantation and GDF-5
Received: 19 July 2018 / Revised: 17 August 2018 / Accepted: 23 August 2018 / Published: 31 August 2018
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Abstract
Tendon injuries represent a clinical challenge in regenerative medicine because their natural repair process is complex and inefficient. The high incidence of tendon injuries is frequently associated with sports practice, aging, tendinopathies, hypertension, diabetes mellitus, and the use of corticosteroids. The growing interest
[...] Read more.
Tendon injuries represent a clinical challenge in regenerative medicine because their natural repair process is complex and inefficient. The high incidence of tendon injuries is frequently associated with sports practice, aging, tendinopathies, hypertension, diabetes mellitus, and the use of corticosteroids. The growing interest of scientists in using adipose-derived mesenchymal stem cells (ADMSC) in repair processes seems to be mostly due to their paracrine and immunomodulatory effects in stimulating specific cellular events. ADMSC activity can be influenced by GDF-5, which has been successfully used to drive tenogenic differentiation of ADMSC in vitro. Thus, we hypothesized that the application of ADMSC in isolation or in association with GDF-5 could improve Achilles tendon repair through the regulation of important remodeling genes expression. Lewis rats had tendons distributed in four groups: Transected (T), transected and treated with ADMSC (ASC) or GDF-5 (GDF5), or with both (ASC+GDF5). In the characterization of cells before application, ADMSC expressed the positive surface markers, CD90 (90%) and CD105 (95%), and the negative marker, CD45 (7%). ADMSC were also differentiated in chondrocytes, osteoblast, and adipocytes. On the 14th day after the tendon injury, GFP-ADMSC were observed in the transected region of tendons in the ASC and ASC+GDF5 groups, and exhibited and/or stimulated a similar genes expression profile when compared to the in vitro assay. ADMSC up-regulated Lox, Dcn, and Tgfb1 genes expression in comparison to T and ASC+GDF5 groups, which contributed to a lower proteoglycans arrangement, and to a higher collagen fiber organization and tendon biomechanics in the ASC group. The application of ADMSC in association with GDF-5 down-regulated Dcn, Gdf5, Lox, Tgfb1, Mmp2, and Timp2 genes expression, which contributed to a lower hydroxyproline concentration, lower collagen fiber organization, and to an improvement of the rats’ gait 24 h after the injury. In conclusion, although the literature describes the benefic effect of GDF-5 for the tendon healing process, our results show that its application, isolated or associated with ADMSC, cannot improve the repair process of partial transected tendons, indicating the higher effectiveness of the application of ADMSC in injured Achilles tendons. Our results show that the application of ADMSC in injured Achilles tendons was more effective in relation to its association with GDF-5. Full article
(This article belongs to the Special Issue Extracellular Matrix Remodeling)
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Open AccessArticle Association of NF-κB and AP-1 with MMP-9 Overexpression in 2-Chloroethanol Exposed Rat Astrocytes
Received: 16 July 2018 / Revised: 3 August 2018 / Accepted: 3 August 2018 / Published: 7 August 2018
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Abstract
Subacute poisoning of 1,2-dichloroethane (1,2-DCE) has become a serious occupational problem in China, and brain edema is its main pathological consequence, but little is known about the underlying mechanisms. As the metabolite of 1,2-DCE, 2-chloroethanol (2-CE) is more reactive, and might play an
[...] Read more.
Subacute poisoning of 1,2-dichloroethane (1,2-DCE) has become a serious occupational problem in China, and brain edema is its main pathological consequence, but little is known about the underlying mechanisms. As the metabolite of 1,2-DCE, 2-chloroethanol (2-CE) is more reactive, and might play an important role in the toxic effects of 1,2-DCE. In our previous studies, we found that matrix metalloproteinases-9 (MMP-9) expression was enhanced in mouse brains upon treatment with 1,2-DCE, and in rat astrocytes exposed to 2-CE. In the present study, we analyzed the association of nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1) with MMP-9 overexpression in astrocytes treated with 2-CE. MMP-9, p65, c-Jun, and c-Fos were significantly upregulated by 2-CE treatment, which also enhanced phosphorylation of c-Jun, c-Fos and inhibitor of κBα (IκBα), and nuclear translocation of p65. Furthermore, inhibition of IκBα phosphorylation and AP-1 activity with the specific inhibitors could attenuate MMP-9 overexpression in the cells. On the other hand, inhibition of p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway suppressed the activation of both NF-κB and AP-1 in 2-CE-treated astrocytes. In conclusion, MMP-9 overexpression induced by 2-CE in astrocytes could be mediated at least in part through the p38 signaling pathway via activation of both NF-κB and AP-1. This study might provide novel clues for clarifying the mechanisms underlying 1,2-DCE associated cerebral edema. Full article
(This article belongs to the Special Issue Extracellular Matrix Remodeling)
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Open AccessFeature PaperArticle New Insights into the Occurrence of Matrix Metalloproteases -2 and -9 in a Cohort of Breast Cancer Patients and Proteomic Correlations
Received: 8 June 2018 / Revised: 19 July 2018 / Accepted: 24 July 2018 / Published: 28 July 2018
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Abstract
Matrix metalloproteases (MMPs) are a family of well-known enzymes which operate prevalently in the extracellular domain, where they fulfil the function of remodeling the extracellular matrix (ECM). Within the 26 family members, encoded by 24 genes in humans, MMP-2 and MMP-9 have been
[...] Read more.
Matrix metalloproteases (MMPs) are a family of well-known enzymes which operate prevalently in the extracellular domain, where they fulfil the function of remodeling the extracellular matrix (ECM). Within the 26 family members, encoded by 24 genes in humans, MMP-2 and MMP-9 have been regarded as primarily responsible for the basement membrane and peri-cellular ECM rearrangement. In cases of infiltrating carcinomas, which arise from the epithelial tissues of a gland or of an internal organ, a marked alteration of the expression and the activity levels of both MMPs is known to occur. The present investigation represents the continuation and upgrading of our previous studies, now focusing on the occurrence and intensity levels of MMP-2 and -9 and their proteomic correlations in a cohort of 80 breast cancer surgical tissues. Full article
(This article belongs to the Special Issue Extracellular Matrix Remodeling)
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Open AccessArticle Action of the Metalloproteinases in Gonadal Remodeling during Sex Reversal in the Sequential Hermaphroditism of the Teleostei Fish Synbranchus marmoratus (Synbranchiformes: Synbranchidae)
Received: 23 February 2018 / Revised: 14 April 2018 / Accepted: 19 April 2018 / Published: 24 April 2018
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Abstract
Teleostei present great plasticity regarding sex change. During sex reversal, the whole gonad including the germinal epithelium undergoes significant changes, remodeling, and neoformation. However, there is no information on the changes that occur within the interstitial compartment. Considering the lack of information, especially
[...] Read more.
Teleostei present great plasticity regarding sex change. During sex reversal, the whole gonad including the germinal epithelium undergoes significant changes, remodeling, and neoformation. However, there is no information on the changes that occur within the interstitial compartment. Considering the lack of information, especially on the role played by metalloproteinases (MMPs) in fish gonadal remodeling, the aim of this study was to evaluate the action of MMPs on gonads of sex reversed females of Synbranchus marmoratus, a fresh water protogynic diandric fish. Gonads were processed for light microscopy and blood samples were used for the determination of plasma sex steroid levels. During sex reversal, degeneration of the ovaries occurred and were gradually replaced by the germinal tissue of the male. The action of the MMPs induces significant changes in the interstitial compartment, allowing the reorganization of germinal epithelium. Leydig cells also showed an important role in female to male reversion. The gonadal transition coincides with changes in circulating sex steroid levels throughout sex reversion. The action of the MMPs, in the gonadal remodeling, especially on the basement membrane, is essential for the establishment of a new functional germinal epithelium. Full article
(This article belongs to the Special Issue Extracellular Matrix Remodeling)
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Review

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Open AccessReview Multifaceted Interweaving Between Extracellular Matrix, Insulin Resistance, and Skeletal Muscle
Cells 2018, 7(10), 148; https://doi.org/10.3390/cells7100148 (registering DOI)
Received: 9 August 2018 / Revised: 7 September 2018 / Accepted: 17 September 2018 / Published: 22 September 2018
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Abstract
The skeletal muscle provides movement and support to the skeleton, controls body temperature, and regulates the glucose level within the body. This is the core tissue of insulin-mediated glucose uptake via glucose transporter type 4 (GLUT4). The extracellular matrix (ECM) provides integrity and
[...] Read more.
The skeletal muscle provides movement and support to the skeleton, controls body temperature, and regulates the glucose level within the body. This is the core tissue of insulin-mediated glucose uptake via glucose transporter type 4 (GLUT4). The extracellular matrix (ECM) provides integrity and biochemical signals and plays an important role in myogenesis. In addition, it undergoes remodeling upon injury and/or repair, which is also related to insulin resistance (IR), a major cause of type 2 diabetes (T2DM). Altered signaling of integrin and ECM remodeling in diet-induced obesity is associated with IR. This review highlights the interweaving relationship between the ECM, IR, and skeletal muscle. In addition, the importance of the ECM in muscle integrity as well as cellular functions is explored. IR and skeletal muscle ECM remodeling has been discussed in clinical and nonclinical aspects. Furthermore, this review considers the role of ECM glycation and its effects on skeletal muscle homeostasis, concentrating on advanced glycation end products (AGEs) as an important risk factor for the development of IR. Understanding this complex interplay between the ECM, muscle, and IR may improve knowledge and help develop new ideas for novel therapeutics for several IR-associated myopathies and diabetes. Full article
(This article belongs to the Special Issue Extracellular Matrix Remodeling)
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Open AccessReview Agonist-Biased Signaling via Matrix Metalloproteinase-9 Promotes Extracellular Matrix Remodeling
Received: 30 June 2018 / Revised: 12 August 2018 / Accepted: 23 August 2018 / Published: 26 August 2018
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Abstract
The extracellular matrix (ECM) is a highly dynamic noncellular structure that is crucial for maintaining tissue architecture and homeostasis. The dynamic nature of the ECM undergoes constant remodeling in response to stressors, tissue needs, and biochemical signals that are mediated primarily by matrix
[...] Read more.
The extracellular matrix (ECM) is a highly dynamic noncellular structure that is crucial for maintaining tissue architecture and homeostasis. The dynamic nature of the ECM undergoes constant remodeling in response to stressors, tissue needs, and biochemical signals that are mediated primarily by matrix metalloproteinases (MMPs), which work to degrade and build up the ECM. Research on MMP-9 has demonstrated that this proteinase exists on the cell surface of many cell types in complex with G protein-coupled receptors (GPCRs), and receptor tyrosine kinases (RTKs) or Toll-like receptors (TLRs). Through a novel yet ubiquitous signaling platform, MMP-9 is found to play a crucial role not only in the direct remodeling of the ECM but also in the transactivation of associated receptors to mediate and recruit additional remodeling proteins. Here, we summarize the role of MMP-9 as it exists in a tripartite complex on the cell surface and discuss how its association with each of the TrkA receptor, Toll-like receptors, epidermal growth factor receptor, and the insulin receptor contributes to various aspects of ECM remodeling. Full article
(This article belongs to the Special Issue Extracellular Matrix Remodeling)
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Open AccessReview MicroRNAs and Osteoarthritis
Received: 11 July 2018 / Revised: 23 July 2018 / Accepted: 29 July 2018 / Published: 1 August 2018
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Abstract
An imbalance in gene expressional events skewing chondrocyte anabolic and catabolic pathways toward the latter causes an aberrant turnover and loss of extracellular matrix proteins in osteoarthritic (OA) articular cartilage. Thus, catabolism results in the elevated loss of extracellular matrix proteins. There is
[...] Read more.
An imbalance in gene expressional events skewing chondrocyte anabolic and catabolic pathways toward the latter causes an aberrant turnover and loss of extracellular matrix proteins in osteoarthritic (OA) articular cartilage. Thus, catabolism results in the elevated loss of extracellular matrix proteins. There is also evidence of an increase in the frequency of chondrocyte apoptosis that compromises the capacity of articular cartilage to undergo repair. Although much of the fundamental OA studies over the past 20 years identified and characterized many genes relevant to pro-inflammatory cytokines, apoptosis, and matrix metalloproteinases (MMPs)/a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS), more recent studies focused on epigenetic mechanisms and the associated role of microRNAs (miRs) in regulating gene expression in OA cartilage. Thus, several miRs were identified as regulators of chondrocyte signaling pathways, apoptosis, and proteinase gene expression. For example, the reduced expression of miR-146a was found to be coupled to reduced type II collagen (COL2) in OA cartilage, whereas MMP-13 levels were increased, suggesting an association between MMP-13 gene expression and COL2A1 gene expression. Results of these studies imply that microRNAs could become useful in the search for diagnostic biomarkers, as well as providing novel therapeutic targets for intervention in OA. Full article
(This article belongs to the Special Issue Extracellular Matrix Remodeling)
Open AccessFeature PaperReview Coagulation, Microenvironment and Liver Fibrosis
Received: 10 June 2018 / Revised: 19 July 2018 / Accepted: 20 July 2018 / Published: 24 July 2018
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Abstract
Fibrosis is the main consequence of any kind of chronic liver damage. Coagulation and thrombin generation are crucial in the physiological response to tissue injury; however, the inappropriate and uncontrolled activation of coagulation cascade may lead to fibrosis development due to the involvement
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Fibrosis is the main consequence of any kind of chronic liver damage. Coagulation and thrombin generation are crucial in the physiological response to tissue injury; however, the inappropriate and uncontrolled activation of coagulation cascade may lead to fibrosis development due to the involvement of several cellular types and biochemical pathways in response to thrombin generation. In the liver, hepatic stellate cells and sinusoidal endothelial cells orchestrate fibrogenic response to chronic damage. Thrombin interacts with these cytotypes mainly through protease-activated receptors (PARs), which are expressed by endothelium, platelets and hepatic stellate cells. This review focuses on the impact of coagulation in liver fibrogenesis, describes receptors and pathways involved and explores the potential antifibrotic properties of drugs active in hemostasis in studies with cells, animal models of liver damage and humans. Full article
(This article belongs to the Special Issue Extracellular Matrix Remodeling)
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Other

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Open AccessBrief Report Sub-Cellular Localization of Metalloproteinases in Megakaryocytes
Received: 13 June 2018 / Revised: 17 July 2018 / Accepted: 18 July 2018 / Published: 20 July 2018
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Abstract
Metalloproteinases (MMPs) are zinc-dependent endopeptidases that play essential roles as the mediator of matrix degradation and remodeling during organogenesis, wound healing and angiogenesis. Although MMPs were originally identified as matrixin proteases that act in the extracellular matrix, more recent research has identified members
[...] Read more.
Metalloproteinases (MMPs) are zinc-dependent endopeptidases that play essential roles as the mediator of matrix degradation and remodeling during organogenesis, wound healing and angiogenesis. Although MMPs were originally identified as matrixin proteases that act in the extracellular matrix, more recent research has identified members of the MMP family in unusual locations within the cells, exerting distinct functions in addition to their established role as extracellular proteases. During thrombopoiesis, megakaryocytes (Mks) sort MMPs to nascent platelets through pseudopodial-like structure known as proplatelets. Previous studies identified gelatinases, MMP-2 and MMP-9, as a novel regulator system of Mks and the platelet function. In this work we have exploited a sensitive immunoassay to detect and quantify multiple MMP proteins and their localization, in conditioned medium and sub-cellular fractions of primary human CD34+-derived Mks. We provide evidence that Mks express other MMPs in addition to gelatinases MMP-2 and MMP-9, peculiar isoforms of MMP-9 and MMPs with a novel nuclear compartmentalization. Full article
(This article belongs to the Special Issue Extracellular Matrix Remodeling)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Authors: Fernández A, Veloso P, Cárdenas A, Astorga J, Hernández M.
Affiliation: Laboratory of Periodontal Biology, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
Tentative title: Expression of Toll-like receptors 2 and 4 and matrix metalloproteinases in symptomatic and asymptomatic apical periodontitis.

Authors: Dr. Sonja E LOBO
Affiliation: Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil
Tentative title: The cellular interactions and crosstalks related to ECM remodeling in healthy and patological conditions

Authors: Maria Cristina d'Agostino 1, Elena Monica Borroni 2, Elisabetta Tibalt, Stefano Respizzi 1, Johannes Holfeld 4, Kenneth Craig S. Vincent 5, Fabio Grizzi 3
Affiliations: 1 ESWT Center, Rehabilitation Department, Humanitas Clinical and Research Hospital, Rozzano, Milan, Italy
2 Department of Medical Biotechnologies and Translational Medicine, University of Milan, Italy
3 Department of Immunology and Inflammation, Humanitas Clinical and Research Hospital, Rozzano, Milan, Italy
4 Department for Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria.
5 Kompass Health Associate, Auckland (NZ) – Shockwave & Isokinetic Centre, Melbourne
Tentative title: Extracorporeal Shock Wave Therapy as Effector in Tissue Healing, Extra-Cellular Matrix Reversal and Immune Cell Network Dynamics
Abstract: The term “fibrosis” defines the abnormal deposition of extra-cellular matrix (ECM) made-up of a variety of collagenic and non-collagenic proteins, glycoproteins, proteoglycans, which together form a complex scaffold on which cells adhere, grow, and differentiate. ECM molecules are predominantly synthesized by activated fibroblasts. Maintenance of the normal structure and function of the ECM involves constant remodeling, which results from regulated, low levels of ECM synthesis and degradation. During wound healing, there is a short-lived shift in the balance of synthesis and degradation, which leads to a transient increase in collagen production and deposition. A continuous imbalance resulting in major alterations in both the quantity, composition and distribution pattern of the ECM causes fibrosis. Excessive accumulation represents a distinctive feature not only in “pathological” skin scars and in diseases such as scleroderma, osteogenesis imperfecta, and scurvy, but also in some other diseases of the lung, kidney and liver characterized by tissue fibrosis. Regardless of the possible heterogenous etiopathogenesis of fibrosis, it is recognized that activated fibroblasts bear receptors, that bind various growth factors and cytokine and that cells mediating innate or adaptive immunity produce the majority of cytokines and chemokines regulating its gene expression. Restoring of a normal structure and “tropism” of tissues and organs, both after trauma and in different diseases represents nowadays a great challenge for scientists, whose main efforts are aimed to Regenerative Medicine. From this point of view, although still under investigation, Extracorporeal Shock Wave Therapy (ESWT), represent nowadays a promising therapeutic tool: as a mechanical force, through mechano-transduction, it may act by positively regulating inflammation (i.e. probably as immunomodulator), to induce neo-angiogenesis and stem cells activities, thus improving tissue regeneration and healing. Here we explore and discuss the potential action of shock wave on the reversibility of the fibrotic process and the effects of mechanical actions on the dynamics of the immune microenvironment.

Authors: Vinicius Guzzoni 1,*, Rita de Cássia Marqueti 2
Affiliation: 1 College of Physical Education, Brasil University, Taquaritinga, Brazil;
 2 University of Brasilia, Distrito Federal, Brazil
Tentative Title: Effects of Anabolic-Androgenic Steroids (AAS), Aging and Exercise Training on Tendon Homeostasis
Abstract: Tendons constitute important structures of musculoskeletal system that transmit muscle-generating tensile force to bones. They are comprised of tissue-specific cells, including tenoblasts and tenocytes, chondrocytes, synovial cells and vascular cells, which synthesize proteins of extracellular matrix (ECM). ECM is composed primarily of collagens, large proteoglycans and small leucine-rich proteoglycans. In this regard, there are various factors that substantially could affect tendon homeostasis, including anabolic androgenic steroids (AAS) and aging. The goal of this narrative review is aggregate findings regarding to the effects of AAS, aging on tendons homeostasis. Also whether exercise training modulates the responses triggered by AAS and aging is worthy of investigation. Data from the last years indicate detrimental effects of AAS and aging on skeletal muscle tissue, even though there are fewer evidences concerning their effects on tendon. In fact, high doses of AAS have been shown to affect the collagen metabolism, which might suppose that AAS would affect molecular or functional and ultrastructural properties of rat tendons. In fact, biomechanical changes and ECM remodeling, as evidenced by alterations on MMP-2 activity, were observed in response to high doses of AAS. Furthermore, concerns related to age-induced musculoskeletal adaptations have been a topic of interest in the scientific and medical communities. In this perspective, we have investigated the effects of aging on tendon homeostasis and the effects of exercise training, particularly resistance training (RT) on this matter. Consistently, we demonstrated that RT attenuated the age-related dysfunction of rat tendons. Noteworthy, while aging has been shown to downregulate the gene expression of key elements related to ECM remodeling, RT was effective to upregulate those ECM-related molecules. Therefore, RT might be considered as a potential intervention to prevent both aging-related loss in ECM proteins and attenuate the detrimental functional effects in tendons in response to aging, as ruptures and tendinopathies.

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