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      Mechanisms of skeletal muscle-tendon development and regeneration/healing as potential therapeutic targets

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      Pharmacology & Therapeutics
      Elsevier BV

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          Abstract

          Skeletal muscle contraction is essential for the movement of our musculoskeletal system. Tendons and ligaments that connect the skeletal muscles to bones in the correct position at the appropriate time during development are also required for movement to occur. Since the musculoskeletal system is essential for maintaining basic bodily functions as well as enabling interactions with the environment, dysfunctions of these tissues due to disease can significantly reduce quality of life. Unfortunately, as people live longer, skeletal muscle and tendon/ligament diseases are becoming more common. Sarcopenia, a disease in which skeletal muscle function declines, and tendinopathy, which involves chronic tendon dysfunction, are particularly troublesome because there have been no significant advances in their treatment. In this review, we will summarize previous reports on the development and regeneration/healing of skeletal muscle and tendon tissues, including a discussion of the molecular and cellular mechanisms involved that may be used as potential therapeutic targets.

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          Most cited references225

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          Is Open Access

          Global estimates of the need for rehabilitation based on the Global Burden of Disease study 2019: a systematic analysis for the Global Burden of Disease Study 2019

          Summary Background Rehabilitation has often been seen as a disability-specific service needed by only few of the population. Despite its individual and societal benefits, rehabilitation has not been prioritised in countries and is under-resourced. We present global, regional, and country data for the number of people who would benefit from rehabilitation at least once during the course of their disabling illness or injury. Methods To estimate the need for rehabilitation, data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 were used to calculate the prevalence and years of life lived with disability (YLDs) of 25 diseases, impairments, or bespoke aggregations of sequelae that were selected as amenable to rehabilitation. All analyses were done at the country level and then aggregated to seven regions: World Bank high-income countries and the six WHO regions (ie, Africa, the Americas, Southeast Asia, Europe, Eastern Mediterranean, and Western Pacific). Findings Globally, in 2019, 2·41 billion (95% uncertainty interval 2·34–2·50) individuals had conditions that would benefit from rehabilitation, contributing to 310 million [235–392] YLDs. This number had increased by 63% from 1990 to 2019. Regionally, the Western Pacific had the highest need of rehabilitation services (610 million people [588–636] and 83 million YLDs [62–106]). The disease area that contributed most to prevalence was musculoskeletal disorders (1·71 billion people [1·68–1·80]), with low back pain being the most prevalent condition in 134 of the 204 countries analysed. Interpretation To our knowledge, this is the first study to produce a global estimate of the need for rehabilitation services and to show that at least one in every three people in the world needs rehabilitation at some point in the course of their illness or injury. This number counters the common view of rehabilitation as a service required by only few people. We argue that rehabilitation needs to be brought close to communities as an integral part of primary health care to reach more people in need. Funding Bill & Melinda Gates Foundation.
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            The Fibroblast Growth Factor signaling pathway

            The signaling component of the mammalian Fibroblast Growth Factor (FGF) family is comprised of eighteen secreted proteins that interact with four signaling tyrosine kinase FGF receptors (FGFRs). Interaction of FGF ligands with their signaling receptors is regulated by protein or proteoglycan cofactors and by extracellular binding proteins. Activated FGFRs phosphorylate specific tyrosine residues that mediate interaction with cytosolic adaptor proteins and the RAS-MAPK, PI3K-AKT, PLCγ, and STAT intracellular signaling pathways. Four structurally related intracellular non-signaling FGFs interact with and regulate the family of voltage gated sodium channels. Members of the FGF family function in the earliest stages of embryonic development and during organogenesis to maintain progenitor cells and mediate their growth, differentiation, survival, and patterning. FGFs also have roles in adult tissues where they mediate metabolic functions, tissue repair, and regeneration, often by reactivating developmental signaling pathways. Consistent with the presence of FGFs in almost all tissues and organs, aberrant activity of the pathway is associated with developmental defects that disrupt organogenesis, impair the response to injury, and result in metabolic disorders, and cancer. © 2015 Wiley Periodicals, Inc.
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              Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche.

              The repair of injured tendons remains a great challenge, largely owing to a lack of in-depth characterization of tendon cells and their precursors. We show that human and mouse tendons harbor a unique cell population, termed tendon stem/progenitor cells (TSPCs), that has universal stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity. The isolated TSPCs could regenerate tendon-like tissues after extended expansion in vitro and transplantation in vivo. Moreover, we show that TSPCs reside within a unique niche predominantly comprised of an extracellular matrix, and we identify biglycan (Bgn) and fibromodulin (Fmod) as two critical components that organize this niche. Depletion of Bgn and Fmod affects the differentiation of TSPCs by modulating bone morphogenetic protein signaling and impairs tendon formation in vivo. Our results, while offering new insights into the biology of tendon cells, may assist in future strategies to treat tendon diseases.
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                Author and article information

                Journal
                Pharmacology & Therapeutics
                Pharmacology & Therapeutics
                Elsevier BV
                01637258
                March 2023
                March 2023
                : 243
                : 108357
                Article
                10.1016/j.pharmthera.2023.108357
                f383a8ee-1d26-491e-b413-d166ea2fc40e
                © 2023

                https://www.elsevier.com/tdm/userlicense/1.0/

                http://www.elsevier.com/open-access/userlicense/1.0/

                https://doi.org/10.15223/policy-017

                https://doi.org/10.15223/policy-037

                https://doi.org/10.15223/policy-012

                https://doi.org/10.15223/policy-029

                https://doi.org/10.15223/policy-004

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