title: Dose-Related and Time-Dependent Development of Collagenase-Induced Tendinopathy in Rats.
abstract: Tendinopathy is a big burden in clinics and it represents 45% of musculoskeletal lesions. Despite the relevant social impact, both pathogenesis and development of the tendinopathy are still under-investigated, thus limiting the therapeutic advancement in this field. The purpose of this study was to evaluate the dose-dependent and time-related tissue-level changes occurring in a collagenase-induced tendinopathy in rat Achilles tendons, in order to establish a standardized model for future pre-clinical studies. With this purpose, 40 Sprague Dawley rats were randomly divided into two groups, treated by injecting collagenase type I within the Achilles tendon at 1 mg/mL (low dose) or 3 mg/mL (high dose). Tendon explants were histologically evaluated at 3, 7, 15, 30 and 45 days. Our results revealed that both the collagenase doses induced a disorganization of collagen fibers and increased the number of rounded resident cells. In particular, the high dose treatment determined a greater neovascularization and fatty degeneration with respect to the lower dose. These changes were found to be time-dependent and to resemble the features of human tendinopathy. Indeed, in our series, the acute phase occurred from day 3 to day 15, and then progressed towards the proliferative phase from day 30 to day 45 displaying a degenerative appearance associated with a very precocious and mild remodeling process. The model represents a good balance between similarity with histological features of human tendinopathy and feasibility, in terms of tendon size to create lesions and costs when compared to other animal models. Moreover, this model could contribute to improve the knowledge in this field, and it could be useful to properly design further pre-clinical studies to test innovative treatments for tendinopathy.
authors.affiliation: Orthopaedic Biotechnology Laboratory, IRCCS Galeazzi Orthopaedic Institute, Milan, Italy.|Department of Drug Sciences, University of Pavia, Pavia, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Perucca Orfei
authors.affiliation: Cell and Tissue Engineering Laboratory, IRCCS Galeazzi Orthopaedic Institute, Milan, Italy.
authors.forename: Arianna B
authors.identifier: http://orcid.org/0000-0002-5230-9718
authors.initials: AB
authors.lastname: Lovati
authors.affiliation: Orthopaedic Biotechnology Laboratory, IRCCS Galeazzi Orthopaedic Institute, Milan, Italy.|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Viganò
authors.affiliation: Orthopaedic Biotechnology Laboratory, IRCCS Galeazzi Orthopaedic Institute, Milan, Italy.
authors.forename: Deborah
authors.initials: D
authors.lastname: Stanco
authors.affiliation: Cell and Tissue Engineering Laboratory, IRCCS Galeazzi Orthopaedic Institute, Milan, Italy.|Department of Veterinary Medicine (DiMeVet), University of Milan, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Bottagisio
authors.affiliation: Department of Health, Animal Science and Food Safety, University of Milan, Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Di Giancamillo
authors.affiliation: IGEA SpA Clinical Biophysics, Carpi (MO), Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Setti
authors.affiliation: Orthopaedic Biotechnology Laboratory, IRCCS Galeazzi Orthopaedic Institute, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: de Girolamo
mesh_terms: D000125:Achilles Tendon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000008:administration & dosage*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007267:Injections; D008297:Male; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D052256:Tendinopathy / Q000139:chemically induced / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014945:Wound Healing / Q000502:physiology
chemical_list: D003094:Collagen; D017364:Collagenases; C417249:collagenase 1