title: p38 MAPK signaling in postnatal tendon growth and remodeling.
abstract: Tendon is a dynamic tissue whose structure and function is influenced by mechanical loading, but little is known about the fundamental mechanisms that regulate tendon growth and remodeling in vivo. Data from cultured tendon fibroblasts indicated that the p38 MAPK pathway plays an important role in tendon fibroblast proliferation and collagen synthesis in vitro. To gain greater insight into the mechanisms of tendon growth, and explore the role of p38 MAPK signaling in this process, we tested the hypotheses that inducing plantaris tendon growth through the ablation of the synergist Achilles tendon would result in rapid expansion of a neotendon matrix surrounding the original tendon, and that treatment with the p38 MAPK inhibitor SB203580 would prevent this growth. Rats were treated with vehicle or SB203580, and subjected to synergist ablation by bilateral tenectomy of the Achilles tendon. Changes in histological and biochemical properties of plantaris tendons were analyzed 3, 7, or 28 days after overload, and comparisons were made to non-overloaded animals. By 28 days after overload, tendon mass had increased by 30% compared to non-overloaded samples, and cross-sectional area (CSA) increased by around 50%, with most of the change occurring in the neotendon. The expansion in CSA initially occurred through the synthesis of a hyaluronic acid rich matrix that was progressively replaced with mature collagen. Pericytes were present in areas of active tendon growth, but never in the original tendon ECM. Inhibition of p38 MAPK resulted in a profound decrease in IL6 expression, and had a modest effect on the expression of other ECM and cell proliferation genes, but had a negligible impact on overall tendon growth. The combined results from this study provided novel insights into tendon mechanobiology, and suggest that p38 MAPK signaling does not appear to be necessary for tendon growth in vivo.
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schwartz
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Dylan C
authors.initials: DC
authors.lastname: Sarver
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Department of Surgery, Section of Plastic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Kristoffer B
authors.initials: KB
authors.lastname: Sugg
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Dzierzawski
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Gumucio
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Mendias
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013710:Tendons / Q000166:cytology* / Q000254:growth & development* / Q000276:immunology / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D015850:Interleukin-6; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580