title: Tendon mineralization is progressive and associated with deterioration of tendon biomechanical properties, and requires BMP-Smad signaling in the mouse Achilles tendon injury model.
abstract: Ectopic tendon mineralization can develop following tendon rupture or trauma surgery. The pathogenesis of ectopic tendon mineralization and its clinical impact have not been fully elucidated yet. In this study, we utilized a mouse Achilles tendon injury model to determine whether ectopic tendon mineralization alters the biomechanical properties of the tendon and whether BMP signaling is involved in this condition. A complete transverse incision was made at the midpoint of the right Achilles tendon in 8-week-old CD1 mice and the gap was left open. Ectopic cartilaginous mass formation was found in the injured tendon by 4weeks post-surgery and ectopic mineralization was detected at 8 to 10weeks post-surgery. Ectopic mineralization grew over time and volume of the mineralized materials of 25-weeks samples was about 2.5 fold bigger than that of 10-weeks samples, indicating that injury-induced ectopic tendon mineralization is progressive. In vitro mechanical testing showed that max force, max stress and mid-substance modulus in the 25-weeks samples were significantly lower than the 10-weeks samples. We observed substantial increases in expression of bone morphogenetic protein family genes in injured tendons 1week post-surgery. Immunohistochemical analysis showed that phosphorylation of both Smad1 and Smad3 was highly increased in injured tendons as early as 1week post-injury and remained high in ectopic chondrogenic lesions 4-weeks post-injury. Treatment with the BMP receptor kinase inhibitor (LDN193189) significantly inhibited injury-induced tendon mineralization. These findings indicate that injury-induced ectopic tendon mineralization is progressive, involves BMP signaling and associated with deterioration of tendon biomechanical properties.
authors.affiliation: Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Kairui
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Asai
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Hast
authors.affiliation: Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Usami
authors.affiliation: Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwamoto
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Soslowsky
authors.affiliation: Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, United States. Electronic address: iwamotom1@email.chop.edu.
authors.forename: Motomi
authors.initials: M
authors.lastname: Enomoto-Iwamoto
mesh_terms: D000125:Achilles Tendon / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001696:Biomechanical Phenomena; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002114:Calcinosis / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D013708:Tendon Injuries / Q000473:pathology / Q000503:physiopathology*; D014945:Wound Healing
chemical_list: D019485:Bone Morphogenetic Proteins; D051785:Smad Proteins
keywords: Achilles tendon; BMP; Biomechanics; Ectopic mineralization; Injury; Smad
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