Bone morphogenetic proteins and Smad expression in ovine tendon-bone healing.
OBJECTIVE
Bone morphogenetic proteins (BMPs) are being developed to improve tendon-bone healing. To do this, it is essential to understand the endogenous expression of BMPs and their downstream signal transduction factors, Smads, during tendon-bone healing.


METHODS
An extra-articular patellar tendon-bone healing ovine model was set up, and histologic evaluation of the healing progress at the tendon-bone interface at 1, 2, 3, and 6 weeks was performed. Immunohistochemical staining of BMP-2, BMP-7, Smad1, Smad4, and Smad5 was carried out in all sections.


RESULTS
The model revealed formation of a loose granuloma tissue layer between the tendon and bone at 1 week, remodeling starting at 2 weeks, and Sharpey-like collagen fiber formation at 3 and 6 weeks. All detected factors were elevated at the tendon-bone interface during healing, and the expression peaked at 2 to 3 weeks. The cells involved were osteoblastic-like cells, osteoclastic-like cells, mesenchymal cells, and fibroblasts. BMP-7 staining was mainly at the interface close to the bony side, whereas BMP-2 expression shifted to the tendon side at 6 weeks. The expression pattern of Smad1 and Smad5 was similar to that of BMP-7. Smad1 was also found to be expressed in osteoclastic-like cells at 1 and 2 weeks. Smad4 expression was the highest among all of the factors at all time points.


CONCLUSIONS
The data suggest that endogenous BMP-2 and BMP-7 participate in tendon-bone healing and their functions involve their downstream signal transduction mediators, Smad1, Smad4, and Smad5.


CONCLUSIONS
The temporal expression of BMPs should be considered when setting up therapeutic strategies using BMPs.
Yu
Yan
Y
Surgical & Orthopaedic Research Laboratories, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia. y.yu@unsw.edu.au
Bliss
James P
JP
Bruce
Warrick J M
WJ
Walsh
William R
WR
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis*; D001842:Bone and Bones / Q000473:pathology / Q000502:physiology*; D004195:Disease Models, Animal; D012756:Sheep; D015398:Signal Transduction; D051785:Smad Proteins / Q000096:biosynthesis*; D051898:Smad1 Protein / Q000096:biosynthesis; D051901:Smad4 Protein / Q000096:biosynthesis; D051902:Smad5 Protein / Q000096:biosynthesis; D013710:Tendons / Q000473:pathology / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014945:Wound Healing / Q000502:physiology*
D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D051785:Smad Proteins; D051898:Smad1 Protein; D051901:Smad4 Protein; D051902:Smad5 Protein; D016212:Transforming Growth Factor beta