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J Bone Joint Surg Am. 2014 Jun 18;96(12):1033-1039.

Acute Rejection of Knee Joint Articular Cartilage in a Rat Composite Tissue Allotransplantation Model.

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Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai-shi, Miyagi 980-8575, Japan. E-mail address for N. Shibuya:



Osteochondral allograft transplantation is used to treat severe cartilage injury or chondral defects, with good outcomes in clinical studies. However, allograft chondrocyte death due to apoptosis may occur during storage or as a result of implantation stress. We investigated a third possible cause, chondrocyte apoptosis resulting from an immune response, by means of composite tissue allografting, thus eliminating the role of storage and implantation stresses on osteochondral grafts.


Vascularized composite tissue allotransplantation (from Fisher 344 to Lewis rat strains) and isotransplantation (from Lewis to Lewis strains) of rat hind limbs were performed. Immunohistochemistry was performed with use of caspase-3 and TUNEL (terminal deoxynucleotidyl transferase mediated dUTP nick end labeling) assays. Analyses were performed immediately after perfusion (day zero) and on postoperative days one, three, seven, twelve, and eighteen (n = 5 for immunohistochemistry). Transmission electron microscopy was used for detection of chondrocyte apoptosis. Laser capture microdissection followed by quantitative real-time polymerase chain reaction assays was used for analysis of postoperative caspase-3 gene expression.


Caspase-3 immunochemistry was increasingly positive in allograft chondrocytes from postoperative day seven onward. In contrast, caspase-3 gene expression decreased in all allografts. TUNEL assays showed increasing apoptosis of allograft chondrocytes, and electron microscopy also revealed evidence supporting the development of apoptosis.


Immunorejection of chondrocytes in transplanted cartilage has been thought to be unlikely, but our data reveal that chondrocytes can undergo apoptosis in allotransplantation. This apoptosis involves the caspase-3 cascade and indicates that chondrocytes may induce acute rejection.

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