Immunosuppression with FK506 Increases Bone Induction in Demineralized Isogeneic and Xenogeneic Bone Matrix in the Rat

Abstract

The aim of the present study was to investigate a systemic induction of bone formation in rats by immunosuppression with FK506 (1 mg/kg body weight intraperitoneally [ip]) in a model of osteoinduction of isogeneic and xenogeneic demineralized bone matrix (DBM) for a period of 28 days. In particular, alterations of in vitro cytokine synthesis and changes of lymphocyte subsets were studied. DBM was implanted intramuscularly in the abdominal wall of Lewis rats (seven per group). Blood was sampled on days ؊7, 0, 7, and 28 for determination of in vitro tumor necrosis factor ␣ (TNF-␣) synthesis and lymphocyte subsets by flow cytometry (CD3؉, CD4؉, CD8؉, CD45؉, ED9؉, and Ia؉ antibodies). Ossicles of de novo formed bone and the tibias were removed on day 28 after double tetracycline labeling for histomorphometric analysis.

Stimulation of osteogenic activity in mesenchymal stem cells by FK506

“…5,6 This is because immunosuppressants influ- ence on bone metabolism indirectly by reducing the amounts of cytokine produced by cells of the immune system. 7 However, recently there have been some studies regarding the effects of immunosuppressants on early bone formation and repair.…”

“…They speculated that this was due to the immunosuppressing role of FK506, because immune reactions can inhibit bone induction from heterotopically transplanted DBM. 7 Yoshikawa et al found that FK506 promoted the formation of bone in MSCs/hydroxyapatite composites in a model of allografts, when it was administered as an immunosuppressant. 8 Isomoto et al investigated the effect of three immunosuppressants on the osteogenic differentiation of MSCs and found that rapamycin decreased the osteogenic effects of Dex; FK506 increased APase activity and the calcium content of the cells; and CsA had a negligible effect.…”

“…They found that FK506 treatment significantly increased the volume of bone generated. 7 In addition, Yoshikawa et al demonstrated that FK506 could directly stimulate the inherent osteogenic activity of allogeneic mineralized bone to increase in vivo bone formation following its intramuscular injection of FK506 as well as suppress the immune reaction to the constructs. 8 The present study addresses the effect of FK506 on osteogenesis in a microenvironment in vivo and in vitro.…”

Anterior lumbar interbody fusion with carbon fiber cage loaded with bioceramics and platelet-rich plasma. An experimental study on pigs

“…We know that white blood cells are responsible for inflammatory reaction in the early stage of fracture healing. The exact influence of higher white blood cell concentration on the β-TCP in the cage in our study is unclear, but in the literature, suppression of leukocyte proliferation or function resulted in higher bone formation and mechanical bending moment in rats [9,28].…”

Simple and effective osteoinductive gene therapy by local injection of a bone morphogenetic protein-2-expressing recombinant adenoviral vector and FK506 mixture in rats

“…Some researchers have reported that FK506 promotes osteoblast activity and is a useful agent for induction of bone formation or for allogeneic bone grafting. 29,30 To determine whether our results were depended on the immunosuppressant or osteogenic effect of FK506, we examined the expression of BMP-2 and ALP mRNA at 1, 3, 5, 7, and 9 days after injection into nude rats and we also performed radiographic, histologic, histomorphometric, and biological assessment of nude rats at 21 days after injection. In the FK506 group, BMP-2 expression remained high until 5 days after administration, but was decreased markedly from 7 days onwards.…”