Interleukin-11 (IL-11) is a pleiotropic cytokine that supports various types of hematopoietic cell growth and is involved in bone resorption. We report here the involvement of recombinant human IL-11 (rHuIL-11) in osteoblast differentiation in mouse mesenchymal progenitor cells, C3H10T1/2. rHuIL-11 alone increased alkaline phosphatase (ALP) activity and upregulated expression levels of osteocalcin (OC), bone sialo protein (BSP), and parathyroid hormone receptor (PTHR) mRNA. rHuIL-11 had no effect on expression of type II collagen, peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), adipocyte fatty acid-binding protein P2 (aP2), and myogenic MyoD protein (MyoD). Recombinant human bone morphogenetic protein (rHuBMP)-2 increased ALP activity and mRNA expression of these genes except for MyoD. The expression patterns of ALP activity and osteoblast-specific or chondrocyte-specific genes suggest that rHuIL-11 may be involved in early differentiation of osteoblasts at a step earlier than that which is affected by rHuBMP-2. In support of this hypothesis, combined treatment with rHuIL-11 and rHuBMP-2 synergistically increased ALP activity and mRNA expression of OC and type II collagen, rHuIL-11 also abrogated the increased levels of PPAR-gamma2, aP2 mRNA caused by rHuBMP-2. Our results suggest that rHuIL-11 alone and in combination with rHuBMP-2 can induce osteoblastic differentiation of progenitor cells and plays an important role in osteogenesis.
Recombinant human interleukin-11 (rHuIL-11) and recombinant human bone morphogenetic protein-2 (rHuBMP-2) have been shown to act synergistically in the induction of osteoblast differentiation. To determine whether these two proteins can be used clinically in fracture healing and reconstructive surgery, we investigated whether rHuIL-11 and rHuBMP-2 act synergistically to heal segmental bone defects in a rabbit model. A 1.5-cm segmental defect was created in the right ulnar diaphysis of 20 Japanese white rabbits. Polylactic-co-glycolic acid (PLGA)-coated gelatin sponges (PGS) permeated with rHuBMP-2 (n = 8), rHuIL-11 plus rHuBMP-2 (n = 8), or rHuIL-11 (n = 4) were implanted into the bone defects. Radiographs were scored by two independent observers for bone formation and union rates after 2, 3, 4, and 8 weeks. Bone formation was higher in rabbits implanted with rHuBMP-2 plus rHuIL-11 than in those implanted with rHuBMP-2 alone, reaching statistical significance after 4 weeks. At early time points, the union rate in rabbits implanted with rHuBMP-2 plus rHuIL-11 was higher than in rabbits implanted with rHuBMP-2. At 2, 4, and 8 weeks, new bone volume was significantly higher in rabbits administered rHuIL-11 plus rHuBMP-2 than in those given rHuBMP-2 alone. In contrast, mechanical testing after 8 weeks showed that bone strength in the two groups of rabbits was equivalent. These findings show that rHuIL-11 and rHuBMP-2 act synergistically to accelerate bone formation without affecting bone strength. Treatment with a combination of rHuIL-11 and rHuBMP-2 may thus be of great benefit in fracture healing and for patients undergoing reconstructive surgery.
We previously demonstrated that recombinant human interleukin-11 (rHuIL-11) induced osteoblast differentiation of C3H10T1/2 progenitor cells and also acted synergistically with recombinant human bone morphogenetic protein-2 (rHuBMP-2) in performing the same function. In this study, we investigated the effect of rHuIL-11 and rHuBMP-2 on bone formation in a rat ectopic model. When placed in rats, implants consisting of polymer-coated gelatin sponges containing various concentrations of rHuBMP-2 showed a dose-dependent increase in calcium content. This was confirmed by radiographic analysis of the implants. Although implants containing rHuIL-11 alone did not accumulate calcium, implants containing a combination of rHuBMP-2 and rHuIL-11 had significantly higher calcium levels than those containing rHuBMP-2 alone. This increase was rHuIL-11 dose dependent. The synergistic effect of 20 micrograms rHuIL-11 and 6 micrograms rHuBMP-2 on bone formation was estimated to be 1 week in advance of that of 6 micrograms rHuBMP-2 alone. Histologic examination revealed that the combination of rHuIL-11 and rHuBMP-2 caused spindle cells to accumulate around implants and induced cell infiltration into implants. Bone formation occurred faster in implants with the combination of rHuIL-11 and rHuBMP-2 compared with rHuBMP-2 alone. These results suggest that rHuIL-11 acts synergistically with rHuBMP-2 to more rapidly stimulate bone formation compared with rHuBMP-2 alone. This novel combined therapy may be of great clinical benefit in bone healing.
The effects of barnidipine on blood flow to major organs and on renal function were investigated in anaesthetized dogsand conscious spontaneously hypertensive rats (SHR), and the results were compared with those for nicardipine, nitrendipine, nisoldipine, manidipine and amlodipine.2. In anaesthetized dogs, barnidipine (0.3-3 pg/kg i.v.) dosedependently decreased blood pressure and increased or preserved blood flow in the vertebral, coronary, femoral and renal arteries. The effect of barnidipine on blood flow was the most potent of the compounds tested. In conscious SHR, barnidipine (0.3-3 mg/kg p.0.) produced a dose-dependent antihypertensive effect and decreased renal vascular resistance. Barnidipine also dose-dependently increased urinary volume. The antihypertensive and diuretic effects of barnidipine were the most potent of the drugs tested.3. In summary, barnidipine was shown to preserve or increase blood flow to major organs and to produce diuretic activity with a decrease in blood pressure. These findings suggest that barnidipine maintains or promotes renal function at antihypertensive doses.
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