Abstract
Many of the bioactive agents capable of stimulating osseous regeneration, such as bone morphogenetic protein-2 (BMP-2) or prostaglandin E2 (PGE2), are limited by rapid degradation, a short bioactive half-life at the target site in vivo, or are prohibitively expensive to obtain in large quantities. Rebamipide, an amino acid modified hydroxylquinoline, can alter the expression of key mediators of bone anabolism, cyclo-oxygenase 2 (COX-2), BMP-2 and vascular endothelial growth factor (VEGF), in diverse cell types such as mucosal and endothelial cells or chondrocytes. The present study investigates whether Rebamipide enhances proliferation and differentiation of osteoblasts when delivered from brushite cement. The reactive oxygen species (ROS) quenching ability of Rebampide was tested in macrophages as a measure of bioactivity following drug release incubation times, up to 14 days. Rebamipide release from brushite occurrs via non-fickian diffusion, with a rapid linear release of 9.70% ±0.37% of drug per day for the first 5 days, and an average of 0.5%-1% per day thereafter for 30 days. Rebamipide slows the initial and final cement setting time by up to 3 and 1 minute, respectively, but does not significantly reduce the mechanical strength below 4% (weight percentage). Pre-osteoblast proliferation increases by 24% upon exposure to 0.4uM Rebamipide, and by up to 73% when Rebamipide is delivered via brushite cement. Low doses of Rebamipide do not adversely affect peak alkaline phosphatase activity in differentiating pre-osteoblasts. Rebamipide weakly stimulates proliferation in macrophages at low concentrations (118 ±7.4% at 1uM), and quenches ROS by 40-60%. This is the first investigation of Rebamipide in osteoblasts.
Highlights
In 2004 alone musculoskeletal conditions cost the US approximately 849 billion dollars[1, 2]
We observed a correlation between hydroxylapatite formation and Rebamipide content, in samples that had been aged for 30 days in phosphate buffered saline (PBS) (R2 = 0.906, Fig 2C)
We report for the first time that Rebamipide is an effective stimulator of osteoblast proliferation and can affect Alkaline phosphatase (ALP) activity in MC3T3 osteoblasts
Summary
In 2004 alone musculoskeletal conditions cost the US approximately 849 billion dollars[1, 2]. Rebamipide Cements Enhance the Proliferation of MC3T3 Osteoblasts. Injectable bone substitutes, such as calcium phosphate cements (CPC), offer many advantages compared to bone grafts. The porosity can be controlled by varying the liquid to powder ratio, amount of crystal growth retardants or adding porosity agents such as foams or porogens.[7,8,9] In addition, CPC’s are effective drug delivery vehicles[10, 11]. Delivery of bone morphogenetic protein (BMP-2), prostaglandin E2 (PGE2) receptor agonist, or vascular endothelial growth factor (VEGF) from calcium phosphates, in vivo, has been shown to yield significant increase in bone mass, bone density, and new bone surface area compared to controls[12,13,14]. It should be noted that dicalcum phosphate dihydrate (DCPD known as brushite) is acidic during and after the setting reaction and, may better suited for small molecule drugs and not labile biological agents [15, 16]
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