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Introduction: Wear particles produced from prosthetic joints may play critical roles in periprosthetic inflammatory reactions and osteolysis. The objective of this study was to quantify and compare the response to wear debris from different biomaterials at the bone-implant interface in a rat knee model., Methods: Sixty rats were divided into titanium alloy (Ti-6Al-4V), cobalt chromium (Co-Cr), ceramic (Al 2 O 3 ), ultrahigh molecular weight polyethylene (UHMWPE), and control (phosphate buffered saline) groups with 12 animals per group. A nonweight-bearing titanium rod was implanted into the right distal femur of each rat followed by intra-articular injections of the biomaterial particles to the surgical knees for up to 16 weeks. Micro-computed tomography scanning was performed monthly and at the time of sacrifice to determine bone densities around the bone-implant interface. Histological evaluations were executed to quantify local inflammatory reactions and osteoclastogenesis., Results: Co-Cr particles resulted in the most severe reductions in bone density. UHMWPE and ceramic particles resulted in a rapid reduction in bone density followed by a recovery. Inflammatory pseudo-membranes were ubiquitously present close to the femoral condyle and pin insertion site. Ceramic particles significantly promoted periprosthetic tissue formation compared with the other groups ( p  < 0.05). Cathepsin K positive cells were dominantly present at the peri-implant site following challenges of metallic alloy and ceramic particles., Conclusion: Different biomaterials in particulate form exert different forms of adverse effects in terms of the amount of osteolysis and inflammatory reactions on bone tissue at the bone-implant interface. It provides information for engineering more appropriate materials for arthroplasty components.

This study investigated the therapeutic influence and potential mechanism of IL-10 in ameliorating orthopedic debris particle-induced inflammation and osteolysis. A murine air pouch with bone implantation and polyethylene particles was also used to evaluate the therapeutic effects of IL-10. The data suggested that the particle challenges significantly promoted macrophage activation and osteoclastogenesis, with dramatically increased macrophage infiltration into the pouch membranes and elevated tartrate-resistant acid phosphatase-positive cell deposition. Immunohistochemical stains revealed a significantly higher ratio of induced nitric oxide synthase-expressing cells in the particle-challenged group; treatment with IL-10 resulted in marked switching to CD163(+) cells. Also, IL-10 effectively reduced tartrate-resistant acid phosphatase-positive stained cells in the pouch membranes, and minimized the bone mineral density loss compared with untreated samples. Real-time PCR and Western blot examination indicated that IL-10 treatment significantly diminished the particle-induced IL-1β expression but promoted expression of CD163, transforming growth factor-β1, and CCR2. Furthermore, IL-10 significantly inhibited the ultra-high-molecular-weight polyethylene particle-elevated phospho-STAT1 and phospho-NF-κB p65 productions, and promoted phospho-STAT3 expression. Overall, the data indicate the pivotal effects of IL-10 on macrophage polarization. The effects of IL-10 in ameliorating local inflammation and osteolysis may be associated with macrophage polarization through the up-regulation of the Janus activating kinase/STAT3 signaling pathway, and the down-regulation of NF-κB and Janus activating kinase/STAT1 expression., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The current study investigates the interactive behavior of titanium alloy particle-challenged osteoblastic bone marrow stromal cells (BMSCs) and macrophage lineage cells in a murine knee-prosthesis failure model. BMSCs were isolated from male BALB/c mice femurs and induced in osteogenic medium. At 24h after isolation, BMSCs in complete induction medium were challenged with 1, 3 or 5mgml(-1) titanium particles for 7days. Culture media were collected at 2, 4 and 6days and cells were harvested at 7days for alkaline phosphatase (ALP) assay/stains. Cell proliferation in the presence of Ti particles was periodically evaluated by MTT assay. Mice implanted with titanium-pin tibial implants were given an intra-articular injection of 50μl medium containing 5×10(5) Ti particles-challenged bone-marrow-derived osteoblastic cells, followed by a repeat injection at 2weeks post-operation. Control mice with titanium-pin implants received a naïve osteoblastic cell transfusion. After sacrifice at 4weeks, the implanted knee joint of each group was collected for biomechanical pin-pullout testing, histological evaluation and reverse transcriptase polymerase chain reaction analysis of mRNA extracted from the joint tissues. Ti particles significantly stimulated the proliferation of BMSC-derived osteoblastic cells at both high and low particle concentrations (p<0.05), with no marked differences between the particle doses. ALP expression was diminished following Ti particle interactions, especially in the high-dose particle group (p<0.05). In addition, the culture media collected from short-term challenged (48h) osteoblasts significantly increased the numbers of TRAP+ cells when added to mouse peripheral blood monocytes cultures, in comparison with the monocytes cells receiving naïve osteoblasts media (p<0.05). Intra-articular introduction of the osteoblastic cells to the mouse pin-implant failure model resulted in reduced implant interfacial shear strength and thicker peri-implant soft-tissue formation, suggesting that titanium particles-challenged osteoblasts contributed to periprosthetic osteolysis. Comparison of the gene expression profiles among the peri-implant tissue samples following osteoblast injection did not find significant difference in RunX2 or Osterix/Sp7 between the groups. However, MMP-2, IL-1, TNF-α, RANKL, and TRAP gene expressions were elevated in the challenged-osteoblast group (p<0.05). In conclusion, titanium alloy particles were shown to interfere with the growth, maturation, and functions of the bone marrow osteoblast progenitor cells. Particle-challenged osteoblasts appear to express mediators that regulate osteoclastogenesis and peri-prosthetic osteolysis., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Osteoporosis is a common pathological condition that influences 20 % of women over 50 years of age. This condition decreases bone strength and increases the risk of bone fracture. Naringin is a major flavonoid found in grapefruit and an active compound extracted from a Chinese herbal medicine (Rhizoma Drynariae). Studies have shown that naringin possesses many pharmacological effects. The current study evaluated the influence of naringin on osteoblastic cell differentiation and proliferation, and assessed its therapeutic effects on a rat osteoporosis model., Method: The proliferation, differentiation, and function of rat bone marrow stromal cells (BMSCs) were determined following treatment with various concentrations of naringin. Ovariectomy (OVX)-induced osteoporotic rats were orally administered naringin daily at low, medium, and high dosages, while a control group received PBS for 2 months. Femoral X-ray images and microCT scans were used for bone mineral density (BMD) and BV/TV (bone volume/total volume) analyses, and histological assessments of left tibiae were employed to check for changes in trabecular thickness (Tb.Th) and trabecular space (Tb.Sp) in the groups., Results: Naringin was effective at enhancing the proliferation and osteogenic differentiation of BMSCs, and a concentration of 10 μg/ml prompted the highest levels of osteocalcin expression among the in vitro study groups. There appeared to be a delayed response pattern of BMSCs to the naringin treatment. Naringin also effectively reversed OVX-induced bone loss via increasing BMD, bone volume, and trabecular thickness. The medium dose (300 mg/kg) appeared to be the optimal dosage for delivering satisfactory therapeutic effects., Conclusion: Naringin promotes the proliferation and differentiation of BMSCs, and increases osteocalcin expression. Naringin also effectively reverses ovariectomy-induced osteoporosis in rats. The study suggests that naringin administration may represent an effective treatment for osteoporosis.

Type II collagen-induced arthritis has played a critical role in the development of novel approaches to the treatment of rheumatoid arthritis. The model has provided insights into autoimmune mechanisms relevant to the pathogenesis of joint disease and permitted the identification of potential targets for arthritis therapy. Notably, the model excelled in the development of cytokine inhibition for rheumatoid arthritis, with investigations demonstrating that a complex network of cytokine interactions regulate the autoimmune response to collagen. Recent studies of collagen-induced arthritis provide indications of novel approaches to disease intervention. New directions include modulation of the recognition and presentation of autoantigens, inhibition of specific T cell subsets responding to autoantigens, blocking of stimulatory cosignals at the cell surface, decoys for cytoplasmic and nuclear activation signals, interference with lymphocyte migration to the synovial joint, and reduction of the mediators of joint destruction. These approaches can be implemented through gene therapy, biological response mediators, or classic pharmacological intervention.

Animal models have played a critical role in the history of modern drug development for rheumatoid arthritis (RA). In this chapter I examine the contributions of animal models in arthritis therapy from adjuvant arthritis and COX-1 inhibitors to transgenic mice and biological response modifiers. Advances in knowledge of the mechanisms of connective tissue disease are frequently derived from the study of animal models, and these findings frequently identify therapeutic targets that are subsequently evaluated in animal models. Hence a critical relationship between insights into the pathology of arthritis and the development of novel therapeutic approaches exists around the study of animal models of arthritis. In particular, we examine how the study of collagen-induced arthritis in rodents led to pioneering work in cytokine inhibitors for the successful therapy of RA.