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Effects of Strontium Ranelate on Wear Particle‑Induced Aseptic Loosening in Female Ovariectomized Mice

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Effects of Strontium Ranelate on Wear Particle‑Induced Aseptic Loosening in Female Ovariectomized Mice MOLECULAR MEDICINE REPORTS 18: 1849-1857, 2018 Effects of strontium ranelate on wear particle‑induced aseptic loosening in female ovariectomized mice TIANXIANG GENG1*, XI CHEN1*, MENGXUE ZHENG1, HAOCHEN YU1,2, SHUAI ZHANG3, SHOUXUAN SUN3, HAOHUI GUO3 and QUNHUA JIN3 1Department of Orthopedic Surgery, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004; 2Biotechnology Laboratory, School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157000; 3Department of Orthopedic Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China Received December 30, 2017; Accepted May 2, 2018 DOI: 10.3892/mmr.2018.9133 Abstract. Aseptic loosening and menopause-induced osteo- protein ratio OPG/RANKL, whereas ALN exhibited the porosis are caused by an imbalance between bone formation opposite effect. Furthermore, SR and ALN suppressed tumor and osteolysis. With an aging population, the probability of necrosis factor-α and interleukin-1β production, with SR simultaneous occurrence of such conditions in an elderly exerting a more marked effect. The present results demon- individual is increasing. Strontium ranelate (SR) is an strate that SR and ALN may stimulate bone formation and anti-osteoporosis drug that promotes bone formation and inhibit bone resorption in the ovariectomized mouse model inhibits osteolysis. The present study compared the effects of wear particle-mediated osteolysis, with SR demonstrating of SR with those of the traditional anti-osteoporosis drug better effects compared with ALN. alendronate (ALN) using an ovariectomized mouse model of osteolysis. The degree of firmness of the prosthesis and Introduction the surrounding tissue was examined, a micro-CT scan of the prosthesis and the surrounding tissue was performed, and the Wear particle-induced aseptic loosening has become one of levels of inflammatory and osteogenic and osteoclast factors the most important causes of arthroplasty failure, and results were examined. It was observed that treatment with SR and in high healthcare costs and complex revision procedures (1). ALN improved the bond between the prosthesis and the Wear particles are the debris from joint replacement implants surrounding bone tissue by reducing the degree of osteolysis, that may induce inflammation and bone resorption at the thus improving the quality of bone around the prosthesis. interface between the surface of a prosthesis and its adjoining SR increased the secretion of osteocalcin, runt-related tran- bone (2). These debris particles stimulate the secretion of scription factor 2 and osteoprotegerin (OPG). It additionally various proinflammatory cytokines, including tumor necrosis decreased the expression of the receptor activator of nuclear factor-α (TNF-α), interleukin (IL)-1 and IL-6 (3). Studies factor-κB ligand (RANKL) and consequently increased the have demonstrated that TNF-α, receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) and IL-8 are present in the serum of patients with aseptic loosening (4,5). At the bone-implant interface, activated macrophages, multinucleated Correspondence to: Dr Qunhua Jin, Department of Orthopedic giant cells, osteoclasts and fibroblasts are detected on the Surgery, General Hospital of Ningxia Medical University, interface membranes (6). Macrophage recruitment and 804 Shengli Street, Yinchuan, Ningxia Hui Autonomous activation increase the concentration of local pro‑inflammatory Region 750004, P.R. China factors and ultimately lead to inflammation-induced E-mail: [email protected] osteoclastogenesis (4). Regulation of the release of osteoblast cytokines, including osteoprotegerin (OPG) and RANKL, is * Contributed equally another mechanism of wear particle-induced osteolysis (7). Therefore, the OPG-RANKL-RANK axis has an important Abbreviations: ALN, alendronate; BV, bone volume; BS/BV, bone role in the pathophysiological process of aseptic loosening (8). surface/bone volume ratio; BV/TV, bone volume fraction; OPG, RANK is primarily expressed on the plasma membrane of osteoprotegerin; RANKL, receptor activator of nuclear factor-κB κ ligand; SR, strontium ranelate; Tb.N, trabecular number; Tb.Th, osteoclasts. RANKL activates the NF- B signaling pathway trabecular thickness and subsequently induces differentiation of osteoclasts and inhibits apoptosis by binding to its specific receptor, Key words: SR, ALN, aseptic loosening, ovariectomy, bone RANK (9). OPG, which is secreted by numerous cells, formation, bone resorption including osteoblasts and mesenchymal stem cells, is a soluble competitive decoy receptor for RANK and inhibits the NF-κB signaling pathway by decreasing the binding of RANKL to 1850 GENG et al: STRONTIUM RANELATE INHIBITS TITANIUM PARTICLE-INDUCED OSTEOLYSIS RANK (10). In other words, it inhibits the differentiation and Materials and methods activation of osteoclasts, and induces their apoptosis. In the regulation of bone metabolism, it is essential for the levels Wear particle preparation. Unmixed titanium particles of OPG and RANKL to be balanced. Therefore, osteolysis (Zimmer Biomet, Warsaw, IN, USA; ~5 µm) were used in the is one of the most intricate complications prosthetic joint present study. Prior to injection, the particles were rinsed in replacements and influences the long‑term functional recovery 70% ethanol for 48 h at room temperature, washed twice in of patients. phosphate-buffered saline, and subsequently autoclaved at The loss of estrogen is one of the physiological characteris- 180˚C for 6 h to remove any endotoxins. A commercial detec- tics of female menopause and mediates primary osteoporosis, tion kit (E-Toxate™; Sigma-Aldrich; Merck KGaA, Darmstadt, which is characterized by a reduction in bone density and Germany) was used to test whether the treated wear debris damage to bone structure (11). In the first few years of meno- contained endotoxins (27). pause, the rapid decline of estrogen levels in women leads to an increase in bone remodeling, which is manifested as Animals. In the present study, 40 female C57BL/6j mice increased bone formation and bone resorption. However, the (18 months-old; Experimental Animal Center of Ningxia original balance of bone metabolism later alters; bone resorp- Medical University, Yinchuan, China) were used, each tion surpasses bone formation, resulting in bone loss and weighing 26±2 g. All the mice were housed in mechanically eventually osteoporosis (12-14). Estrogen deficiency during ventilated cages (4‑5 mice per cage) and maintained at 25˚C menopause has a direct effect on the differentiation and activity constant temperature, constant pressure, and on a 12/12 h of osteoblasts and osteoclasts, and it additionally increases the light/dark cycle, with ad libitum access to water and food. secretion of inflammatory cytokines, which may increase the The experimental protocol was conducted in accordance activity of osteoclasts and reduce their apoptosis (15,16). With with the National Institutes of Health guidelines for the care the advancement of medical technology, numerous chronic and use of laboratory animals (28) and was approved by the diseases are effectively treated. Humans have a longer lifespan, Ethics Committee of the General Hospital of Ningxia Medical however, consequently face the complications of osteopo- University (Yinchuan, China). rosis and possible total joint replacement due to aging (17). A previous study demonstrated that the cortical bone of Experimental groups and treatments. The mice were randomly patients with osteoporosis is markedly thinner compared subdivided into four groups (10 mice per group): Sham group; with a healthy individual, particularly in the medial, lateral control group; SR group; and ALN group. Ovariectomy or and posterior parts of the bone (18). An osteoporotic bone sham surgery was performed on the mice at 18 months of age. (particularly the medial and posterior parts) lacks a complete At 3 months after the induction of osteoporosis, all the mice structure and the intramedullary canal is wider compared were subjected to joint prosthesis implantation into the right with a normal bone. These factors will slow bone growth lower extremity under general anesthesia induced by intra- in the direction of the implant following joint replacement, peritoneal injection of Nembutal (0.6% pentobarbital sodium, thereby increasing the risk of aseptic loosening (19). In certain NeoBioscience Technology Co., Ltd., Shenzhen, China). patients with severe osteoporosis, the surgical treatment must All the experimental methods were conducted as described be postponed until enough bone mass has been restored (20). previously (29). In an aseptic environment, the tibial plateau Diphosphate is a drug that controls osteoporosis and inhibits was exposed through the medial parapatellar approach, and osteoclast-mediated bone resorption (21). A previous study one titanium pin was implanted gently into the proximal tibia demonstrated that bisphosphonates may increase bone mass so that the head of the pin was kept in the same plane as the in patients with osteoporosis and delay the development of surface of the tibial plateau. The cut was washed with normal the disease (22). Another study revealed that bisphosphonates saline containing 100 U/ml penicillin and 100 µg/ml strepto- reduce bone resorption at the bone-implant interface and may mycin, and each layer was closed separately with absorbable prevent aseptic loosening following an arthroplasty (23). string
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