RESUMO
Currently, there are no medications available to treat aseptic loosening of orthopedic implants. Using osteoprotegerin fusion protein (OPG-Fc), we previously blocked instability-induced osteoclast differentiation and peri-prosthetic osteolysis. Wnt/ß-catenin signaling, which regulates OPG secretion from osteoblasts, also modulates the bone tissue response to mechanical loading. We hypothesized that activating Wnt/ß-catenin signaling by inhibiting glycogen synthase kinase-3ß (GSK-3ß) would reduce instability-induced bone loss through regulation of both osteoblast and osteoclast differentiation. We examined effects of GSK-3ß inhibition on regulation of RANKL and OPG in a rat model of mechanical instability-induced peri-implant osteolysis. The rats were treated daily with a GSK-3ß inhibitor, AR28 (20 mg/kg bw), for up to 5 days. Bone tissue and blood serum were assessed by qRT-PCR, immunohistochemistry, and ELISA on days 3 and 5, and by micro-CT on day 5. After 3 days of treatment with AR28, mRNA levels of ß-catenin, Runx2, Osterix, Col1α1, and ALP were increased leading to higher osteoblast numbers compared to vehicle-treated animals. BMP-2 and Wnt16 mRNA levels were downregulated by mechanical instability and this was rescued by GSK-3ß inhibition. Osteoclast numbers were decreased significantly after 3 days of GSK-3ß inhibition, which correlated with enhanced OPG mRNA expression. This was accompanied by decreased serum levels of TRAP5b on days 3 and 5. Treatment with AR28 upregulated osteoblast differentiation, while osteoclastogenesis was blunted, leading to increased bone mass by day 5. These data suggest that GSK-3ß inactivation suppresses osteolysis through regulating both osteoblast and osteoclast differentiation in a rat model of instability-induced osteolysis.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteólise/prevenção & controle , Falha de Prótese , Inibidores de Proteínas Quinases/farmacologia , Tíbia/efeitos dos fármacos , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Placas Ósseas , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Masculino , Osteoblastos/enzimologia , Osteoblastos/patologia , Osteoclastos/enzimologia , Osteoclastos/patologia , Osteólise/enzimologia , Osteólise/genética , Osteólise/patologia , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Implantação de Prótese/instrumentação , Ligante RANK/genética , Ligante RANK/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Fosfatase Ácida Resistente a Tartarato/sangue , Tíbia/enzimologia , Tíbia/patologia , Tíbia/cirurgia , Fatores de Tempo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética , beta Catenina/metabolismoRESUMO
BACKGROUND: The blood-conserving effect of intravenous (IV) tranexamic acid (TXA) is well-documented for total hip arthroplasty (THA) and total knee arthroplasty (TKA). However, the risk of thromboembolic (TE) events after routine use of TXA is unclear and the safety profile is debated. This retrospective study investigates patient characteristics, occurrences, and predictors of TE events after routine administration of IV TXA in THA and TKA. METHODS: Three thousand one hundred fifty-nine THA or TKA procedures performed from 2007-2013 at our institution were included. IV TXA, 1 g, was administered preoperatively if not contraindicated. Relevant patient characteristics and comorbidity information were extracted locally from the database. Data on TE events occurring within 90 days postoperatively came from The Danish National Patient Registry. Patient characteristics, comorbidities, and TE events were compared between TXA groups. A logistic regression model was used to evaluate predictors of TE events. RESULTS: Of 3159 procedures, 2766 (87.6%) received TXA (TXA+ group) preoperatively, whereas 393 (12.4%) did not (TXA- group). Mean age, distributions of gender, American Society of Anesthesiologists score, anesthesia method, duration of surgery, diagnosis, and survival status were all statistically significant different (P values <.05) between TXA groups. The studied comorbidities were all significantly different (TXA+ vs TXA- group; P values ≤.002). We found 31 (1.0%) TE events out of 3159 procedures, with no significant group difference in TE events (TXA+: 27 out of 2766 = 1.0%, TXA-: 4 out of 393 = 1.0%, P value = .55 for any event). For the TXA+ group, 0.5% suffered from deep venous thrombosis, 0.3% from acute myocardial infarction, and 0.2% from a pulmonary embolism. In the TXA+ group, higher age (odds ratio [OR] = 1.06, 95% confidence interval = 1.02-1.11, P = .005) and present cardiovascular disease (OR = 4.78, 95% confidence interval = 1.72-13.28, P = .003) were associated with an increased risk of TE events. CONCLUSION: The findings suggest that routine use of IV TXA for TKA and THA as safe with low occurrence of TE events, although a large prospective trial should confirm this.