Siebelt M, Waarsing J H, Groen H C, Müller C, Koelewijn S J, de Blois E, Verhaar J A N, de Jong M, Weinans H
Department of Orthopaedics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Department of Orthopaedics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Bone. 2014 Sep;66:163-70. doi: 10.1016/j.bone.2014.06.009. Epub 2014 Jun 13.
Osteoarthritis (OA) is a non-rheumatoid joint disease characterized by progressive degeneration of extra-cellular cartilage matrix (ECM), enhanced subchondral bone remodeling, osteophyte formation and synovial thickening. Alendronate (ALN) is a potent inhibitor of osteoclastic bone resorption and results in reduced bone remodeling. This study investigated the effects of pre-emptive use of ALN on OA related osteoclastic subchondral bone resorption in an in vivo rat model for severe OA. Using multi-modality imaging we measured effects of ALN treatment within cartilage and synovium. Severe osteoarthritis was induced in left rat knees using papain injections in combination with a moderate running protocol. Twenty rats were treated with subcutaneous ALN injections and compared to twenty untreated controls. Animals were longitudinally monitored for 12weeks with in vivo μCT to measure subchondral bone changes and SPECT/CT to determine synovial macrophage activation using a folate-based radiotracer. Articular cartilage was analyzed at 6 and 12weeks with ex vivo contrast enhanced μCT and histology to measure sulfated-glycosaminoglycan (sGAG) content and cartilage thickness. ALN treatment successfully inhibited subchondral bone remodeling. As a result we found less subchondral plate porosity and reduced osteophytosis. ALN treatment did not reduce subchondral sclerosis. However, after the OA induction phase, ALN treatment protected cartilage ECM from degradation and reduced synovial macrophage activation. Surprisingly, ALN treatment also improved sGAG content of tibia cartilage in healthy joints. Our data was consistent with the hypothesis that osteoclastic bone resorption might play an important role in OA and may be a driving force for progression of the disease. However, our study suggest that this effect might not solely be effects on osteoclastic activity, since ALN treatment also influenced macrophage functioning. Additionally, ALN treatment and physical activity exercised a positive effect in healthy control joints, which increased cartilage sGAG content. More research on this topic might lead to novel insights as to improve cartilage quality.
骨关节炎（OA）是一种非类风湿性关节疾病，其特征在于细胞外软骨基质（ECM）的进行性退化、软骨下骨重塑增强、骨赘形成和滑膜增厚。阿仑膦酸盐（ALN）是一种有效的破骨细胞性骨吸收抑制剂，可减少骨重塑。本研究在重度OA的体内大鼠模型中研究了预先使用ALN对OA相关破骨性软骨下骨吸收的影响。使用多模态成像，我们测量了ALN治疗对软骨和滑膜的影响。通过木瓜蛋白酶注射联合适度跑步方案在大鼠左膝诱导重度骨关节炎。20只大鼠接受皮下ALN注射，并与20只未治疗的对照进行比较。使用体内μCT纵向监测动物12周，以测量软骨下骨变化，并使用基于叶酸的放射性示踪剂通过SPECT/CT确定滑膜巨噬细胞活化。在6周和12周时，通过离体对比增强μCT和组织学分析关节软骨，以测量硫酸化糖胺聚糖（sGAG）含量和软骨厚度。ALN治疗成功抑制了软骨下骨重塑。结果，我们发现软骨下板孔隙率降低，骨赘形成减少。ALN治疗并未减轻软骨下硬化。然而，在OA诱导期后，ALN治疗可保护软骨ECM免于降解，并减少滑膜巨噬细胞活化。令人惊讶的是，ALN治疗还改善了健康关节中胫骨软骨的sGAG含量。我们的数据与破骨性骨吸收可能在OA中起重要作用且可能是疾病进展驱动力的假设一致。然而，我们的研究表明，这种作用可能不仅仅是对破骨细胞活性的影响，因为ALN治疗也影响巨噬细胞功能。此外，ALN治疗和体育活动对健康对照关节有积极作用，可增加软骨sGAG含量。对该主题的更多研究可能会带来关于改善软骨质量的新见解。
