摘要:退化性關節炎(osteoarthritis)又稱骨關節炎’是一種漸進退化性的關節疾病’主要 好發於老年人;其症狀主要包含關節發炎、疼痛、腫脹及僵硬。退化性關節炎嚴 重影響許多組成關節的部分,包括關節周圍的骨頭、滑膜關節内襯、以及相鄰支 撐的結締組織。當滑膜組織受到免疫細胞所分泌之細胞激素刺激後,會促進發炎 反應、軟骨退化以及血管新生的進行。目前已知有許多危險因子都和退化性關節 炎的病程進展有關,包含了關節的不穩定以及排列不整、肥胖、年齡的增加、關 節内有結晶的沉積、肌肉無力以及周圍神經病變等,尤以老年和肥胖被認為是退 化性關節炎的兩個主要危險因子。在老化過程中,體内形成糖化終產物(advanced glycation end products, AGEs)的量會明顯增加且被堆積起來。AGEs的堆積已被證 實與糖尿病併發症、衰老和年齡相關性疾病如退化性關節炎有關;另外,也有研 究指出糖尿病病患血糖濃度較高的狀況下,AGEs的形成與堆積會大量增加。然 而,目前對於老年或糖尿病相關骨關節炎之分子機制並不清楚,且AGEs和高血 糖在人類軟骨及滑膜細胞發炎反應中所扮演的角色也仍尚待釐清。因此,本計晝 主要目的在於探討老年及糖尿病狀態下AGEs和高血糖在軟骨及滑膜細胞發炎反 應中所扮演的角色,以及找尋將來可以用於臨床治療退化性關節炎的方向。由本 計晝預實驗結果顯示,AGEs和高血糖狀態會刺激軟骨及滑膜細胞產生發炎反應; 而AGEs的作用需經由其受體(RAGE)來引發發炎反應。因此在此三年計晝中: 第一年計晝將以細胞模式實驗為主,以培養的人類關節軟骨細胞和滑膜細胞、骨 髓前驅細胞及造骨細胞,更深入探討AGEs和高血糖造成人類軟骨細胞及滑膜細 胞發炎反應的相關分子機制,以及在軟骨細胞、滑膜細胞和骨路細胞(造骨細胞 和破骨細胞生成或活性)間相互作用之角色及可能之影響;第二年,本計晝將以 動物模式實驗為主,探討AGEs在老年正常小鼠或餵食高單位AGEs飼料之年輕 成年小鼠關節發炎反應中所扮演的角色及相關之細胞分子機制;第三年,本計晝 將以動物模式實驗為主,探討高血糖及AGEs在以streptozotocin誘導之第一型糖 尿病小鼠以及db/db第二型糖尿病小鼠關節發炎反應中所扮演的角色及相關之細 胞分子機制。另外,目前針對於退化性關節炎的治療方式主要採取保守的物理性 治療,或者是給予非類固醇消炎止痛藥物進行消炎止痛,然而此類藥物治療方式 往往容易引起不必要之副作用。因此,在此三年計晝中,我們也將探討及比較藥 物 metformin (口服降血糖藥)、pioglitazone (PPARy 致效劑)、alagebrium (AGEs 聯結物阻斷劑)和aminoguanidine (AGEs生成抑制劑)是否能減緩由AGEs或高血 糖相關骨關節細胞發炎反應的產生。藉由本計晝詳細探討AGEs和高血糖在老年 及糖尿病相關骨關節炎中的致病機轉以及所扮演的角色,期望將來能夠提供用於 臨床對於退化性關節炎治療上不同的新選擇。
Abstract: Osteoarthritis (OA) is a progressive degenerative joint disease with signs and symptoms of inflammation, including joint pain, swelling, and stiffness in older adults. In response to macrophage-derived proinflammatory cytokines, synovial fibroblasts produce chemokines that promote inflammation, cartilage degradation, and neovascularization. Ageing and obesity have been suggested to be the two main risk factors for OA. The aging process has been ultimately associated with elevated advanced glycation end products (AGEs) presence contributing to chronic diabetic complications, senescence, and age-related diseases such as OA. On the other hand, the increase in the occurrence of AGEs formation by hyperglycemia has been illustrated in diabetic patients. Glucose is necessary for articular chondrocytes to maintain cell homeostasis, and synthesize cartilage matrix molecules. However, hyperglycemia-induced deleterious effects on cartilage mediated by AGEs lead to numerous events such as inflammation, matrix stiffness and chondrocytes dysfunction. Therefore, the role of AGEs and hyperglycemia in inflammatory responses of synoviocytes and chondrocytes still need to be clarified. In our preliminary study, we investigated whether AGEs and high concentration of glucose would trigger inflammatory responses in human chondrocytes and synoviocytes. We also evaluated the role of receptor of AGEs (RAGE) in the inflammatory responses. Our data showed that AGEs could induce expression of COX-2 and production of PEG2 in human chondrocytes and synoviocytes. Moreover, RAGE is involved in AGEs-induced increase of inflammatory responses. This is a three-year project. First, we will further investigate the inflammatory effects and possible mechanisms of AGEs and high-glucose on the progression of inflammatory arthritis. We will also investigate the interactions between AGEs and receptor of AGEs (RAGE). Human chondrocytes, synoviocytes, bone marrow stromal cells, and osteoblasts will be used to test the effects of AGEs and high-glucose on these cells alone or interaction among these cells (co-culture). The cell growth, inflammatory responses, bone cell differentiation and related cellular and molecular signalings will be determined. In the second year, the aging mice and high-AGEs diets-fed young-adult mice will be used to investigate the role of AGEs in OA and their related molecular mechanisms. In the third year, db/db diabetic mice (type-2 diabetic model) and streptozotocin-induced diabetic mice (type-1 diabetic model) will be used to study the role of hyperglycemia and AGEs in OA and their related molecular mechanisms.. On the other hand, to date, pharmacological treatments of OA are focused on the alleviation of pain and inflammation by using nonsteroidal anti-inflammatory drugs (NSAIDs) or other agents; however, the disease remains a challenge for treatment due to its multiple risk factors. Therefore, alternative managements are becoming popular for their clinical efficacy with minimal side effects. In this project, we will also evaluate the therapeutic potential of metformin (oral hypoglycemic drug), pioglitazone (PPARy agonist), alagebrium (AGEs cross-link breaker), and aminoguanidine (AGEs formation inhibitor) on OA. Taken together, this project tries to reveal the roles and detailed mechanisms of AGEs and hyperglycemia in aging and diabetes-related inflammatory responses of OA and will provide possible therapeutic strategy of OA in the future.