退化性關節炎是很常見的疾病。在關節尚未產生嚴重變形前，可嘗試關節內注射玻尿酸或濃厚血小板生長因子。若已產生嚴重變形，就必須接受全人工膝關節置換手術。然而全人工膝關節置換手術會有感染，術後骨折等後遺症，一旦發生對病人是莫大的折磨。也因此，關節保存的治療(joint preservation therapy)是對病人福祉最高的選項。遇到關節變形嚴重的病患，怎樣使用更精準、對組織破壞更少的關節置換手術方式，則是重要的課題。
Transforming growth factor-b1 (TGF-b1) 是ㄧ個具有抗發炎與免疫調節功能的分子，在退化性關節炎的致病機轉中扮演重要的角色，也跟手術引發之發炎反應(surgically induced inflammation)有關係。我們試圖全方位地探討，TGF-b1從關節炎致病機轉的基礎研究層面，到反映關節置換手術引發之發炎反應的臨床應用層面的多面向角色。
近來的研究發現，看似配角的滑膜細胞在退化性關節炎的致病機轉中扮演重要的角色。TGF-b1已知會造成滑膜纖維化，也知道具有抗發炎效果，但鮮少有研究去探討TGF-b1對於滑膜細胞的抗發炎特性。Heme oxygenase 1 (HO-1) 是ㄧ個可誘導性的抗發炎與抗氧化的分子。儘管TGF-b1與HO-1都具有抗發炎特性，目前卻無文獻討論兩者間的關係。我們的研究發現，TGF-b1 能藉由促進PLC-g/PKC-a的活性與抑制miRNA-519b的表現量，最終造成HO-1表現量上升。這些結果有助於對退化性關節炎的致病機轉有更深入的了解。
先前的研究指出，TGF-b1 跟手術引發之發炎反應(surgically induced inflammation)有所關係。我們因此推測，關節置換手術中對骨髓的破壞越少，術後TGF-b1的濃度越低。我們的研究發現，跟接受傳統術式的病人相比，接受不破壞骨髓腔的電腦導航技術的病人，術後24小時與72小時血清中發炎介質濃度(IL-6, IL-10, TNF-a)的上升幅度較為輕微，TGF-b1術後血清濃度甚至比術前低。接受導航術式的病人hemovac引流液中IL-10的濃度也比較低。先前的研究指出，手術後血中發炎介質的濃度較高，發生併發症與死亡的機會也較高。我們因此建議，若病人需要接受人工膝關節置換手術，應避免對骨髓腔的破壞。
我試圖以TGF-b1銜接我日後研究工作的兩大面向─藉由更深入研究關節炎的致病機轉，來研發關節內注射的藥物來延緩甚至避免關節退化的進程；針對不得已需要接受關節置換的病人，讓手術更精準、破壞更少。我希望藉由我的努力，能讓更多病友免於關節炎之苦。
Osteoarthritis (OA) is a highly prevalent disease. Treatmentscomprise intra-articular injection with hyaluronic acid and platelet rich plasma for not severely deformed and total knee arthroplasty (TKA) for severely deformed knees. Despite the high satisfactory rates, periprosthetic joint infection and periprosthetic fracture after TKA are devastating and can lead to mortality. Joint-preserving treatment for degenerative osteoarthritis is the ultimate goal. As for the patients who are inevitable for the arthroplastic surgeries, accuracy and the avoidance of invasiveness are the main issues.
Transforming growth factor-b1 (TGF-b1) is an anti-inflammatory cytokine. TGF-b1 not only plays a pivotal role in the pathogenesis of osteoarthritis but also correlates with the severity of surgically induced inflammation. We thus tried to investigate the comprehensive functions of TGF-b1 from the basic to the clinical points of view.
The interactions between synovial tissues and the OA-related cytokines actively participate in OA pathogenesis. TGF-b1 has been known to exert the fibrogenic effects on the synovial cells and exert the anti-inflammatory effects on various cell types. However, the anti-inflammatory effects of TGF-b1 on the synovial cells have not been discussed. Heme oxygenase 1 (HO-1) is an inducible anti-inflammatory enzyme. Despite the similar anti-inflammatory profile and their involvement in OA pathogenesis, no studies have explored the association between TGF-1 and HO-1.We showed that TGF-b1 stimulated the expression of HO-1 via activating the PLC-g/PKC-a pathway and suppressing the downstream expression of miRNA-519b. These results may shed light on the pathogenesis and treatment of OA.
TGF-b1 also reflects the severity of surgically-induced inflammation. We thus hypothesize that in the TKA surgeries, the milder the extent of bone marrow violation, the lower the postoperative serum TGF-b1 level. We showed that the patients receiving navigation TKAs will have milder postoperative increment of serum inflammatory markers 24 and 72 hours after TKAs, including IL-6, IL-10, TNF-a. The postoperative level of TGF-b1 after navigation TKA was even lower than the preoperative baseline .The concentration of IL-10 in hemovac drainage is also lower after navigation technique. All the inflammatory markers are predictive of major mobility and mortality for patients undergoing lower limb surgeries. Based upon our results, we suggest that the violation of bone marrow during TKA surgeries should be minimized.
I would like to incorporate the two major domains of my future work under the linkage of TGF-b1. On the one hand, I try to unravel the pathogensis of OA in order to invent the novel joint-preserving therapy for OA. On the other hand, I would like to refine the existing arthroplastic surgeries to minimize the invasiveness. I hope that my endeavor would make more patients free from the threat of degenerative osteoarthritis and lead a happy life.
