Bhattarai Govinda, Kook Sung-Ho, Kim Jae-Hwan, Poudel Sher Bahadur, Lim Shin-Saeng, Seo Young-Kwon, Lee Jeong-Chae
Cluster for Craniofacial Development & Regeneration Research, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju 54896, South Korea.
Cluster for Craniofacial Development & Regeneration Research, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju 54896, South Korea; Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Chonbuk National University, Jeonju 54896, South Korea.
Bone. 2016 Nov;92:168-179. doi: 10.1016/j.bone.2016.09.002. Epub 2016 Sep 6.
COMP-Ang1, a chimera of angiopoietin-1 (Ang1) and a short coiled-coil domain of cartilage oligomeric matrix protein (COMP), is under consideration as a therapeutic agent enhancing tissue regeneration with increased angiogenesis. However, the effect of COMP-Ang1 on periodontitic tissue damages and the related mechanisms are not yet investigated. We initially explored whether a local delivery of COMP-Ang1 protects lipopolysaccharide (LPS)/ligature-induced periodontal destruction in rats. As the results, μCT and histological analyses revealed that COMP-Ang1 inhibits LPS-mediated degradation of periodontium. COMP-Ang1 also suppressed osteoclast number and the expression of osteoclast-specific and inflammation-related molecules in the inflamed region of periodontitis rats. Implanting a COMP-Ang1-impregnated scaffold into critical-sized mandible bone defects enhanced the amount of bone in the defects with increased expression of bone-specific markers. The addition of COMP-Ang1 prevented significantly osteoclast differentiation and activation in LPS-stimulated RAW264.7 macrophages and inhibited the phosphorylation of c-Jun, mitogen-activated protein kinases, and cAMP response element-binding protein in the cells. On contrary, COMP-Ang1 increased the level of phosphatidylinositol 3-kinase (PI3K) in LPS-exposed macrophages and a pharmacological PI3K inhibitor diminished the anti-osteoclastogenic effect of COMP-Ang1. Similarly, COMP-Ang1 blocked the expression of inflammation-related molecules in LPS-stimulated human periodontal ligament fibroblasts (hPLFs). Further, the COMP-Ang1 enhanced differentiation of hPLFs into osteoblasts by stimulating the expression of bone-specific markers, Tie2, and activator protein-1 subfamily. Collectively, our findings may support the therapeutic potentials of COMP-Ang1 in preventing inflammatory periodontal damages and in stimulating new bone growth.
COMP-Ang1是血管生成素-1（Ang1）与软骨寡聚基质蛋白（COMP）的短卷曲螺旋结构域的嵌合体，正被考虑作为一种通过增加血管生成来促进组织再生的治疗剂。然而，COMP-Ang1对牙周组织损伤的影响及其相关机制尚未得到研究。我们首先探究了局部递送COMP-Ang1是否能保护大鼠免受脂多糖（LPS）/结扎诱导的牙周破坏。结果显示，μCT和组织学分析表明COMP-Ang1可抑制LPS介导的牙周组织降解。COMP-Ang1还可抑制牙周炎大鼠炎症区域破骨细胞数量以及破骨细胞特异性和炎症相关分子的表达。将负载COMP-Ang1的支架植入临界大小的下颌骨骨缺损处，可增加缺损部位的骨量，并提高骨特异性标志物的表达。添加COMP-Ang1可显著抑制LPS刺激的RAW264.7巨噬细胞中的破骨细胞分化和激活，并抑制细胞中c-Jun、丝裂原活化蛋白激酶和cAMP反应元件结合蛋白的磷酸化。相反，COMP-Ang1可增加LPS刺激的巨噬细胞中磷脂酰肌醇3激酶（PI3K）的水平，而一种药理学PI3K抑制剂可减弱COMP-Ang1的抗破骨细胞生成作用。同样，COMP-Ang1可阻断LPS刺激的人牙周膜成纤维细胞（hPLF）中炎症相关分子的表达。此外，COMP-Ang1通过刺激骨特异性标志物、Tie2和激活蛋白-1亚家族的表达，增强hPLF向成骨细胞的分化。总的来说，我们的研究结果可能支持COMP-Ang1在预防炎症性牙周损伤和刺激新骨生长方面的治疗潜力。
