Senescence of Pre-Osteoclasts in Non-Traumatic OA

摘要/摘要 骨性关节炎是最常见的与年龄相关的慢性关节疾病。虽然直接关节损伤和 过度的机械过载被认为是导致骨性关节炎发展的重要因素，只有 大约12%的症状性骨性关节炎的患病率可归因于髋关节创伤后骨性关节炎， 膝盖或脚踝。衰老被认为是骨性关节炎最重要的危险因素，而代谢表型 成为参加临床研究的患者中第二常见的骨性关节炎亚型。最近，它已经 人们已经认识到，细胞衰老是创伤后骨性关节炎进展的关键驱动因素。然而， 衰老细胞(SNC)是否以及如何参与非创伤性骨性关节炎的发展仍然很少。 明白了。在我们的初步研究中，我们在两者的关节软骨下骨髓中发现了积聚的SNCs 自发衰老的骨关节炎小鼠和STR/Ort小鼠，一种与代谢失调相关的自发性骨关节炎小鼠。 创伤后骨性关节炎小鼠的软骨下骨髓中未检测到SNCs的增加。因此， 软骨下骨髓细胞衰老可能是非创伤性骨性关节炎的一种独特特征 与创伤后骨性关节炎不同。此外，我们发现近80%的SNCs是骨髓。 破骨前细胞(前OC)。与年轻小鼠相比，从老年小鼠分离的前OCS基因表达增加 常见的衰老相关分泌表型因子(SASP)和更高的表达 血管生成因子PDGF-BB，一种强大的血管生成因子。已知软骨下骨量增加 血管生成是骨性关节炎发生发展的主要因素。因此，细胞分泌过量的PDGF-BB 软骨下骨髓SNCs可能参与了软骨下骨血管的异常生成。我们的中央 假说是衰老的前OCS通过过度分泌诱导异常的软骨下骨血管生成 PDGF-BB，导致骨关节炎相关关节结构损伤。这一假设将通过以下具体情况进行检验 目标。在目标1中，我们将追踪滑膜组织、关节软骨和软骨下骨组织中的SNCs。 通过检测自发衰老的OA小鼠和STR/Ort小鼠的关节细胞衰老标志物。我们会 追踪OC谱系不同阶段的SNCs，并验证骨髓细胞的SASP表型 在老鼠身上。目标2将检查OCS前衍生的PDGF-BB在年龄相关患者中的必要性和充分性 软骨下骨血管生成与骨性关节炎的发生。在目标3中，我们将首先定义细胞的贡献 选择性清除骨性关节炎小鼠软骨下骨血管生成和成骨细胞的衰老。 然后，我们将使用遗传学和药理学方法来测试是否阻止卵巢癌前期衰老 延缓骨性关节炎的进展。

SUMMARY/ABSTRACT Osteoarthritis (OA) is the most prevalent age-associated chronic joint disease. Although direct joint injury and excessive mechanical overloading are considered as important contributors to the development of OA, only approximately 12% of the overall prevalence of symptomatic OA is attributable to posttraumatic OA of the hip, knee, or ankle. Aging is recognized as the most important risk factor for OA, and the metabolic phenotype becomes the second most frequent subtype of OA among patients enrolled in clinical studies. Recently, it has been recognized that cellular senescence is a key driver for the progression of post-traumatic OA. However, whether and how senescent cells (SnCs) are involved in the development of non-traumatic OA remain poorly understood. In our preliminary study, we found accumulated SnCs at the joint subchondral bone marrow of both spontaneous aging OA mice and STR/Ort mice, a spontaneous OA mice associated with metabolic dysregulation. Increased SnCs were not detected in subchondral bone marrow of a post-traumatic OA mice. Therefore, subchondral bone marrow cell senescence may represent a unique feature of non-traumatic subtype of OA distinguishable from post-traumatic OA. Moreover, we identified that close to 80% of the SnCs are bone marrow Pre-osteoclast (Pre-OC). Pre-OCs isolated from old mice, relative to young mice, had increased expression of common senescence-associated secretory phenotype (SASP) factors and much higher expression of angiogenesis factor PDGF-BB, a potent angiogenesis factor. It is known that increased subchondral bone angiogenesis is a major contributor to the development of OA. Therefore, the excessive PDGF-BB secreted by subchondral bone marrow SnCs may contribute to aberrant subchondral bone angiogenesis. Our central hypothesis is that senescent Pre-OCs induce aberrant subchondral bone angiogenesis by secreting excessive PDGF-BB, leading to OA-related joint structural damage. The hypothesis will be tested by the following Specific Aims. In Aim 1, we will trace the SnCs in synovial tissue, articular cartilage, and subchondral bone tissue of the joints by detecting the cellular senescence markers in spontaneous aging OA mice and STR/Ort mice. We will also trace the SnCs at different stages of OC lineage and verify the SASP phenotype of the cells in bone marrow of the mice. Aim 2 will examine the necessity and sufficiency of Pre-OCs-derived PDGF-BB in age-associated subchondral bone angiogenesis and OA development. In Aim 3, we will first define the contribution of cellular senescence to subchondral bone angiogenesis and osteogenesis by selectively eliminating the SnCs in OA mice. We will then test if blockage of Pre-OC senescence using both genetic and pharmacologic approaches attenuates OA progression.