Fetuin-A in post-traumatic osteoarthritis: at the crossroad between joint and muscle degeneration

项目摘要 创伤造成的关节损伤可发展为创伤后骨关节炎(PTOA)，目前尚无治愈方法。 肌肉位于关节附近，对吸收关节负荷至关重要。股四头肌无力是 在骨性关节炎患者中最早的发现，可先于临床骨性关节炎，并与疼痛增加相关。然而，如何 肌肉无力与PTOA的关系尚不清楚。在确定可以影响这两个组织的OA治疗方法的努力中 为了减少关节退行性变和疼痛，确定对关节和肌肉起作用的新因素至关重要。在这方面， 胎球蛋白-A代表了理想的候选者。胎球蛋白-A是一种在肝脏合成的循环糖蛋白，具有 已被证明在损伤中具有抗炎作用，尽管其在关节炎中的作用仍不清楚。减少 血清胎球蛋白-A水平与更严重的放射学骨性关节炎和疼痛相关。胎球蛋白-A是一种 BMP信号的拮抗剂，调节骨代谢。因此，BMP的拮抗性损失通过减少 在骨性关节炎期间，胎球蛋白-A可能导致BMPs局部活性的失衡，导致更多的软骨细胞 甲状旁腺肥大和骨骼损伤。一项临床研究表明，从晚期骨性关节炎收集的硬化性成骨细胞 胎球蛋白-A的含量显著低于非硬化性；我们在小鼠PTOA模型中的初步数据 (内侧半月板失稳，DMM)显示OA软骨显示胎球蛋白-A起始水平急剧下降。 在早期阶段，在DMM小鼠中给予OA和全身性胎球蛋白-A可以减轻这种损害。重要的是，它 已经证明，胎球蛋白-A对BMP的拮抗作用在肌肉发育和动态平衡中也是至关重要的。我们的 DMM的数据显示，轻度和中度股四头肌的胎球蛋白-A蛋白水平都有所下降 此外，人类骨性关节炎肌肉中的初步数据显示， OA股四头肌与对照组比较。综上所述，这些研究表明胎球蛋白-A的减少可能起到了 在骨性关节炎及其相关疼痛中起关键作用，影响关节和肌肉组织。我们假设损失了 损伤后的胎球蛋白-A会导致软骨和骨骼损伤，以及肌肉损伤，最终导致 PTOA和疼痛。通过使用体内DMM小鼠创伤后骨性关节炎模型，我们建议确定 胎球蛋白-A通过BMP信号起作用，是一种保护软骨、骨骼和肌肉的治疗因素 在骨性关节炎期间保持正直，减轻疼痛。具体地说，我们将确定胎球蛋白-A在 DMM通过系统过表达胎球蛋白-A以及局部注射胎球蛋白-A诱导骨性关节炎 关节上使用微粒进行持续缓释；我们将跟踪软骨/骨损伤，炎症 以及PTOA不同阶段的痛觉(Aim1)。我们通过测量获得的新的体内初步数据 腓肠肌比目鱼肌显示，在DMM期间，肌肉力量从中度骨性关节炎开始下降 因此，在另一组实验中，我们将使用体内和体外对肌肉功能的分析， 研究全身注射胎球蛋白-A或关节内注射胎球蛋白-A如何影响骨关节炎进展期间的肌力(AIM2)。 我们还将测定关节和肌肉组织中胎球蛋白-A下游通路的变化。

PROJECT ABSTRACT Joint damage caused by trauma can proceed to post-traumatic osteoarthritis (PTOA), with no cure available. Muscles are situated in joint proximity and are critical to absorb joint loads. Quadriceps weakness is one of the earliest findings in OA patients, can precede clinical OA, and is associated with increased pain. However, how muscle weakness relates to PTOA is unclear. In the efforts to identify OA treatments that can impact both tissue degeneration and pain, it is critical to identify novel factors acting on both joints and muscles. In this respect, fetuin-A represents an ideal candidate. Fetuin-A is a circulating glycoprotein synthesized in the liver and has been shown to have an anti-inflammatory role in injury, although its role in arthritis is still not clear. Decreased fetuin-A serum levels were shown to be correlated with more severe radiographic OA and pain. Fetuin-A is an antagonist of BMP signaling and regulates bone metabolism. Therefore, loss of BMP antagonism by reduced fetuin-A during OA, could allow for an unbalance in the local activity of BMPs, resulting in more chondrocyte hyperthrophy, and bone damage. A clinical study showed that sclerotic osteoblasts collected from late stage OA have significantly lower amounts of fetuin-A than non-sclerotic; our preliminary data in a mouse PTOA model (destabilization of medial meniscus, DMM) show that OA cartilage shows a drastic decrease of fetuin-A starting at the early stage OA and systemic fetuin-A administration in DMM mice reduced such damage. Importantly, it has been shown that BMP antagonism by Fetuin-A is also critical in muscle development and homeostasis. Our data in the DMM show that fetuin-A protein levels in quadriceps were decreased at both the mild and moderate OA stages; in addition, preliminary data in human OA muscles showed that protein fetuin-A levels were lower in OA quadriceps compared to controls. Taken together, these studies suggest that reduction in fetuin-A might play a key role in OA and its associated pain, affecting both joint and muscle tissues. We hypothesize that loss of fetuin-A after injury leads to cartilage and bone damage, along with muscle impairment, ultimately leading to PTOA and pain. By using the in-vivo DMM mouse post-traumatic OA model, we propose to determine whether fetuin-A, acting through BMP signaling, represents a therapeutic factor to preserve cartilage, bone and muscle integrity during OA and alleviate pain. Specifically, we will determine the fetuin-A protective effect during the DMM-induced OA by systemically overexpressing fetuin-A, as well as by local administration of fetuin-A intra- articularly using micro-particles for sustained slow release; we will follow cartilage/bone damage, inflammation and pain perception at different stages of PTOA (Aim1). Our new in-vivo preliminary data obtained by measuring the gastrocnemius soleus showed that muscle strength during DMM decreases starting at the moderate OA stage; therefore, in a separate set of experiments, we will use in-vivo and ex-vivo analyses of muscle function, to examine how systemic or intra-articular injected fetuin-A affect muscle strength during OA progression (Aim2). We will also determine fetuin-A downstream pathway changes in joint and muscle tissues.