Combined Stem Cell and Rehabilitation Therapies for Osteoarthritis

描述：骨关节炎(OA)是一种使关节衰弱的疾病。关节炎是最流行的第三大疾病 退伍军人群体中的健康问题影响到43%的退伍军人系统用户和退伍军人的可能性增加约36% 与普通人群相比，易受骨质疏松症影响。这项提案将利用临床前模型 并测试再生干细胞疗法与康复相结合的疗效 养生法。拟议研究的总体目标是检查软骨退变的进展情况。 治疗前后对比负荷条件下功能能力的变化 骨髓间充质干细胞使用成熟的损伤/手术诱导的大鼠膝关节骨性关节炎模型的好处。我们的整体 假说是，虽然关节负荷降低仍不利于软骨健康，但关节负荷升高 相反，将增强骨髓间充质干细胞在减轻创伤性膝关节损伤后PTOA方面的治疗效果。 研究计划：为了实现上述目标，我们制定了两个目标：目标1：{确定效果 通过非负重或跑步引起的软骨退行性变，关节运动学改变 内侧半月板横断(MMT)手术后大鼠的运动和自主活动程度。目标 2：检查改变的膝关节负荷(通过非负重或跑步)如何影响MSC的疗效 大鼠软骨退变、运动时关节运动学及自主活动程度的治疗 在MMT之后。 方法：采用MMT诱导的大鼠骨性关节炎模型。同种异体间充质干细胞或生理盐水(对照) 术后一天通过关节内注射来评估对骨性关节炎发病的影响(目标1)。 然后将两个注射组的大鼠随机分配到以下3种负荷条件：1)常规 负重，2)后肢悬吊不负重，3)每天在跑步机上跑步。老鼠将接受测试，并 在伤后8周处死动物，评价其三维显微结构和成分的变化。 使用我们之前开发的EPIC-µCT对膝关节软骨进行扫描，并经组织学验证。评估 分别于术前、术后2周、4周、6周、8周对大鼠进行功能评定。在每个时间 点，我们将通过量化跑步的量(时间和距离)来评估自愿活动的水平 安装在笼子内的轮子。我们将量化3D肢体运动学(即臀部、膝盖和脚踝角度) 在跑步机运动过程中，使用高速X射线运动分析系统。 我们预计拟议的研究将导致对再生康复方案的新见解 患有骨性关节炎的退伍军人，将通过出版物和我们的临床顾问进行沟通，以影响 军人和退伍军人关心。

Description: Osteoarthritis (OA) is a debilitating condition of articular joints. Arthritis is the 3rd most prevalent health problem in the Veterans population affecting 43% of VA system users and veterans are ~36% more likely to be affected by OA as compared to the general population. This proposal will utilize preclinical models of osteoarthritis and test the efficacy of regenerative stem cell therapies in combination with rehabilitation regimens. The overall objective of the proposed study is to examine the progression of cartilage degeneration and changes in functional capacities under contrasting loading conditions with and without the therapeutic benefits of MSCs using a well-established injury/surgery induced knee OA model in rats. Our overall hypothesis is that while reduced joint loading will remain detrimental to cartilage health, an elevated joint load will instead enhance the therapeutic effects of MSCs on attenuating PTOA following traumatic knee injuries. Research Plan: To address the above objective we have developed two aims: Aim 1: {To establish the effects of altered knee loading via non-weight bearing or running on cartilage degeneration, joint kinematics during locomotion, and degree of voluntary activity in rats following a medial meniscal transection (MMT) surgery. Aim 2: To examine how altered knee loading (via non-weight bearing or running) influences the efficacy of MSC treatment on cartilage degeneration, joint kinematics during locomotion, and degree of voluntary activity in rats following MMT.} Methods: The rat MMT-induced OA model will be used for this study. Allogeneic MSCs or saline (control) will be administered via intra-articular injection one day post-surgery to assess the effects on the onset of OA (Aim 1). Rats in both injection groups will then be randomly assigned to the following 3 loading conditions: 1) regular loading, 2) non-weight bearing via hind limb suspension, and 3) daily treadmill running. Rats will be tested and sacrificed at the end of the 8th week post-injury to assess the changes in 3D microstructure and composition in the knee articular cartilage using our previously developed EPIC-µCT and validated with histology. To assess functional capacities rats will be evaluated at pre-surgery and 2, 4, 6, and 8 weeks post-surgery. At each time point, we will assess the level of voluntary activity by quantifying the amount (time and distance) of running on a wheel mounted inside the cage. We will quantify 3D lower limb kinematics (i.e., hip, knee, and ankle angles) during treadmill locomotion using a high-speed X-ray motion analysis system. We anticipate the proposed research will result in new insights on regenerative rehabilitation protocols for veterans with OA and will be communicated through publications and our clinical consultants in order to impact military and Veterans care.