CAN OSTEOCLAST BIOMARKERS DETECT EXCESSIVE SUBCHONDRAL BONE RESORPTION IN RACEHORSES?

赛马患有特定部位的灾难性骨折和关节退化。它们是由比赛和训练的过度重复性创伤引起的。这个问题是一个重要的经济和福利问题。这些创伤性应力性骨折通常发生在关节软骨（软骨下骨- SCB）下的致密骨，并可导致关节内骨折或创伤后骨关节炎。局灶性骨微损伤首先积累，然后吸收消化骨的破骨细胞来移除受损的骨。然而，它们会造成局部松解，从而进一步削弱骨骼并导致骨折。活性破骨细胞在这些部位停留约2周。及早发现这一问题，以防止其恶化，有时甚至造成灾难性后果，这一需求尚未得到满足。目前在临床上很难对马进行这样的检查，因为早期的损伤是显微镜下的，x光片无法检测到。***我的研究计划是对马关节的相关问题进行超过20年的调查，将集中在赛马骨骼中过度破骨细胞活性对骨折和关节退变的贡献这一重要主题上。我们之前的研究由NSERC资助，为我们目前的假设铺平了道路，即血液中的破骨细胞特异性产物反映了马体内的SCB吸收，并且可能证明作为早期检测过度SCB吸收的生物标志物（测试）的价值。生物标志物或生物标记物是疾病过程或对治疗反应的可测量指标，在本提案的情况下，是由破骨细胞或其骨降解释放的蛋白质或分子，并且对该过程具有特异性。***目前没有测试（生物标志物）可用于专门监测马破骨细胞活性与早期SCB吸收的关系，这是本应用的主题。该项目的长期目标是开发一种特异性的诊断血清试验，用于马破骨细胞活性，以反映临床前SCB的过度吸收。这项测试可以通过早期调整锻炼计划来保护骨骼，从而发现和/或阻止其发展。具体来说，我们将研究细胞培养中已知和新的马破骨细胞活性生物标志物的释放。然后，我们将采用最先进的技术来发现马破骨细胞释放的特定蛋白质，以发现新的更好的生物标志物。然后，我们将评估有希望的候选生物标志物，用于检测赛马体液中过度软骨下骨吸收。该研究项目涉及马兽医学中一个新兴的重要领域，有望缩小赛马软骨下过度吸收的早期发病机制的知识差距，并防止其发展。**

Racehorses are afflicted with catastrophic fractures and joint degeneration that occur at specific sites. They are caused by the excessive repetitive trauma of racing and training. This problem is an important economic and welfare issue. These traumatic stress fractures often arise in the dense bone, underlying the cartilage (subchondral bone- SCB), of the joints and can lead to intra-articular fracture or post-traumatic osteoarthritis. Focal bone microdamage first accumulates and then osteoclast cells, that digest bone, are recruited to remove the damaged bone. However, they create focal lysis, that can further weaken the bone and lead to fracture. The active osteoclasts remain in the sites for approximately 2 weeks. There is a great unmet need to identify this problem early to prevent its progression and sometimes catastrophic consequences. It is currently difficult to do so clinically in horses as the early damage is microscopic and radiographs cannot detect it. ***My research program, investigating questions related to equine joints for over 20 years, will focus on the important topic of the contribution of excessive osteoclastic activity in racehorse bones to both fractures and joint degeneration. Our prior studies, funded by NSERC, have paved the way to our current hypothesis that osteoclast-specific products in blood reflect equine SCB resorption in vivo and may prove of value as biomarkers (tests) for the detection of early excessive SCB resorption. A biomarker, or biological marker, is a measurable indicator of a disease process or response to a treatment and, in the case of this proposal, are proteins or molecules released by osteoclasts or their degradation of bone and are specific for this process. ***There is presently no test (biomarker) available to specifically monitor equine osteoclastic activity in relation to early SCB resorption, the subject of this application. The long term objective of the program is to develop a specific diagnostic serum test for equine osteoclastic activity that will reflect excessive, pre-clinical, SCB resorption. This test could permit its detection and/or prevent its progression by early tailoring of the exercise program to preserve bone. Specifically, we will study the release of known and novel biomarkers of equine osteoclast activity in cell cultures. We will then employ state of the art technology to discover specific proteins released by equine osteoclasts to discover new better biomarkers. We will then assess promising candidate biomarkers for the detection excessive subchondral bone resorption in racehorse body fluids. The research program addresses a novel, emerging, important field in equine veterinary medicine that holds the promise to close the knowledge gap on the early pathogenesis of excessive subchondral resorption in racehorses and prevent its progression. **