Bone-targeted delivery of TGFβ inhibition for osteoarthritis

摘要 骨关节炎是最常见的退行性关节疾病，也是导致身体残疾的主要原因。 除关节置换手术外，目前尚无有效的疾病修正治疗方法。我们已经揭开了 软骨下骨的异常改建导致关节软骨的退变。升高型破骨细胞 骨性关节炎软骨下骨吸收导致转化生长因子β-1过量，使骨吸收和骨形成解偶联 并导致软骨下骨的退化。重建软骨下骨结构完整性的方法 抑制软骨下骨转化生长因子β活性可预防骨性关节炎的进展和软骨退变。 疼痛是骨性关节炎最突出的症状，促使人们寻求医疗护理。我们的初步研究 提示破骨细胞衍生因子在软骨下骨中诱导轴突挤压和神经支配。 极大地增加了骨性关节炎的痛苦。唑来膦酸是一种双膦酸盐，可以抑制破骨细胞的活动，已经被 据报道，在减轻膝关节疼痛和BMLS大小方面有效。 用I型转化生长因子β受体抑制剂抑制转化生长因子β信号通路 软骨下骨病理，减轻软骨退变。然而，转化生长因子βS是多功能的。 参与一系列生物过程的细胞因子。全身抑制转化生长因子β信号转导可能导致 未能维持其他器官的组织动态平衡，尤其是关节软骨转化生长因子β 作为一种主要的合成代谢因素。因此，开发一种新的战略来留住或 甚至可以提高转化生长因子β抑制剂的疗效，同时提高其在治疗应用中的安全性。 我们合成了一种新的药物，将双膦酸类药物阿仑磷酸酯与LY 2109761偶联 (Ly)，一种选择性的TβRI和TβRII激酶抑制剂，通过代谢可切割的连接子。利用高亲和力 在ALN中，我们实现了TβR抑制剂的骨靶向递送和缓释骨释放。此外，我们预计 这种结合物在缓解骨性关节炎疼痛方面有更好的效果，因为ALN也被认为可以缓解骨骼疼痛。 在这项应用中，我们建议研究结合物在预防糖尿病发展中的作用。 骨性关节炎的病理以及缓解关节疼痛。我们还将优化治疗剂量、频率 并在骨性关节炎动物模型上评价其毒性。预计这一结果将提供强有力的 为未来的临床试验奠定了技术和理论基础。

Abstract Osteoarthritis (OA) is the most common degenerative joint disorders and the leading cause of physical disability. There is no effective disease modifying treatment for OA except the joint replacement surgery. We have revealed that aberrant subchondral bone remodeling leads to degeneration of joint articular cartilage. Elevated osteoclast resorption in the OA subchondral bone leads to excessive TGFβ1 that uncouples bone resorption and formation and resulted in deterioration of subchondral bone. Restoring the structural integrity of subchondral bone by inhibiting TGFβ activity in subchondral bone can prevent OA progression and cartilage degeneration. Pain is the most prominent symptom of OA that urged people to seek for medical care. Our preliminary study suggests that osteoclasts derived factor induces axonal extrusion and innervations in the subchondral bone and substantially contribute OA pain. Zoledronic acid, a bisphosphonate that inhibits osteoclasts activity, has been reported effective in reducing knee pain and the BMLs size. Suppressing of TGFβ signaling pathway with type I TGFβ receptor inhibitor has been demonstrated to rescue subchondral bone pathology and attenuate cartilage degeneration. However, TGFβs are multifunctional cytokines that are involved in a range of biological processes. Systemic inhibition of TGFβ signaling may lead to a failure in the maintenance of tissue homeostasis of other organs, particularly articular cartilage where TGFβ severs as a major anabolic factor. Thus, it is of great importance to develop a novel strategy that can retain or perhaps even increase the efficacy of the TGFβ inhibitor while improving its safety in the therapeutic applications. We have synthesized a novel drug that conjugates alendronate (ALN), a bisphosphonate drug, with LY 2109761 (LY), a selective TβRI and TβRII kinase inhibitor, through a metabolically cleavable linker. Utilizing the high affinity of ALN, we achieve bone targeted delivery and sustained bone release of TβR inhibitor. Moreover, we anticipate that this conjugate has superior effect in alleviating OA pain as ALN has also been known to relieve bone pain. In this application, we propose to investigate the effects of the conjugate in preventing the development of osteoarthritic pathologies as well as alleviating joint pain. We will also optimize the treatment dosage, frequency and evaluate the toxicity of the conjugate in OA animal model. The results are expected to provide a strong technological and theoretical foundation for future clinical trials.