关节痛是美国最常见的疼痛类型之一。在患有炎症性疾病如骨关节炎(OA)和痛风的患者的情况下,由于几种关键细胞因子的长期过度表达而导致的持续性炎症与关节内神经元超敏反应和损伤有关.最终,一部分患者出现慢性疼痛.关节痛的药物治疗包括使用镇痛药,如对乙酰氨基酚,非甾体抗炎药(NSAIDs),阿片类药物,抗抑郁药,以及关节内注射皮质类固醇和透明质酸。然而,NSAIDs是短效的,不能缓解剧烈的疼痛。阿片类药物通常在控制慢性疼痛方面无效,所有的治疗选择都会增加严重副作用的风险。
■我们探索了转化生长因子-β-活化激酶1(TAK1)在单碘乙酸盐(MIA)和尿酸单钠(MSU)关节疼痛模型中的治疗和镇痛作用,作为缓解慢性炎性疼痛的创新策略。机械性异常性疼痛(VonFrey),在接受选择性TAK1抑制剂的单独大鼠组中测量负重和组织学变化,HS-276,加巴喷丁或车辆。
■我们的数据支持,TAK1抑制有效地防止了MIA模型中机械性异常疼痛和差别性负重的发展。在痛风性关节炎的MSU模型中,HS-276治疗可显着减少雌性大鼠的机械性异常疼痛和膝关节水肿,但不是雄性老鼠.两种模型中受影响的关节的组织学评估表明,HS-276治疗可显着降低疾病引起的关节降解。
■我们的结果支持TAK1是炎性关节疾病如OA和痛风性关节炎的关键信号节点。选择性药理抑制显著减弱疾病的几个方面,包括关节退化和机械性疼痛。因此,TAK1是治疗疼痛性炎症性关节疾病的新治疗靶点。
■本文报道了TAK1在治疗OA和痛风等慢性炎症性关节疾病中的治疗潜力。使用选择性TAK1抑制剂,HS-276,我们显示了TAK1抑制在两种临床前鼠炎性关节痛模型中的治疗和镇痛作用。
UNASSIGNED: Joint pain is one of the most commonly reported pain types in the United States. In the case of patients suffering from inflammatory diseases such as osteoarthritis (OA) and gout, persistent inflammation due to long-term overexpression of several key cytokines has been linked to neuronal hypersensitivity and damage within the joints. Ultimately, a subset of patients develop chronic pain. Pharmacologic treatment of joint pain involves the use of analgesics such as acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, antidepressants, as well as intra-articular injections of corticosteroids and hyaluronic acid. However, NSAIDs are short-acting and fail to alleviate severe pain, opioids are generally ineffective at managing chronic pain, and all therapeutic options involve increased risks of serious side effects.
UNASSIGNED: We explored the therapeutic and analgesic effects of transforming growth factor-β-activated kinase 1 (
TAK1) inhibition in both the monoiodoacetate (MIA) and monosodium urate (MSU) models of joint pain as an innovative strategy for alleviating chronic inflammatory pain. Mechanical allodynia (Von Frey), weight-bearing and histological changes were measured in separate groups of rats receiving either the selective TAK1 inhibitor, HS-276, gabapentin or vehicle.
UNASSIGNED: Our data support that
TAK1 inhibition effectively prevented the development of mechanical allodynia and differential weight-bearing in the MIA model. In the MSU model of gouty arthritis, treatment with HS-276 significantly reduced mechanical allodynia and knee edema in female rats, but not male rats. Histological evaluation of effected joints in both models showed that HS-276 treatment significantly reduced disease-induced degradation of the joint.
UNASSIGNED: Our results support that TAK1 is a critical signaling node in inflammatory joint diseases such as OA and gouty arthritis. Selective pharmacological inhibition significantly attenuated several aspects of the disease, including joint degeneration and mechanical pain. Thus,
TAK1 is a novel therapeutic target for the treatment of painful inflammatory joint diseases.
UNASSIGNED: This article reports on the therapeutic potential of
TAK1 in the treatment of chronic inflammatory joint diseases such as OA and gout. Using the selective
TAK1 inhibitor, HS-276, we show the therapeutic and analgesic effects of
TAK1 inhibition in two preclinical murine models of inflammatory joint pain.