Subchondral Bone Cavities in Osteoarthritis Pain

摘要 慢性疼痛是骨关节炎(OA)最突出的症状，也是患者求医的关键原因 帮助。持续性的休息疼痛深刻地影响着生活质量和日常体力活动。痛苦本身就是一种风险 未来功能衰退和疼痛增加的发展因素是身体功能的预测因素 限制和残疾。骨关节炎疼痛被认为是由细小的有髓或无髓纤维引起的。 在一个或多个组织中，包括滑膜、韧带、软骨下骨和半月板。临床上，软骨下 MRI显示的骨髓水肿样病变(BMLS)与骨性关节炎疼痛高度相关。因此， 观察表明，疼痛的来源很可能是软骨下骨。详细的机制是如何 然而，软骨下骨会产生骨性关节炎疼痛，这在很大程度上是未知的。在骨性关节炎进展过程中，异常的破骨细胞 (OC)骨吸收扩大软骨下骨腔，促进感觉神经支配，导致骨性关节炎 疼痛。PGE2介导感觉神经对骨密度的调节。骨中前列腺素E_2浓度呈负值 与骨密度呈正相关。我们的试验数据显示前列腺素E_2水平和感觉神经支配显著增加 在骨性关节炎软骨下骨腔内，类似骨质疏松时的极低骨密度。这 促使我们提出，高水平的PGE2使高度专业化的感觉神经元、伤害性感受器、 在软骨下骨中促进疼痛。在骨性关节炎的发病过程中，衰老细胞在骨性关节炎的发病过程中增多。 软骨下骨，至少40%为破骨细胞。我们最近发现OC分泌Netrin-1， 轴突引导分子，诱导软骨下骨内感觉神经轴突生长，介导骨性关节炎疼痛。 因此，我们假设衰老的OCS扩大了软骨下骨腔，提高了PGE2水平和 进一步增强感觉神经，调节骨性关节炎疼痛。为了检验这一假说，我们将调查 衰老的OC诱导软骨下骨腔和感觉神经支配。我们将研究这一角色 衰老OC软骨下骨腔诱导的PGE_2和PGE_2升高的异常骨重建 随之而来的骨性关节炎疼痛。然后我们将测试消除衰老破骨细胞对软骨下骨腔的影响 对OA小鼠给予感觉神经降解剂ABT263。最后，我们会 探讨挽救软骨下骨改建对感觉神经支配和骨性关节炎疼痛的影响。我们有 开发了一种新型的骨特异性转移生长因子β抑制剂和OC抑制剂阿伦磷酸酯的结合物。这个 这种小分子结合物对软骨下骨和骨性关节炎的感觉神经支配的影响将被检测。 疼痛。

ABSTRACT Chronic pain is the most prominent symptom of osteoarthritis (OA) and a key reason why patients seek medical help. Persistent pain at rest profoundly affects the quality of life and daily physical activity. Pain itself is a risk factor for the development of future functional decline and increasing pain is a predictor of physical functional limitation and disability. Osteoarthritic pain is thought to emanate from small myelinated or unmyelinated fibers in one or more tissues including synovium, ligament, subchondral bone, and meniscus. In clinic, subchondral bone marrow edema-like lesions (BMLs) visualized by MRI are highly correlated with OA pain. Thus, the observation suggests that the source of pain is likely from subchondral bone. The detailed mechanism how subchondral bone generates OA pain, however, is largely unknown. During OA progression, aberrant osteoclast (OC) bone resorption enlarges subchondral bone cavity, which promotes sensory innervation and leads to OA pain. PGE2 mediates sensory nerve regulation of bone density. PGE2 concentration in bone negatively correlated with bone density. Our pilot data showed PGE2 levels and sensory innervation significantly increased in the cavity of OA subchondral bone which resembles extreme low bone density as seen in osteoporosis. This prompted us to propose that high levels of PGE2 sensitize the highly specialized sensory neurons, nociceptors, in the subchondral bone to promote pain. During the pathogenesis of OA, senescent cells are increased in the subchondral bone with at least 40% being osteoclastic cells. We have recently shown that OC secrete Netrin-1, an axonal guidance molecule, to induce sensory nerve axon growth in the subchondral bone to mediate OA pain. Therefore, we hypothesize that enlarged subchondral bone cavity by senescent OCs elevates PGE2 levels and further enhances sensory innervation to mediate OA pain. To test the hypothesis, we will investigate the role of senescent OC in inducing subchondral bone cavity and sensory innervation. We will examine the role of subchondral bone cavity by senescent OC induced abnormal bone remodeling in the elevation of PGE2 and subsequent OA pain. We will then test the effect of eliminating senescent osteoclast on subchondral bone cavity and sensory innervation for OA pain by administration of senolytic drug ABT263 to OA mice. Finally, we will investigate the effect of rescuing subchondral bone remodeling on sensory innervation and OA pain. We have developed a novel conjugate that bone-specifically delivers a TGFβ inhibitor and OC inhibitor alendronate. The effect of this small molecule conjugate will be examined on sensory innervation in subchondral bone and OA pain.