Zhao Yang, Ou Qianhua, Huang Hong, Li Delong, Chen Jianmao, Xue Song, Zhou Zuoqing, Ruan Guangfeng, Ding Changhai
Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, Guangdong, China.
Department of Intensive Care Unit, Zhongshan City People's Hospital, Zhongshan, 528403, Guangdong, China.
J Orthop Translat. 2025 May 12;52:387-403. doi: 10.1016/j.jot.2025.03.018. eCollection 2025 May.
The effects of vitamins D and K on osteoarthritis (OA) progression remain ambiguous, particularly in its subtype, osteoporotic OA (OPOA), where aberrant activation of osteoclasts exacerbates subchondral bone remodeling. This study aimed to investigate the effect of 1,25-dihydroxyvitamin D3 (calcitriol) and menaquinone-4 (MK4) on OA and OPOA progression and explore their combined mechanisms in osteoclastogenesis inhibition.
Therapeutic effects of calcitriol and MK4 were evaluated in OA and OPOA models induced by medial meniscus destabilization (DMM) and bilateral ovariectomy (OVX). In vitro analyses assessed their impact on chondrocyte degradation and osteoclastogenesis. RNA sequencing of preosteoclasts elucidated the vitamins' anti-osteoclastogenic mechanisms.
Combined administration of calcitriol and MK4 significantly attenuated cartilage degradation in OA and OPOA mouse models, though direct effects on chondrocyte degradation were limited. Importantly, calcitriol and MK4 jointly suppressed osteoclastogenesis in vivo and in vitro, ameliorating subchondral remodeling and reducing pain levels in OPOA mice. Mechanistically, osteoclast-associated receptor (OSCAR) mediated their anti-osteoclastogenic effects.
Calcitriol and MK4 confer enhanced benefits on OA and OPOA progression through OSCAR-mediated osteoclastogenesis inhibition in preosteoclasts.
This study demonstrates vitamins D and K as dual-action agents inhibiting osteoclastogenesis and normalizing subchondral bone remodeling both in OA and OPOA models, making it a potential therapeutic alternative for the disease.
维生素D和K对骨关节炎（OA）进展的影响仍不明确，尤其是在其亚型骨质疏松性骨关节炎（OPOA）中，破骨细胞的异常激活会加剧软骨下骨重塑。本研究旨在探讨1,25 - 二羟基维生素D3（骨化三醇）和甲萘醌 - 4（MK4）对OA和OPOA进展的影响，并探索它们在抑制破骨细胞生成中的联合机制。
在内侧半月板不稳定（DMM）和双侧卵巢切除术（OVX）诱导的OA和OPOA模型中评估骨化三醇和MK4的治疗效果。体外分析评估它们对软骨细胞降解和破骨细胞生成的影响。对破骨前体细胞进行RNA测序，以阐明维生素的抗破骨细胞生成机制。
骨化三醇和MK4联合给药显著减轻了OA和OPOA小鼠模型中的软骨降解，尽管对软骨细胞降解的直接影响有限。重要的是，骨化三醇和MK4在体内和体外共同抑制破骨细胞生成，改善软骨下重塑并降低OPOA小鼠的疼痛水平。机制上，破骨细胞相关受体（OSCAR）介导了它们的抗破骨细胞生成作用。
骨化三醇和MK4通过在破骨前体细胞中由OSCAR介导的破骨细胞生成抑制作用，对OA和OPOA的进展具有更大的益处。
本研究表明维生素D和K作为双作用剂，在OA和OPOA模型中均能抑制破骨细胞生成并使软骨下骨重塑正常化，使其成为该疾病潜在的治疗选择。
