Vitamins D and K jointly protect against osteoarthritis via regulating OSCAR during osteoclastogenesis.

Objective: 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. Methods: 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. Results: 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. Conclusions: Calcitriol and MK4 confer enhanced benefits on OA and OPOA progression through OSCAR-mediated osteoclastogenesis inhibition in preosteoclasts. The Translational potential of this article: 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.