The bone anabolic carotenoid p-hydroxycinnamic acid promotes osteoblast mineralization and suppresses osteoclast differentiation by antagonizing NF-κB activation.

Numerous plant derived nutritional factors including p-hydroxycinnamic acid (HCA), a member of the carotenoid family, have long been held to possess bone protective properties. Studies in animals have provided a mechanistic basis for these observations by demonstrating the capacity of HCA to promote bone formation and suppress bone resorption in vivo. However, the molecular mechanism by which HCA achieves these effects remains unclear. We have demonstrated that a centralized mechanism by which several other nutritional factors achieve similar effects is through modulation of the nuclear factor-κB (NF-κB) signal transduction pathway. NF-κB activation is essential for osteoclast formation and resorption but potently antagonizes osteoblast differentiation and mineralization. In this study we demonstrate that HCA does indeed antagonize the activation of NF-κB by the key osteoclastogenic cytokine receptor activator of NF-κB (RANKL) in RAW264.7 osteoclast precursors, suppressing their differentiation into osteoclasts. Furthermore, HCA augmented the in vitro differentiation of MC3T3 preosteoblastic cells into mineralizing osteoblasts and relieved the inhibitory action of tumor necrosis factor-α (TNF-α)-induced NF-κB signaling on transforming growth factor-β (TGF-β)- or bone morphogenetic protein-2 (BMP-2)-induced Smad activation, an important pathway in osteoblast commitment and differentiation. Our data provide a mechanism to explain the dual pro-anabolic and anti-catabolic activities of HCA.