Nicotinamide phosphoribosyltransferase inhibits receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation in vitro

Abstract

The adipokine nicotinamide phosphoribosyltransferase (Nampt), also known as pre-B-cell colony-enhancing factor or the insulin-mimetic hormone visfatin, has a crucial role in the conversion of nicotinamide to nicotinamide mononucleotide during biosynthesis of the coenzyme nicotinamide adenine dinucleotide. Previous reports have demonstrated the inhibitory effects of Nampt on osteoclast formation from human peripheral blood mononuclear cells and CD14+ monocytes. However, the effects of Nampt on bone marrow macrophage (BMM)-derived osteoclastogenesis and its precise role in the process remain unclear. The present in vitro study used recombinant Nampt and BMMs as osteoclast precursors demonstrated that Nampt suppresses receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis by decreasing the phosphorylation of various early signal transducers, including c-Jun N-terminal kinase, Akt, glycogen synthase kinase-3 β, Bruton's tyrosine kinase and phospholipase C γ-2. In addition, western blotting and reverse transcription-quantitative polymerase chain reaction analysis indicated that Nampt downregulates the mRNA and protein expression levels of c-Fos and nuclear factor of activated T cells, cytoplasmic 1, leading to a decrease in the expression of osteoclast-specific genes including tartrate-resistant acid phosphatase, osteoclast-associated receptor and cathepsin K. However, the bone-resorbing activity of mature osteoclasts treated with Nampt was similar to untreated control osteoclasts. This finding indicates that Nampt exerts its anti-osteoclastogenic activity by targeting osteoclast precursor cells rather than mature osteoclasts. Consequently, the present study demonstrated that Nampt acts as a negative regulator of RANKL-mediated differentiation of BMMs into osteoclasts, suggesting the potential therapeutic targets to treat bone-related disorders such as osteoporosis.

Tetrandrine attenuates the bone erosion in collagen‐induced arthritis rats by inhibiting osteoclastogenesis via spleen tyrosine kinase

“…RANKL stimulation provides an essential signal for osteoclast differentiation (34). Tetrandrine showed no significant effect on the formation of TRAF6‐TAK1 and the subsequent activation of IKK/IκBα, MAPKs/c‐fos, and AKT induced by RANKL.…”

NAMPT expression in osteoblasts controls osteoclast recruitment in alveolar bone remodeling

“…In addition, recombinant NAMPT induces glucose uptake, proliferation, and type I collagen expression in cultured human osteoblasts (Xie et al, ). Recombinant NAMPT inhibits the early stage of osteoclast differentiation during osteoclastogenesis by downregulating early RANKL‐dependent signaling pathways in bone marrow macrophage‐derived osteoclast cultures (Baek et al, ).…”

At the Crossroads of the Adipocyte and Osteoclast Differentiation Programs: Future Therapeutic Perspectives

“…The adipokine visfatin, also known as nicotinamide phosphoribosyltransferase (Nampt) or pre-B-cell colony-enhancing factor is essential for the biosynthesis of the coenzyme nicotinamide adenine dinucleotide (NAD) [69]. In contrast to chemerin, some reports suggest an inhibitory role for visfatin in the osteoclast differentiation program [69,70]. For example, Baek et al (2017) reported that visfatin inhibited the phosphorylation of various early signal transducers, including c-Jun N-terminal kinase, Akt, glycogen synthase kinase-3 β, Bruton's tyrosine kinase and phospholipase C γ-2 to suppress RANKL-induced osteoclastogenesis [70].…”

“…In contrast to chemerin, some reports suggest an inhibitory role for visfatin in the osteoclast differentiation program [69,70]. For example, Baek et al (2017) reported that visfatin inhibited the phosphorylation of various early signal transducers, including c-Jun N-terminal kinase, Akt, glycogen synthase kinase-3 β, Bruton's tyrosine kinase and phospholipase C γ-2 to suppress RANKL-induced osteoclastogenesis [70]. However, other studies using FK866, an inhibitor of visfatin, have demonstrated that visfatin is also required for the recruitment of osteoclasts to the bone surface [66].…”