Apelin promotes RANKL‑mediated osteoclastogenesis by activating MAPK and NF‑κB pathways.

The regulation of bone mass relies on a dynamic interplay between bone‑forming osteoblasts and bone‑resorbing osteoclasts. Imbalances in this regulatory system favor bone resorption and are implicated in the development of osteolytic disorders such as osteoporosis. Although current treatments targeting osteoclast activity are effective, safety concerns remain a notable limitation. As a multifunctional adipokine, apelin (APLN) serves a role in angiogenesis and metabolic regulation. However, to the best of our knowledge, its involvement in osteoclast differentiation has not yet been characterized. The present study thus examined the effects of APLN on osteoclastogenesis using a murine‑macrophage model stimulated with receptor activator of NF‑κB ligand (RANKL). The results revealed that APLN augmented RANKL‑induced osteoclast differentiation, promoting the formation of tartrate‑resistant acid phosphatase‑positive multinucleated cells and the development of organized F‑actin rings. Transcriptome analyses of a public dataset confirmed the temporal upregulation of osteoclast‑related genes under RANKL stimulation. It was further discovered that co‑treatment with APLN and RANKL significantly enhanced the expression of these osteoclast‑specific markers. APLN co‑treatment with RANKL upregulated the ERK, JNK, p38 and NF‑κB signaling pathways, and this activation was effectively attenuated by specific pathway inhibitors. In conclusion, these findings identified APLN as an enhancer of RANKL‑dependent osteoclast differentiation and signaling, suggesting that the modulation of APLN activity may provide a promising strategy for controlling excessive bone resorption in skeletal diseases.