Abstract:
Increased bone fracture is one of the health risk factors in patients with bone loss related disorders such as
osteoporosis and breast cancer metastasis to bone. Over activity of osteoclasts leads to uncoupling of bone
remodeling favoring bone loss over bone formation. Receptor activator of nuclear factor-κβ ligand (RANKL)
triggers the differentiation pathway leading to multinucleated osteoclast formation. Modulation of RANKL or its
downstream signaling pathways involved in osteoclast formation is of significant interest in the development of
anti-resorptive agents. In this study, we investigated the effects of piperine, an alkaloid present in Piper nigrum
L. on osteoclast formation. Piperine inhibited tartrate-resistant acid phosphatase (TRAP)-positive multinucleated
osteoclast formation in murine RAW264.7 macrophages and human CD14+ monocytes induced by RANKL and
breast cancer cells. Piperine attenuated the p38-mitogen activated protein kinase (MAPK) pathway activation,
while the extracellular-signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) or NF-κβ pathways
downstream of RANKL remained unaffected. Concomitantly, expression of c-Fos and nuclear factor of activated
T-cells, cytoplasmic 1 (NFATc1), the key transcription factors involved in osteoclastogenesis were remarkably
inhibited by piperine. Furthermore, piperine disrupted the actin ring structure and bone resorption, a characteristic
hallmark of osteoclasts. Collectively, these results suggest that piperine inhibits osteoclast differentiation by
suppressing the p38/NFATc1/c-Fos signaling axis.
