Amyloid β Peptide Enhances RANKL-Induced Osteoclast Activation through NF-κB, ERK, and Calcium Oscillation Signaling

Osteoporosis and Alzheimer's disease (AD) are common chronic degenerative disorders which are strongly associated with advanced age. We have previously demonstrated that amyloid beta peptide (A beta), one of the pathological hallmarks of AD, accumulated abnormally in osteoporotic bone specimens in addition to having an activation effect on osteoclast (Bone 2014,61:164-75). However, the underlying molecular mechanisms remain unclear. Activation of NF-kappa B, extracellular signal-regulated kinase (ERK) phosphorylates, and calcium oscillation signaling pathways by receptor activator NF-kappa B ligand (RANKL) plays a pivotal role in osteoclast activation. Targeting this signaling to modulate osteoclast function has been a promising strategy for osteoclast-related diseases. In this study, we investigated the effects of A beta on RANKL-induced osteoclast signaling pathways in vitro. In mouse bone marrow monocytes (BMMs), A beta exerted no effect on RANKL-induced osteoclastogenesis but promoted osteoclastic bone resorption. In molecular levels, A beta enhanced NF-kappa B activity and I kappa B-alpha degradation, activated ERK phosphorylation and stimulated calcium oscillation, thus leading to upregulation of NFAT-c1 expression during osteoclast activation. Taken together, our data demonstrate that A beta enhances RANKL-induced osteoclast activation through I kappa B-alpha degradation, ERK phosphorylation, and calcium oscillation signaling pathways and that A beta may be a promising agent in the treatment of osteoclast-related disease such as osteoporosis.