The adaptor protein p62/SQSTM1 in osteoclast signaling pathways

Encoded by SQSTM1, the ubiquitin-binding protein p62 or sequestosome 1 is a scaffold and an adaptor protein that modulates protein-protein interactions, and as major component of multiprotein complexes, it mediates various cell functions, including cell signaling, receptor internalization, protein turnover, and gene transcription [1]. Mutations of the SQSTM1 gene have been detected in a high proportion of patients with Paget's disease of bone (PDB), thus highlighting the critical importance of p62 in the regulation of bone physiology [2]. While the most clearly established function of p62 is its role as a scaffold protein for intracellular signaling and the selective activation of NF-κB [1,3], p62 also plays a major role as a shuttling factor that targets polyubiquitinated proteins for degradation by either the autophagy or proteasome pathways [4,5].Bone remodeling is constant and dynamic, with a balance maintained between bone resorption and subsequent new bone formation. The cells responsible for these interrelated processes include the bone-resorbing cells, i.e. osteoclasts, which are derived from hematopoietic cells, and bone-forming cells, i.e. osteoblasts, which are of mesenchymal origin. Skeletal homeostasis depends on maintaining tight control of the number of osteoclasts active at any site [6]. Accelerated or increased bone resorption may involve elevated osteoclastogenesis from precursor cells, an increase in the fusion and/or activation of osteoclasts, and the prolongation of their lifespan via the inhibition of osteoclast apoptosis [7,8]. Osteoblasts or stromal cells support osteoclast differentiation and activation, and these processes are regulated by two signaling pathways, which are activated by M-CSF and receptor activator of NF-κB ligand (RANKL) respectively, and an ITAM (immunoreceptor tyrosine-based activation motif)-mediated co-stimulatory signaling [9]. RANKL is a membrane-bound, TNF-related factor expressed by osteoblast/stromal cells and acti