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Animals; Blotting, Southern; Bone Marrow; Bone Remodeling/physiology; Bone Resorption; Carrier Proteins/genetics/*metabolism; Cell Count; Cells, Cultured; Comparative Study; ElectrophoreticMobility Shift Assay; Embryo; Enzyme-Linked mmunosorbent Assay; Fibroblasts/drug effects/metabolism; Gene Expression/physiology; Glycoproteins/genetics/physiology; Hematoxylin/metabolism; Immediate-Early Proteins/genetics/metabolism; Immunoblotting; Interleukin-6/blood; Macrophage Colony-Stimulating Factor/pharmacology; Macrophages/metabolism; Mice; Mice, Knockout; NF-kappa B/metabolism; Osteoclasts/metabolism; Osteogenesis/physiology; Parathyroid Hormone-Related; Protein/metabolism; Precipitin Tests; Protein Kinase C/genetics/metabolism; Protein-Serine-Threonine Kinases/metabolism; Proteins/metabolism; Receptors, Cytoplasmic and Nuclear/genetics/physiology; Research Support, Non-U.S. Gov't; TNF Receptor-Associated Factor 6; Time Factors; Transcription Factors
Abstract:
The atypical PKCs (aPKCs) have been implicated genetically in at least two independent signaling cascades that control NF-kappa B and cell polarity, through the interaction with the adapters p62 and Par-6, respectively. P62 binds TRAF6, which plays an essential role in osteoclastogenesis and bone remodeling. Recently, p62 mutations have been shown to be the cause of the 5q35-linked Paget's disease of bone, a genetic disorder characterized by aberrant osteoclastic activity. Here we show that p62, like TRAF6, is upregulated during RANK-L-induced osteoclastogenesis and that the genetic inactivation of p62 in mice leads to impaired osteoclastogenesis in vitro and in vivo, as well as inhibition of IKK activation and NF-kappa B nuclear translocation. In addition, RANK-L stimulation leads to the inducible formation of a ternary complex involving TRAF6, p62, and the aPKCs. These observations demonstrate that p62 is an important mediator during osteoclastogenesis and induced bone remodeling.
