IBMS BoneKEy | Perspective
The role of the proteasome in bone formation and osteoclastogenesis
Shmuel Yaccoby
DOI:10.1138/20100439
Abstract
The findings that proteasome inhibitors are bone-anabolic in normal and pathological bones corroborate mounting evidence on the critical role of the proteasome in regulating activity of key osteoblastogenic transcription factors (e.g., RUNX2, ATF4) and signaling pathways (e.g., Hedgehog, BMP, Wnt/β-catenin). E3 ubiquitin ligases such as Smurf1, β-TrCP1, WWP1, and related adapter proteins (e.g., Schnurri 3) regulate protein activity of RUNX2 or ATF4 by promoting their proteasomal-dependent degradation. Therefore, knocking down each of these ligases results in increased bone mass, and increasing Smurf1 expression (by factors such as TNFα or sustained PTH administration) may lessen bone formation. The clinically approved proteasome inhibitor bortezomib is bone-anabolic in patients with multiple myeloma, and various other proteasome inhibitors consistently increase bone mass in experimental animals. Proteasome inhibitors impact various signaling pathways in osteogenic cells; BMP signaling is induced by enhancing Hedgehog signaling-induced BMP-2 expression and by preventing degradation of relevant Smad receptors. Bortezomib stabilizes the Wnt signaling mediator β-catenin by reducing expression of the Wnt inhibitor DKK1 and also independently of Wnt signaling. The canonical and noncanonical NF-κB pathways are tightly regulated the proteasome, and inhibition of this pathway promotes osteoblastogenesis and suppresses osteoclast differentiation. In vivo proteasome inhibition simultaneously increases osteoblastogenesis by stabilizing RUNX2 and reduces osteoclast numbers directly and indirectly by lowering the RANKL/OPG ratio Increased bone mass resulting from proteasome inhibition is, therefore, mediated by multiple mechanisms of action that involve different cellular components, various signaling pathways within each cell type, and, possibly, systemic endocrine factors. IBMS BoneKEy. 2010 April;7(4):147-155.
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