Molecular Bases of Disease
Hdac3 regulates bone modeling by suppressing osteoclast responsiveness to RANKL
Hdac3 is a lysine deacetylase that removes acetyl groups from histones and additional proteins. Although Hdac3 functions within mesenchymal lineage skeletal cells are defined, little is known about Hdac3 activities in bone-resorbing osteoclasts. In this study we conditionally deleted Hdac3 within Ctsk-expressing cells and examined the effects on bone modeling and osteoclast differentiation in mice. Hdac3 deficiency reduced femur and tibia periosteal circumference and increased cortical periosteal osteoclast number.Deficiency in the phosphatase PHLPP1 suppresses osteoclast-mediated bone resorption and enhances bone formation in mice
Enhanced osteoclast-mediated bone resorption and diminished formation may promote bone loss. Pleckstrin homology (PH) domain and leucine-rich repeat protein phosphatase 1 (Phlpp1) regulates protein kinase C (PKC) and other proteins in the control of bone mass. Germline Phlpp1 deficiency reduces bone volume, but the mechanisms remain unknown. Here, we found that conditional Phlpp1 deletion in murine osteoclasts increases their numbers, but also enhances bone mass. Despite elevating osteoclasts, Phlpp1 deficiency did not increase serum markers of bone resorption, but elevated serum markers of bone formation.Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2
Background: Osteogenic differentiation is initiated by transcriptional and post-transcriptional epigenetic mechanisms. Results: Inhibition of H3K27 methyltransferase EZH2 enhances osteogenic commitment of human mesenchymal progenitors, and its depletion in mouse mesenchymal cells causes multiple skeletal abnormalities. Conclusion: EZH2 is required for skeletal patterning and bone formation. Significance: EZH2-dependent epigenetic mechanisms control osteogenesis both in vitro and in vivo.Deletion of the PH-domain and Leucine-rich Repeat Protein Phosphatase 1 (Phlpp1) Increases Fibroblast Growth Factor (Fgf) 18 Expression and Promotes Chondrocyte Proliferation
Background: Phlpp1 is a tumor suppressor that represses Akt2 and other signaling pathways.Results: Chondrocyte proliferation, matrix production, Akt2 phosphorylation, and Fgf18/Erk1/2 signaling were increased in Phlpp1−/− mice, but levels of the transcription factor FoxO1 were reduced.Conclusion: Phlpp1 deficiency increases Akt2 activity, which diminishes FoxO1 levels and induces Fgf18 expression to stimulate Erk1/2 activity and chondrocyte proliferation.Significance: Phlpp1 inhibition may promote cartilage regeneration.
