The Molecular and Epigenetic Regulation of Osteoblast and Osteoclast Differentiation and the Implications in Osteoporosis

The human skeleton undergoes continuous bone remodeling, a process relying on orchestrated balance between the actions of osteoblasts and osteoclasts. Complex molecular signaling networks govern the differentiation and functions of mesenchymal stem cell (MSC)-derived osteoblasts and monocyte macrophage-derived osteoclasts, as local factors, immune cytokines and systemic hormones exert their regulatory effects. Moreover, the lineage decisions of MSCs to choose osteogenesis over adipogenesis is critical for maintenance of bone mass. MSC cell fate is determined by epigenetic regulations of various lineage-specific genes and genes promoting `stemness'. In most bone pathologies especially osteoporosis, the balance in bone remodeling and in MSC lineage decisions become disrupted. To explore the molecular regulation of bone cells, we evaluated the effect of Wnt4 on bone loss associated with osteoporosis and skeletal aging. We generated transgenic mice overexpressing Wnt4 in osteoblasts, and discovered that Wnt4 signaling could attenuate bone loss and suppress inflammation in models of osteoporosis, inflammatory and age-related bone loss. Mechanistically, non-canonical Wnt4 signaling could attenuate Nf-κb signaling by competitive sequestering of transforming growth factor associated kinase 1 (Tak1) in bone marrow macrophages. Furthermore, Wnt4 recombinant protein injection effectively prevented and reversed bone loss induced by estrogen-deficiency. Hence, non-canonical Wnt4 signaling could not only promote bone formation, but also inhibit bone resorption and inflammation in marrow microenvironment by a novel crosstalk with NF-κB signaling. To explore the epigenetic regulation of MSC differentiation towards osteoblasts, we discovered two novel histone demethylases KDM4B and KDM6B, which promoted osteogenesis and inhibited adipogenesis of human MSCs. Mechanistically, KDM4B and KDM6B epigenetically activated different osteogenic transcription factors by removing gene silencing marks H3K9me3 and H3K27me3 respectively. Furthermore, H3K27me3- and H3K9me3- positive MSCs in osteoporotic and aged mouse bone marrow become elevated, along with a reduction in KDM4B and KDM6B. These findings supported that these histone demethylases play a critical role in MSC cell fate decisions, and may become potential therapeutic targets for treatment of osteoporosis