Epigenetic regulation of autophagy and stemness of MSCs in skeletal aging

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Project Summary/Abstract The long-term objectives of this application are to understand epigenetic mechanisms that control long and orofacial bone aging and to explore whether targeting epigenetic factors could help to prevent age-associated bone loss. The age-related bone loss is a critical risk factor for osteoporosis that affects millions of patients worldwide. It also represents a significant challenge for functional reconstruction or regeneration of dental, oral, and craniofacial tissues such as dental implants for replacing missing teeth in elderly people. Bone marrow mesenchymal stromal/stem cells (MSCs) are believed to be the common progenitors for both osteoblasts and adipocytes in bone marrow, but commitments to these two lineages are mutually exclusive. Aging reduces the bone marrow MSC number and its self-renewal, and favors their differentiation into adipocytes at the expense of osteoblasts, resulting in bone loss. Using siRNA screening, we discover that the histone demethylase KDM4B plays a critical role in osteogenic differentiation of MSCs by erasing trimethylated histone H3 at lysine 9 (H3K9me3). The expression of Kdm4b is significantly downregulated in MSCs isolated from aging mice compared to young mice. Very recently, we demonstrate that the knockout of KDM4B in MSCs in vivo exacerbated skeletal aging and osteoporosis by reducing bone formation and increasing marrow adiposity via increasing H3K9me3. To explore whether the induction or activation of KDM4B prevent skeletal aging in vivo, we generated knockin mice overexpressing Kdm4b. Very excitingly, we find that the overexpression of Kdm4b significantly attenuates mouse skeletal aging. Unexpectedly, our RNA-seq analysis reveals that the induction of KDM4B in aged MSCs epigenetically promotes autophagy and inhibits the senescence gene signature in addition to the modulation of cell fate and stemness. Growing evidence shows that autophagy helps to maintain the self-renewal of adult stem cells by preventing their senescence. The impaired autophagy attenuates MSC stemness and promotes MSC senescence and exhaustion in skeletal aging. While key molecules or signaling pathways associated with autophagy have been elucidated, how autophagy in skeletal aging is epigenetically regulated is poorly understood. Based on our exciting novel discoveries, we hypothesize that KDM4B epigenetically regulates autophagy, senescence and self-renewal of MSCs in skeletal aging. We propose to examine whether the induction or activation of KDM4B in aging mice rejuvenates MSCs and prevents skeletal aging by promoting autophagy and stemness using genetic and small molecule approaches. New findings from our studies will have important implications in developing innovative therapeutic strategies for preventing skeletal aging and osteoporosis as well as promoting MSC-mediated bone regeneration.