Bone remodelling is regulated by a complex network of pathways and factors where multiple cell types coordinate to maintain bone strength. Different regulatory mechanisms controlling the transcription of cell type specific genes have been previously identified. The traditional transcription regulation model has been complemented through studies on mechanisms modifying chromatin availability for transcription, called epigenetic regulation. One essential epigenetic regulator modifying the accessibility of DNA is Lysine-specific demethylase 1, LSD1. LSD1 was first found in an epigenetic regulator complex with REST corepressor 1 (RCOR1). RCOR2, a paralogue of RCOR1, was later shown to replace RCOR1 in some complexes with LSD1. LSD1 has been shown to regulate differentiation of mesenchymal and hematopoietic stem cells in vitro and in vivo. However, data on the effects of LSD1 expression or loss of function on bone tissue homeostasis are conflicting between different studies and experimental models.

In this thesis, the roles of LSD1 and RCOR2 in osteoblast differentiation and function were studied using both pharmacological inhibition of LSD1 and shRNA-mediated downregulation of LSD1 and RCOR2 mRNA expression in vitro. The roles were further investigated in vivo using global and mesenchymal cell targeted conditional knockout mouse models and applying ovariectomy and closed tibial fracture healing models to highlight the effects of RCOR2 on bone formation in adult mice. Loss of LSD1 demethylation activity through pharmacological inhibition or mRNA expression led to loss of osteoblast activity both in vitro and in vivo, resulting also in the loss of growth plate chondrocyte organization and in a bone phenotype resembling osteogenesis imperfecta. The downregulation of RCOR2 in vitro led to inhibition of osteoblast differentiation, which was not replicated to the same extent in the mouse models in vivo.

These results emphasize the importance of epigenetic regulation on mesenchymal cell differentiation and bone remodelling through the histone demethylation effects of RCOR2 expression and LSD1 activity. Further understanding of various epigenetic mechanisms could lead to new therapeutic approaches for bone diseases, expanding beyond the current treatment methods.