Functional Imaging of Osteocyte Autophagy, Senescence and Apoptosis in Human Bone

• Applicant: Privatdozentin Dr. Katharina Jähn-Rickert, Ph.D.
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 384087252

Bone is a dynamic living tissue with a highly porous mineralized extracellular matrix housing a widespread cellular network of dendritic osteocytes. Osteocytes are connected to surface cells, namely bone forming osteoblasts and bone resorbing osteoclasts. It is well established that during adult life the bone matrix is turned over by a timely and locally coordinated action of osteoclasts and osteoblasts to maintain bone functionality. Therefore, it is not surprising that in situations of unbalanced bone turnover e.g. the highly prevalent age related bone loss (osteoporosis), pharmaceutical therapies focus on osteoclast and osteoblast activities. These therapies can improve bone mineral density and reduce fracture incidences, yet none of them is able to cure the underlying disease, suggesting additional factors are essential for the loss of bone functionality.It is the hypothesis of this proposal that osteocytes have a crucial role in the local regulation of bone remodeling and that the osteocyte viability is a determining factor. Osteocyte longevity is one of the most striking feature of this cell type. Osteocytes are considered to be one of the longest living cells in the human body and their cell viability is highly influenced by external stressors experienced within their osteocyte network. However, it is the embeddedness of osteocytes in the mineralized bone matrix that creates a challenging situation to functionally visualize this cell type. This project will use advanced functional imaging of the osteocyte to investigate the cellular life cycle by means of i) apoptosis as cell death mechanism, ii) autophagy as survival strategy, and iii) senescence as an aging process and the status in the cell cycle. Furthermore, osteocyte viability will be linked locally to bone turnover activities by osteoblasts and osteoclasts as determined by histomorphometry. This will create a novel mechanistic map connecting the osteocyte life cycle to bone turnover. To enable clinical relevance, human bone samples from young adults and aged adults with unbalanced bone turnover will be used for the investigation. Our work and the work of others demonstrated the vital importance of osteocyte viability by showing that osteocytes appear superior in maintaining their cell viability. With the recent research advancements demonstrating the multifunctionality of osteocytes, the death of osteocytes is a hallmark of bone diseases with unbalanced bone turnover. Against this background, this project will unravel the link between the life cycle of osteocytes and the local activities of osteoblasts and osteoclasts during bone turnover in human bone. Investigating this link will generate a novel mechanistic understanding that can aid to optimize future treatment regimens for bone diseases.

• DFG Programme: Research Grants