Pathways regulating bone formation

Published on July 30, 2015   28 min
0:00
Hello, my name is Michaela Kneissel. And I'm based at the Novartis Institutes for BioMedical Research in Switzerland. I'm going to talk today about some of the pathways which control bone formation.
0:13
I will start off with a brief introduction to bone homeostasis before speaking about three pathways which regulate bone formation. I choose to highlight those out of the range of relevant pathways, as they are the major pathways targeted to date for the treatment of bone diseases and injuries. First and foremost, I will introduce you to Wnt signaling, its crucial role in bone formation, and how the pathway is currently targeted for the treatment of bone fragility. In particular, I will spend some time explaining the role and mode of action of the Wnt antagonist sclerostin which is a key negative regulator of bone formation. I will then also introduce briefly the impact of parathyroid hormone, or PTH signaling on bone formation, and how it is used to treat osteoporosis. Finally, I will touch on the importance of bone morphogenetic protein, or BMP signaling, and how its modulation can be used to promote bone healing or hinder excessive formation. And I will highlight some of the cross-talk that exists between these three pathways and the regulation of bone homeostasis.
1:25
The skeleton contains three major cell types-- osteoblasts and the derived osteocytes and osteoclasts. Osteoblasts form bone. Osteoclasts resorb bone. And osteocytes maintain bone and contribute to the regulation of osteoblast and osteoclast activity.
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Bone forming osteoblasts arise from pluripotent mesenchymal stem cells. Wnts, PTH, and BMPs are amongst the key factors that enable mesenchymal stem cell differentiation towards the osteoblast lineage. Osteoblasts originate together with chondrocytes from a common osteochondre-progenitor cell. Subsequent osteoblast precursors undergo proliferation, followed by differentiation into osteoblasts. Osteoblast differentiation requires activation of the key transcription factor Runx2, also termed Cbfa1. Osteoblasts deposit extracellular matrix, which then mineralizes end materials. At the end of the bone matrix forming activity, osteoblasts either undergo apoptosis or become dormant lining cells on the bone surface or turn into matrix-embedded terminally differentiated osteocytes. The latter represent over 90% of all bone cells, and are interconnected with each other in cells on the bone surface by an extensive canalicular network in which the osteocyte dendritic processes are contained. Intensive cross-talk also exists between cells of the osteoblastic lineage and osteoclasts which are of hematopoietic origin.
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Pathways regulating bone formation

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