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.
1:46
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.
3:09
The activity of the three major bone cell types is coordinated through autocrine, paracrine, endocrine, and magneto-sensing signals, to ensure the maintenance of appropriate bone architecture and balance of calcium phosphate metabolism. In addition, the interaction of bone with bone marrow is crucial for hematopoiesis. The actions of osteoblasts, osteocytes, and osteoclasts take place within two settings: bone modelling and remodeling. In bone modeling, bone formation and resorption occur in an uncoupled manner and on separate surfaces. Bone modeling is required for accrual of appropriate bone morphology and mass during growth. Bone modeling also occurs at a low rate throughout life, and is necessary in the adult skeleton for bone repair and adaptation to changes in mechanical loading. Bone remodeling, on the other hand, is based on the coupled activities of bone resorption and formation that occur in packages of cells on the same bone surface, also termed the basic multicellular unit. Bone remodeling enables tissue turnover in the mature skeleton, while maintaining bone mass, and also allows in part for adaptation to the requirements of calcium and phosphate metabolism.
4:28
Bone loss occurs when the balance between bone resorption and formation is disrupted in favor of osteoclastic bone resorption. This results in osteoporosis, which is characterized by micro-architectural deterioration of bone and increased fragility, predisposing to fractures. The most widely used treatments for osteoporosis are, to date, antiresorptive treatments. However, they do not only decrease bone resorption, but also bone formation, based on the coupling of these two processes during bone remodeling. Hence destructs/stops bone loss, but do not restore bone mass. Since many patients have already lost a substantial amount of bone at the time of diagnosis, the medical community has been on the outlook for treatments that could stimulate bone formation of new bone to restore bone mass and strength. The best path towards this therapeutic goal may have been found only relatively recently.
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Pathways regulating bone formation

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