CSB327 Lecture 15 Summary

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Cell and Systems Biology
Maurice Ringuette

Lecture 15 - Types of bone o Cortical bone (lamellar/compact) is dense, found in the shaft of long bones o Spongy bone (trabecular/cancellous) is lighter and less dense, consists of plates (trabeculae) - SIBLING family of small calcium binding glycoproteins that bind to integrin o Bone sialoprotein (BSP)  promote mineralization  Binding of HA to stretches of glutamic residues  Highly phosphorylated and sulfated  RFD integrin binding site (e.g., BSP is integrin binding protein)  High sialic acid content  Bone specific o Osteopontin (OPN)  block mineralization  Binding of HA to polyaspartic acid motif  Highly phosphorylated  RGD integrin binding site (e.g., OPN is integrin binding protein)  Broad tissue distribution o Expressed in tissues that undergo mineralization, but also found in other tissues (except BSP) - Composition of bone o 25% organic  90% type I collagen  10% BSP and OPN  5% cells (e.g., osteoblasts, osteocytes, osteoclasts, etc.) o 70% hydroxyapatite o 5% water - Temporal expression of bone-associated genes o Proliferation  Differentiation  Mineralization o BSP is expressed at the onset of mineralization  BSP interacts with α2 chain of type I collagen  BSP is localized in hole zone of collagen fibrils  HA is localized in hole zone too  BSP serve as a nucleator for HA crystal formation  BSP localized in Golgi and nascent bone matrix in vivo  BSP localized at sites of early mineralization in vitro o OPN has a biphasic expression before and after mineralization  OPN acts as an inhibitor of mineralization - Mineralization-competent matrix vesicles (MVs) o MVs secreted by osteoblasts (e.g., released into the matrix by exocytosis) o MVs can initiate HA crystal formation  NPP1 hydrolyzes NTP into NMP and PPi  PPi inhibits tissue mineralization  TNAP on vesicles hydrolyzes PPi into Pi (or PO )- 4  Type III Na+-dependent transporter bring extracellular phosphate molecules into the vesicle  Annexin bring extracellular calcium into the vesicle  Binds to collagens (CII and CX) in the hypertrophic zone  Phosphotidylserine bring calcium and phosphate in close proximity  During mineralizatoin, osteoblasts make MVs to begin HA formation within a confined space  When the MVs bind to collagen, they fall apart  They release and deposit nanocrystals into collagen fibrils  They set the stage for interaction of BSP within hole zone - Bone mineralization o Osteoblasts  Derived from mesenchymal cell precursors stimulated with BMP-2/4/7  Runx2 and Osx are master genes for osteoblast differentiation (e.g., osteogenesis)  Runx2 and Osx are transcription factors that promote pre-osteoblast  osteoblast  Runx2 is a master regulator of early osteogenesis o In Runx2 null mice, no osteoblast differentiation in endochondral and intramembranous ossification  Osx is a master regulator of late osteogenesis o In Osx null mice, no osteoblast differentiation and virtua
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