lecture 11 - building bones Flashcards
What are osteoblasts?
Differentiate from mesenchymal stem cells.
Plump, mono-nuclear cells on the bone surface.
Primary function: Synthesis of type I collagen and other bone matrix proteins. Initiate mineralisation.
What are osteocytes?
Differentiated osteoblasts (about 15% become osteocytes), embedded in the bone matrix.
Primary function: Detect damage and changes to mechanical environment.
What are osteoclasts?
Differentiate from haematopoietic stem cells.
Large, multi-nucleated cells.
Form tight seals on bone matrix using avb3 integrins.
Primary function: Secrete H+ and Cl- ions to form acidic environment, cathepsin K and tartrate-resistant acid phosphatase (TRAP) to aid bone resorption.
What is bone remodelling?
Highly coordinated turnover of bone tissue involving sequential activities of osteoclasts and osteoblasts.
Repair of microdamaged bone.
Renewal of old bone tissue.
Maintains calcium homeostasis.
How does bone development take place?
During embryogenesis, the skeleton develops through two different processes:
Flat bones, such as those found in the skull (calvaria), develop through a process known as intramembranous ossification.
Most other bones (long bones, vertebrae) develop by endochondral ossification.
During development, both intramembranous and endochondral ossification begin with mesenchymal condensation – an aggregation of undifferentiated mesenchymal cells – that will eventually develop into mineralised bone.
Intramembranous ossification is direct:
Mesenchymal cells to osteoblasts to bone.
Endochondral ossification is indirect:
Mesenchymal cells via cartilage to osteoblasts to bone.
What is Endochondral ossification?
Development of long bones, via a cartilage intermediate
Endochondral skeletal development begins with the formation of a mesenchymal condensation, expressing type II collagen. Centrally, cells differentiate into chondrocytes, which hypertrophy and express type X collagen. Progression to the mature growth plate accompanies development of the perichondrium, vascular invasion, and the formation of a center of ossification containing type I collagen-expressing osteoblasts.
What is the role of Runx2?
Runx2 is an osteoblast transcription factor that is essential for normal bone development via intramembranous and endochondral ossification.
Describe the role of FGFs in endochondral ossification?
FGF receptor 3 is expressed in proliferating chondrocytes, FGFR1 is expressed in prehypertrophic and hypertrophic chondrocytes and perichondrium (not shown), and FGFR2 (purple) is expressed in the perichondrium, periosteum and the primary spongiosa. FGF18 is expressed in the perichondrium and the phenotype of its knockout suggests that it acts on FGFR3 to decrease chondrocyte proliferation and, perhaps, on FGFR1 to delay terminal differentiation of hypertrophic chondrocytes and on FGFR1 and -2 to delay osteoblast development. FGF7, -8 and -17 are also expressed in the perichondrium, although knockout of these genes either has no phenotype or leads to early fetal demise, so their function in the growth plate is unknown.
What is the effect of FGFR3 mutations for endochondral ossification?
Activation of FGFR3 (FGF receptor 3) acts to inhibit chondrocyte proliferation and differentiation in the growth plate.
Mutations in the FGFR3 gene can result in over-active FGFR3 signalling, enhancing this inhibitory effect.
Activating mutations in the FGFR3 gene produces dwarf mice compared to normal wild-types (WT)
Activating mutations in the FGFR3 gene in humans causes achondroplasia (dwarfism)
What is the growth plate?
cartilage tissue that enables continued bone lengthening in children and adolescents
Growth plate eventually replaced by bone and bone lengthening stops.
