bone development Flashcards
What are the core differences between bone and cartilage?
- calcified and rigid
- vascular
- contains nerves
- dynamic
- only appositional growth
What are the functions of the bone?
- structure support for soft tissues
- protection
- locomotion
- metabolic resevoir: stores Ca 99%, PO4 85%, Mg, Na
- Hematopoiesis: osteoblast support stem cell niche in bone marror and regulate stemness of HSC and immune cells
- endocrine organ: regulate pancreatic B cell proliferation, insulin synthesis, sensitivity and male fertility through secreted osteocalcin
Why is the bone an ultimate biomaterial?
light, strong, adapt to body physiologic and functional demands and repair itself
What is the composition of bone?
Mature bone is a composite material and composed of:
30% organic (collagen and noncollagenous proteins)
50% inorganic (minerals)
20% water
What composes of the organic matter of bone?
90% of the matrix proteins are collagen;
- fibers: type 1 collagen, highly organized
- ground substance: little consists of SLRPs
- Structural glycoproteins: osteonectin (cell adhesion), osteopontin (cell migration), bone silo protein, osteocalcin (Ca binding)
What is the biological role of fibronectin in bone formation; effect of knockout
relatively abundant, regulate osteoblast differentiation
Lethal
What is the biological role of osteonectin in bone formation; effect of knockout
bone connector, may regulate mineralization
osteoporosis
What is the biological role of thrombospondin in bone formation; effect of knockout
may inhibit bone cell precursors
dense bones
What is the biological role of osteocalcin in bone formation; effect of knockout
binds calcium
bones seem normal
What is the biological role of matrix-gla-protein in bone formation; effect of knockout
inhibits mineralizations
normal bones but calcified blood vessels
What are the SIBLINGS (small integrin binding ligand, N-linked glycoprotein family) involced with bone formation?
- bone sialoprotein
- osteopontin
- matrix extracellular glycoprotein
What is the biological role of bone sialoprotein in bone formation; effect of knockout?
binds to integrins, may assist cancer cells
reduced bone formation
What is the biological role of osteopontin in bone formation? Effect of knockout?
increases angiogenesis (makes new blood vessels) which enhances bone resorptionin some situations
resistant to ovariectomy and PTH mediated bone loss
What is the biological role of matrix extracellular glycoprotein in bone formation? Effect of knock out?
may induce a bone disease called osteomalacia
increased bone mass, osteoblast number, activity
What is the major proteoglycan in bone? Effect of knockout?
biglycan
osteopenia
What composes inorganic bone?
the mineral component is primarily composed of calcium and phophorous salts and small amounts of magnesium, sodium, and bicarbonate.
What are compositional differences between cartilage and bone?
There is mineral in bone but not in cartilage. There is much higher water(70-75%) in cartilage than in bone. Greater fibrillar collagen (20%) in cartilage, only 5% in bone. Greater PGs in cartilage vs bone, less than 1%; major PGs in bone is SLRPs; major PGs in cartilage is aggrecans
What is the function of chondrocytes?
responsible for producing cartilage template, growth
and post-natal lengthening of bone.
what is the function of osteoprogenitor cells?
fibroblast-like cells in periosteum (outer CT
capsule) and endosteum (inner lining of bone); immature cells but
divide to give appositional growth to bone.
what is the function of osteoblasts?
What are the 3 different fates of osteoblasts?
derived from osteoprogenitors; exclusively located at the surface of bone tissue; synthesize and secrete osteoid, which becomes mineralized to give bone; also synthesizes: collagen type 1, proteoglycans, glycoproteins; once differentiated do not divide.
- undergo apoptosis
- bone lining cells
- osteocytes
what is the function of osteocytes?
surrounded by matrix, maintain matrix; do not divide; has mechano-sensor abilities
what is the function of fibroblasts?
in peri- and endosteum
what is the function of osteoclasts?
large multinucleate cells, resemble macrophage in
function, remodel bone by resorbing bone matrix. Derive from monocyte/macrophage lineage, arrive from blood through marrow and blood vessels of haversian canas, periosteum and endosteum
what is the function of endothelial cells?
blood vessels
what is the function of neuronal cells?
nerves present
Explain the developmental origin of skeletal cells.
Different parts of the skeleton are formed by mesenchymal cells derived from three different compartments:
- neural crest - gives rise to craniofacial bones
- sclerotome/somite - gives rise to most axial skeletal element
- lateral plate mesoderm - gives rise to limb bones
What is the first sign of skeletal development?
condensation of mesenchymal progenitor cells
What signaling pathways are required for skeletal patterning?
Wnts, BMPs, FGFs, Hedgehogs, Notch
How do osteocytes maintain bone matrix?
sclerostin (inhibitor of bone formation)
What factors regulate phosphate homeostasis in bone development?
FGF-23, Phex, DMP1
What is the composition of bone cells in adult skeleton?
90-95% osteocytes
4-6% osteoblasts
1-2% osteoclasts
What is the bone mineralization process?
orchestrated process in which crystals of calcium phosphate are produced by cells and laid down in precise amounts within the fibrous organic matrix
what is the primary mineral of bone?
hydroxyapetitie
What are the 2 way to increase crystal dimension?
- addition of ions to crystals
2. aggregation of crystal
What are factors determining mineralization rate?
- pH
- concentration of calcium and phosphate
- ratio of inorganic phosphate and pyrophosphate
- presence of other ions and charged macromolecules
- strong anionic proteins have high affinity for Ca2+ therefore they function as hydroxyapetite nucleators
What are the types of bone?
- woven bone (immature/primary)
- lamellar bone (mature/secondary)
- cancellous/trabecular
- compact/cortical
what is the periosteum?
covers the outer surface of the bone except articular surface and tendon; it is vascularized and contains osteoprogenitor cells
what is the endosteum?
consists of marrow stromal cells, resting osteoblasts, and lining cells of the haversian canal
What consists of the haversian system?
haversian canal, volkmans, canliculi
What is the haversian canal?
contains blood vessels, nerve cells, and lymphatic vessels
what is the volkmann canal?
runs perpendicular to the haversian canal; connects blood and nerve supply in the periosteum to those in the haversian canals, endosteum and medullary cavity
what is the canaliculi?
carry processes for linking osteocytes in adjacent lamallae both within haversian systems and inner and outer circumferntial lamellae; osteocytes contact each other and blood vessels
what is the structure of osteon?
- its the haversian system cylinder
- extends the length of the anatomic bone and composed of 4-20 concentric lamellae arranged in layers
- haversian canal in the center of osteon
Explain the 3D structure of bone
Haversian canals at the center of osteons –> volkmanns perpendicular to osteons –>osteocyte processes are linked through canaliculi –>periosteum to endosteum and bone marrow
What are examples of intramembranous bone formation?
calvaria, maxilla from direct placement of mesenchyme
what are examples of endochondral bone formation?
long bones, ribs from cartilage template
What is intramembranous ossification responsible for?
Intramembranous ossification is responsible for frontal, parietal bones and part of occipital, temporal, mandible, and maxilla bones.
What is required of intramembranous ossifcation requires?
- well vascularized primitive CT
- bone formation is not preceded by the formation of cartilage
- an aggregate of mesenchymal cells differenitates directly into osteoid producing osteoblasts
What percentage of postnatal skull growth occurs during the first year of life?
85%
Due to the pressure of growing brain, how are osteoblasts and osteoclasts contribute?
Osteoblasts- add more osteoid on the outside
Osteoclasts- on the inside degrading bone
What is craniosynostosis?
premature closure of the sutures that disrupts normal brain and skull growth
what is deformation plagiocephaly?
failed fusion of the skull sutures
what is cleft lip and cleft palate?
the sides of the lip and roof od the mouth do not fuse together
Provide the steps of endochondral bone formation.
- induction: cartilage template
- induction of mesenchyme to chondroblasts to form hyaline cartilage; this progresses within limb buds to give a long avascular cartilage template - ossification: conversion of cartilage to bone
a: Perichondrium converts to periosteum as a collar of bone around the cartilage. This deprives central chondrocytes of
nutrition by diffusion.
b: Chondrocytes undergo hypertrophy, resorb cartilage and this
leads to development of large interconnected spaces.
c: Space allows blood vessels to enter from periosteum. This
vascularization allows chondroclasts (like osteoclasts) to arrive
in blood and accelerate cartilage degradation.
d: Osteoblasts from progenitor cells in periosteum lay down
osteoid on spicules of calcified cartilage.
e: Osteoclasts remodel bone - Bone enlargement: cartilage continues to grow so template lenghtens and widens
- Secondary ossifcation:
cartilage replaced by bone in epipyhsis - growth/remodeling: continues at epiphyseal growth plates until adult (~20 yrs)When growth ceases, diaphysis fuses with epiphyses, spongy bone starts to be destroyed and the space becomes the medullary cavity; only layer of cartilage remains, the articular cartilage, which lacks capacity to repair.
Describe the zones of epiphyseal growth plate.
- Zone of reserve (resting) cartilage: hyaline cartilage
- Zone of proliferation: rows of chondrocytes parallel to the direction of bone growth
- Zone of maturation/hypertrophy: chondrocytes mature, increase in size
- Zone of calcification: chondrocytes die, cartilage matrix becomes calcified
- Zone of ossification: osteoprogenitor cells invase and differentiate into osteoblasts, secrete osteoid into calcifed cartilage, mineralization converts this to bone
What causes dwarfism?
- excessive FGFR3 signaling (most common)
- GH resistance and deficiency
what causes gigantism (child)/acromegaly(adult)?
- excessive GH
what does HOX genes do?
proximal-distal polarity (should-hand)
what does sonic hedgehog do?
anterior to posterio limb patterning (thumb to pinky)
what does Wnt7, BMP, engrail genes do?
dorsal-ventral axis (knuckle-palm)
What does Tbx5 do?
initiation of forelimb
what does mutation in the TBX5 gener cause?
Halt oram syndrome
What is Runx2 and Sp 7 required for?
skelelatogenesis
What happens when Runx2 and Sp 7 are deleted?
complete lack of mineralized tissue formation and perinatal lethality
What occurs with mutation in Runx2 gene?
cleidocranial dysplasia - missing clavicles, hypoplastic bone, supernumerary teeth
What occurs with mutation in sp7?
osteogeneisis imperfecta
