9: Intro to Bone Flashcards
Osteoblasts are derived from:
mesenchymal stem cells, which also give rise to
fibroblasts, chondrobasts/cytes, and adipocytes.
Function of Osteoblasts
Their function is to synthesize the
organic components of the bone matrix. Mineralization appears to be a passive process that does not require cellular activity once mature matrix is present.
Osteoblast are commited to their lineage via expression of which to TFs
RUNX2 (Cbfa1) and osterix (SP7).
In the Alizarin red/alcian blue prep… what do we expect to see if the RUNX2 is missing
all blue.. no formation of bone
cartilage = blue
calcified stuff = red
Osteoblasts have two fates:
osteoblasts either undergo apoptosis or are embedded within newly secreted
matrix, and undergo terminal differentiation to osteocytes.
Cells in bones responsible for mechanotransduction in bone.
Osteocytes
Important mechanotransductive
functions rely on the primary cilium, and mechanotransduction at the tissue level
depends on intercellular communications via gap junctions.
Helpful stains for osteocytes
dental matrix protein 1 (DMP1) and sclerostin
(SOST) are useful histochemical stains for osteocytes.
origin of Osteoclasts (what are they structually related to?)
Osteoclasts are of hematopoietic origin and are closely related to macrophages in
lineage, structure, and function.
Terminal differentiation of osteoclasts requires
combinatorial signaling of both
M-CSF and RANKL
What makes RANK ligand?
osteoblasts.
What does osteoblasts make as a soluble decoy receptor for RANKL?
osteoprotegerin (OPG),
RANKL that binds to OPG is not able to bind RANK, and so high OPG levels inhibit terminal osteoclast differentiation.
What stimulates osteoclast activity
PTH and 1, 25 di-OH-D
What inhibits osteoclast activity
CAlcitonin
multinucleated giant cells that bind tightly to the bone surface via
the sealing zone to enclose a compartment in which bone matrix can be degraded.
Osteoclasts
multinucleated giant cells that bind tightly to the bone surface via the sealing zone to enclose a compartment in which bone matrix can be degraded.
Mature osteoclasts
What two things do osteoclasts secreate to
- Degrade mineral
- Degrade bony matrix
Within this compartment, osteoclasts secrete HCl to dissolve the mineral and cathepsin
K to degrade the bone matrix proteins.
STain to see osteoclasts
tartrate resistant acid phosphatase (TRAP)
makes up ~80-85% of the total bone. Its function is primarily structural, providing protection for organs and levers used for movement.
Cortical bone
Organization of Cortical Bone
osteons (also called Haversian systems), cylindrical structures in which concentric layers of bone matrix form lamellae around a central canal.
What about cortical bone lends its resistance to fracture
The lamellar organization of osteons
_____ of cortical bone is calficied
80-90%
What part of bone is always on outside of bone and surrounds trabecular bone?
Cortical Bone
What % of trabecular bone is calcified
15-25
Function of trabecular bone
metabolic
Accounts for most of the bone surface area and most of the remodeling activity. The large surface area is necessary to allow for mineral homeostasis.
Trabecular bone
How is trabecular organization similar and different from cortical bone?
trabecular bone is normally organized in a lamellar fashion, but the individual trabeculae are too small to contain osteons.
When do osteocytes make sclerosin and why
Make is when bone is mechanically loaded… goes to osteoblast to inhibit maturation. When mechanical loading is gone, remove repression
formed by formation of osteoblasts from mesenchymal stem cells present within what will become the periosteum.
Intramembranous bone
What bones are intramembranous
Examples of bones that are intramembranous in origin include many bones of the skull and the ribs.
What type of bone is formed at the bone collar of a healing frx. ?
Intramembranous bone
How do long bones remodel to increase in diameter?
Via intramembranous bone at the periosteal surface of long bones
bones replace previously formed cartilage models
Endochondral
How do Endochondral bones grow?
grow in length by proliferation of chondrocytes within the growth plate, a specialized structure present within growing endochondral bones. Linear growth ceases when the growth plates fuse.
Examples of endrochondral bones
the long bones of the limbs.
highly organized tissue in which chondrocytes are arrayed in columns, with different positions within the column occupied by cells at a distinct point of maturation.
The growth plate
How do chondrocytes grow during growth phase
is a Chondrocytes in the proliferative zone divide, replenishing the growth plate. The chondrocytes then hypertrophy, undergo apoptosis, and are mineralized. Blood vessels invade the zone of calcified cartilage, which is resorbed by chondroclasts and the space is filled by osteoblasts and bone matrix.
Linear growth of the long bones
depends on
the relative speed with which cells in the hypertrophic zone undergo apoptosis and those in the proliferative zone divide.
In humans, the growth plates close in late adolescence in response to
estrogen signaling.
Which has more active remodeling: cortical or trabecular
At any given time, about 10%
of the skeleton is being remodeled. Trabecular bone is much more actively remodeled than cortical bone. This makes sense in light of its more prominent role in maintaining mineral homeostasis.
2 key principles in bone remodeling
First, bone resorption and bone formation are coupled processes.
Second, bone resorption is relatively rapid, requiring ~2 weeks, while bone formation is slow, requiring
4-6 months for full mineralization to take place.
Method of measuring bone remodel?
Tetracycline labeling
Bone’s role in moment-moment homeostasis
The amount of Ca exchanged by trabecular bone each day is approximately twice the amount that is
absorbed from food or lost in urine each day. This active exchange of minerals between the bone and the circulation is essential for moment-to-moment mineral
homeostasis.
Bones do not only grow in length, but grow in radial size and change shape as well: this is called
Bone modeling (dt mechanical loading)
At the level of the whole bone, ________is the primary stimulus to modeling
strain (fractional change in length)
At the level of the cell, ________, requiring both anchoring of osteocytes by focal adhesion complexes and fluid flow sensed by each cell’s primary
cilium appear to be the critical stimulus.
shear stress
How do bones direct their growth at the appropriate site?
The connections among the osteocytes via
their processes allow integration of the response across cells, allowing new bone
growth to be directed to the sites experiencing the greatest strain.
_____forms at the fracture site, which becomes organized as a consequence of
the inflammatory process.
hematoma
After hematoma formation… mesenchymal stem cells are present and become chondrocytes so they can:
form a cartilaginous soft callus.
How does a hard callus form
Blood vessels invade the soft callus and bone replaces cartilage in a process very similar to that seen in the growth plate, forming a hard callus.
Durning hard callus formation… what goes on with the osteoblasts
osteoblasts on the subperiosteal surface form an intramembranous bone collar.
The hard callus is much bigger at first then what it ends up being… how does that happen
callus undergoes remodeling to form lamellar bone and modeling
How long does it take to heal a fracture
Time required is ~8-12 weeks, though the final remodeling and mineralization may take considerably longer.
bone, compressive strength comes from the
mineral phase (about 2/3 of the bone extracellular matrix by mass),
Bone tensile strength comes from the
protein and water (about 1/3 of the bone extracellular matrix by mass).
Primary protein compoment of bone’s ECM
type 1 collagen. This is a large triple helical protein that self-assembles into fibrils with an offset of ~1/4 the
molecule length, leading to a regular striped appearance on electron microscopy, with a periodicity of ~6.7 nM.
Assembly of toropcollagen into fibers provides
tensile strength: more x-linking = stronger
IN type I collagen: mature aromatic cross-links have higher bond energy than the aliphatic cross-links, thus:.
and are therefore harder to break
Collagen:
packs tight or loose
forms covalent bonds, non-covalent bonds
formation depends on which Vitamin
Tight
covalent
Vit C dependent
______ structure of the individual collagen molecules allows them to be stretched, for tensile strength
Helical
Cracks in bone have outcomes based on cement lines and toughness:
Which cracks propagate ealisly
ones along longitudinal lines
Transverse cracks are less able to propagate
Most abundant minerals in bone
Ca and PO4 are the most abundant ions in bone mineral, but significant amounts of Mg,
Na, OH, CO3, SO4, and Cl are also present
Disease of OsteoBlasts resulting in bones that easily frx
Osteogenesis Imperfecta
What is the pathology of osteogeneis imperfecta
Type I col defect, either synthesis or assembly. See bent fibrils, see bowing of legs
inadequate mineralization of the bone matrix and can be a consequence of several different conditions, including various malabsorptive disorders, vitamin D deficiency or resistance, phosphate wasting disorders, or even low Ca diet.
Cause Osteomalacia
Osteomalacia causes what type of bones
weak, undermineralized bones
What happens in growing individual gets osteomalacia
bone modeling is abnormal and the long bones assume a bowed shape. This is called rickets. –not dt abnormal cellular funx but lack of appropriate substrates
disorders in which the skeletal mass is
abnormally high, due to mutations of the protein sclerostin.
Sclerosteosis and Van Buchem’s disease
Pathology of Sclerosteosis
Lack of sclerostin the mechanosensory system, resulting in bones perceiving that they are being loaded even
when they are not. These can be thought of as osteocyte diseases.
group of diseases in which osteoclast function or maturation is impaired. As a result, remodeling is deficient.
Osteopetrosis
disorder characterized by focally excessive and
disorganized bone remodeling.
Pagets
see presenence of woven bone and increased serum alkaline phosphatase and urinarly hydroporline increase
Pagets
Pagets increases disposition to
osteosarcoma
