What cells are found in Haversian systems?
What are the main components of bone?
The organic matrix is compsed primarily of the protein collagen which provides flexibility. 10% of adult bone mass is collagen
The mineral component is composed of hydroxyapatite, which is an insoluble salt of calcium and phosphorus. About 65% of adult bone mass is hydroxyapatite.
* Bone also contains small amounts of magnesium, sodium, and bicarbonate.
* Water comprises approximately 25% of adult bone mass.
large cells with many nuclei that derive from monocytes and are formed from fusion of precursors. After resorbing bone, osteoclasts undergo apoptosis
Cuboidal and columnar shaped with a central nucleus located on the bone surface. They come from bone marrow precursor cells. These precursors are capable of turning into either osteoblasts or fat cells, and various factors determine which kind of cells will be made. One of the factors is called Cbfa 1, which will cause the cell to differentiate into an osteoblast.
How do osteoblasts communicate?
Gap junctions with neighboring osteoblasts allow cells to communicate with each other
What receptors do osteoblasts have?
They have receptors for hormones such as vitamin D, estrogen, and parathyroid hormone.
What is PHEX?
a protein secreted by osteoblasts that helps to regulate the amount of phosphate excreted by the kidney.
What happens to osteoblasts when they finish making bone?
When the team of osteoblasts has finished making new bone, some become surrounded with matrix and differentiate into osteocytes. Others will remain on the surface of the new bone and differentiate into lining cells. The rest undergo apoptosis (cell suicide) and disintegrate
What are osteocytes?
These live inside the bone and have long branches which allow them to contact each other as well as the lining cells on the bone surface.
* . . . are in a perfect position to sense any mechanical strain on the bone.
* . . . can secrete growth factors which activate the lining cells or stimulate the osteoblasts.
* Their exact role is still under investigation, but probably the osteocytes direct bone remodeling to accomodate mechanical strain and repair fatigue damage.
What are lining cells?
former osteoblasts which have become flat and pancake-shaped.
* . . . line the entire surface of the bone.
What are the roles of lining cells?
These are responsible for immediate release of calcium from the bone if the blood calcium is too low.
-protect the bone from chemicals in the blood which dissolve crystals (such as pyrophosphate).
-have receptors for hormones and factors that initiate bone remodeling.
This diagram summarizes the origins and fates of the bone cells. Mesenchymal refers to cells which were deep within the embryo during early development; some of them remain in the bone marrow but do not form blood cells. The hematopoietic cells form the liquid part of the bone marrow, and some of them circulate with the blood.
What are Bone morphogenetic proteins (BMPs)?
BMPs are produced in the bone or bone marrow. They bind to BMP receptors that are on mesenchymal stem cells within the bone marrow. This causes the cells to produce Cbfa1, a transcription factor that causes cells to differentiate into mature osteoblasts. Without Cbfa 1, the cells would turn into fat cells instead!
What do Insulin-like growth factors (IGFs) do?
These growth factors are produced by osteoblastic cells in response to several bone active hormones, such as PTH and estrogens, or BMPs. IGFs accumulate in the bone matrix and are released during the process of bone remodeling by osteoclasts. IGFs stimulate osteoblastic cell replication -- in other words, they cause the osteoblasts to divide, forming new cells. They may also induce differentiation.
What do Interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) in terms of bone?
These factors are produced by osteoblastic cells in response to systemic hormones or other cytokines.
IL-6 can cause:
* Bone marrow stem cells to differentiate into pre-osteoclasts
* Changes in proliferation and differentiation of osteoblasts
* Inhibition of apoptosis of osteoblasts
What is the role of RANKL (RANK-ligand)?
This is a cytokine that stays on the surface of osteoblast-related cells. The cells make RANKL in response to systemic hormones (such as 1,25dihydroxyvitamin D3) and cytokines (such as IL-6). Cell contact between RANKL-expressing osteoblastic cells and RANK-expressing osteoclast precursors induces osteoclast development.
Apoptosis of bone
The mature bone is always remodeling: the old bone is resorbed and replaced with new bone. A team of osteoblasts and osteoclasts move along the bone, dissolving and rebuilding. What happens to the cells when they have finished rebuilding an area of bone? The osteoclasts and most of the osteoblasts undergo apoptosis. They are not killed. There is no lack of oxygen or nutrients. There are no toxic materials. Instead, there are genes in the cell which can be activated, causing the cell to disintegrate. These genes (of course) are carefully regulated within the cell. The factors that regulate apoptosis are currently under investigation. Some are related to estrogens, or to interleukins. Medications which could modify apoptosis have the potential for treating or preventing osteoporosis.
•Osteoclasts are multinucleate giant cells formed by differentiation and fusion of monocytes. Differentiation involves cell-cell interaction with lining cells/pre-osteoblasts through a RANK-RANKL interaction.
•They resorb a region of bone matrix sealed off below the cell body by releasing acid and proteases into the sealed off space.
•Demand for calcium stimulates bone resorption to release Ca2+ from mineralized matrix. Bone acts like a bank for deposits and withdrawals of calcium.
•Differentiated osteoblasts make _____ a collagenous matrix containing bone-specific proteins.
Osteoblasts that become entrapped in the matrix are called _______ that can communicate with each other and with osteoblasts through cell processes in canaliculi.
How do long bones grow in children?
from a growth plate, composed of cartilage, near the end of the bone. After new bone is formed under the growth plate, the wide sides are resorbed by osteoclasts (because the diaphysis narrower). These stages are accompanied by periosteal expansion, which increases the size of the sides of bone
How does growth in flat bones occur?
Intramembranous ossification: The growing skull, mandible (jaw) and clavicle (collar bone) form directly from osteoblasts, and do not have a cartilage stage.
A layer of cells which can differentiate into the osteoblasts lines the bone, with a special concentration between the bones of the skull. These precursor cells turn into osteoblasts which secrete collagen in a haphazard pattern called woven bone. Later osteoclasts resorb (dissolve) the woven bone and new osteoblasts form the mature, lamellar (layered) bone.
How does bone respond to stress (1 of 2)?
1) The osteocytes near the crack undergo apoptosis
2) Other osteocytes detect the strain and secrete factors, including growth factors, prostaglandins, and NO
3) The lining cells pull away from the bone matrix and form a canopy which merge with the blood vessles (steps here are not well understood). Meanwhile, stromal cells are now released from sclerostin inhibition and/or exposed to other factors like IL-1 and generate pre-osteoblasts and secrete M-CSF which helps generate pre-osteoclasts
4) The pre-osteoblasts proliferate and secrete more factors, such as WnT, ILs and BMPs
5) The pre-osteoblasts then start to express RANK-L
6) Pre-osteoclasts bind to RANKL receptors and enlarge and fuse into mature osteoclasts
How does bone respond to stress (2 of 2)?
1) The osteoclasts then bind to bone matrix with integrins and secrete acid and cathepsin K to resorb the bone. This takes about 2 weeks. Bone-derived growth factors IGF adn TGF-B are released
2) Eventually the osteoclast undergoes apoptosis.
3) Pre-osteoblasts mature into osteoblasts which stop making RANKL and secrete OPG to block differentiation of pre-osteoclasts
4) The osteoblasts proliferate and line the resorbed cavity
5) the osteoblasts secrete osteoid and then mineralize it to fill in the cavity in 3-4 months. The matrix also contains IGF and TGF-B. Some osteoblasts turn into osteocytes some into lining cells, and rest undergo apoptosis
6) The canopy regresses and the osteocytes reform a network with each other and the lining cells
7) The new matrix will accumulate mineral and icnrease in density for about 3 yrs
What is a BMU?
BMU means "Basic Multicellular Unit" and also has been called "Bone Remodeling Unit". Remodeling actually happens in 3-D, spreading over an area on the surface of the bone
How does fracture repair occur?
1) blood clot forms immediately after the fracture
2) fibroblasts arrive from the periosteum and blood
3) some fibroblasts become osteoblasts, which make collagen (similar to formation of a scar)
4) After about 2 weeks, the collagen becomes mineralized which results in a 'callus'
5) The callus gradually remodels and eventually is replaced
The first x-ray was taken right after a fracture. The second was 2 months later, showing some callus. Notice that the leg is now in a cast, so the entire bone looks a little more dense and fuzzy. The last x-ray was 4 months after the fracture, showing a good callus. The bone now can bear weight, but it will take many months to remodel the area and complete the repair.
Endochondral bone formation
•Bone forms on a cartilage scaffold in the process of endochondral bone formation. The cartilage becomes calcified and then is replaced by bone matrix and a vascular bed at the growing ends of bone.
•Components of cartilage like type II collagen and aggrecan are replaced by bone specific proteins like osteocalcin and a highly crosslinked type I collagen (bone collagen crosslinks are a commonly used marker for clinical bone turnover measurement).
What are the effects of estrogen on bone?
inhibit osteoclasts and osteoclast precursors
may enhance osteoblast survival
Effects of PTH?
stimulates osteoblast activity
increases RANK-L expression on pre-osteoclasts
What are the effects of VitD on bone?
promotes differentiation of osteoblasts and osteoclast precursors
What are the effects of calcitonin on bone?
inhibits osteoclast function
What are the effects of cortisol on bone?
promotes osteoblast apoptosis and increases bone resorption
decreases GI calcium absorption
increases renal calcium excretion
decreases sex steroid production
What are the effects of VitA?
directly stimulates osteoclasts
What are the effects of thyroid hormone?
What are the effects of GH/IGF-1?
increase osteoblast function
The osteoporotic fractures occur throughout the skeleton. The most typcial fractures are of the spine, wrist and hip. Osteoporosis is not painful until the bone actually breaks. Fractures in hips and wrists are always painful, but about 2/3 of the spine fractures do not cause pain. The spine (vertebral) fractures cause height loss, curvature of the spine, disfiguring posture, and muscle aching. In severe cases the ribs can touch the pelvic bones. The lungs can't expand normally and heartburn is more frequent.
Osteoporosis is more common in what ethnicities?
caucasians and asians
What is Paget's disease?
A disorder of bone remodeling which is focal (located in discrete areas in the bones and not throughout the entire skeleton). The abnormal remodeling results in overgrowth or deformity of bone.
Epidemiology of Paget's disease
Paget's disease usually occurs in adults who are older than 55 years old, and there are slightly more men than women with the disease. The disease does not spread, but remains in the same bones as patients grow older. It it most commonly found in the skull, spine, pelvis, femur, and tibia.
Whereas some patients have only one bone with Paget's disease, others have Paget's in many bones.