BONE REMODELING PROCESS
- Pre-osteoclasts circulate in the blood vessels
- if a new crack appears, the osteocytes near the crack undergo apoptosis
- osteocytes detect strain and secrete factors, includine growth factors, prostaglandins and nitric oxide
- the lining cells pull away from the bone matrix and form a canopy which merges with the blood vessels. The actual steps here are not well understood. Some of the canopy cells look like pre-osteoblasts. Stem cells appear to be near the blood vessels.
- the stromal cells generate pre-osteoblasts. Stromal cells also secrete M-CSF (macrophage colony stimulating factor) which helps generate pre-osteoclasts.
- the pre-osteoblasts proliferte and also secrete more factors, such as Wnt, interleukins and bone morphogenic proteins.
- the pre-osteoblasts start to express RANK-L on their surfaces. Pre-osteoclasts have RANK receptors on their surfaces.
- the pre-osteoclasts enlarge and fuse into mature osteoclasts
- the osteoclasto bind to bone matrix with integrins and secrete acid and cathepsin K to resorb the bone. Bone resorption at this spot take about two weeks. Bone derived growth factors IGF and TGF-Beta are released
- eventually the osteoclast undergoes apoptosis. The lifespan is regulated by estrogen and other factors
- pre-osteoblast mature into osteoblasto which stop making RANK-L and secrete OPG (osteoprotegerin). The OPG binds to RANK-L (decoy receptor) which clocks activation of the pre-osteoclasts.
- pre-osteoblasts proliferate and then mature into osteoblasto which line the resorbed cavity.
- the osteoblasto secrete osteoid and then mineralize it to fill in the cavity in 3-4 months. The matrix also contains other proteins and growth factors such as IGF and TGF-Beta. Some osteoblasto turn into osteocytes, some into linig cells and the rest undergo apoptosis.
- the ostsocytes have been re-establishing a network with each other and with the lining cells.
Bone remodelling follows the loading directions:
- The bone remodeling process is conducted by osteoclasts and osteoblasts, collaborating in Basic Multi-cellular Units (BMU’s).
- In cortical BMUs, osteoclasts excavate cylindrical tunnels in the predominant loading direction of the bone.
They are followed by osteoblasts, filling the tunnel, creating secondary osteons of renewed tissue.
- Trabecular bone remodeling is mainly a surface event, in which osteoclasts dig a trench rather than a tunnel and also here they are followed by bone forming osteoblasts creating hemi-osteons.
- That osteoblasts follow osteoclasts in such a coordinated manner indicates that a coupling mechanism must exist.
- It was suggested that BMU activity is controlled by osteocytes in the bone matrix, serving as mechanosensors, sending signals through the osteocytic canalicular network to the BMU cells.
- each BMU has a finite lifetime, so new units are continuously forming as old units are finishing;
* in normal bone, number of BMUs, bone resorption rate, and bone formation rate are all relatively constant;
OSTEOBLASTS STIMULATING FACTORS:
- currently sixteen different bone morphogenetic proteins (BMP-1 through BMP-16) have been identified;
- osteoinduction is mediated by BMP-2 thru BMP-7 and BMP-9: these allow differentiation of mesenchymal stem cells into osteoblasts;
- osteogenic proteins usually require type I collagen as a carrier protein;
- It enhances bone resorption.
- 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 Cbfa 1, which is a factor that activates the DNA so proteins can be made -* a process known as gene transcription. When Cbfa 1 activates the genes, the cells differentiate into mature osteoblasts. Without Cbfa 1, the cells would turn into fat cells instead.
- Insulin-like growth factors (IGFs): These growth factors are produced by osteoblastic cells in response to several bone active hormones, such as parathyroid hormone 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.
- Osteoblast receptors:
- estrogen
- parathyroid hormone: activation of RANKL and OAF production
- vit D: activation of RANKL and OAF production
OSTEOCLASTS STIMULATING FACTORS:
RANKL (RANK-ligand) 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.
OAF (osteoclasts activating factor) is probably a mixture of IL1-beta, TNF-alpha, LIF, and some other locally produced factors with IL1-beta being the major component. Interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) family of
cytokines: 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
OSTEOCLASTS INHIBITING FACTORS
Main inhibition factor: Osteoprotegerin
Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF), is a cytokine, which can inhibit the production of osteoclasts. Osteoprotegerin inhibits the differentiation of osteoclast precursors. Osteoprotegerin is a RANK homolog, and works by binding to RANKL ligand on osteoblast/stromal cells, thus blocking the RANKL-RANK ligand interaction between osteoblast/stromal cells and osteoclast precursors. This has the effect of inhibiting the differentiation of the osteoclast precursor into a mature osteoclast.
- Osteoclasts receptors:
- calcitonin:
- calcitonin is a polypeptide hormone that is a potent inhibitor of osteoclastic bone resorption, but its effects are only transient;
- the calcitonin receptor is specific for osteoclasts;
- estrogen (indirect)
- PTH, 1-25 Vit D & prostaglandin E, do not have receptors on osteoclasts (which is strange since these are bone resorption hormones.
THE BMU REMODELING PROCESS
Origination
(+) PTH, IGF, IL-1, IL-6, PGE, calcitriol, TNF, NO
(-) estrogen
After microdamage to the bone, following mechanical stress, following exposure to some cytokines, or at random, a BMU will originate. The osteocytes secrete messages to the surface cells. A circulatory canopy is formed from the lining cells.
Osteoclast recruitment
- (+) RANK-ligand, M-CSF
- (-) osteoprotegerin (OPG), GM-CSF
Stromal cells that have been activated by messages from osteocytes or IL-1, PTH, calcitriol, etc (but not IL-6) will then produce M-CSF (macrophage colony stimulating factor) which stimulates differentiation of cells into pre-osteoclasts. The stromal cells also divide to produce pre-osteoblasts, which express RANK-ligand (RANK-L) on their cell surfaces. Pre-osteoclasts have membrane receptors called RANK, related to the TNF family. When RANK-L activates these receptors the cells fuse and differentiate into mature multinucleared osteoclasts which develop a ruffled border and resorb bone. Meanwhile, OPG is a free-floating decoy receptor, made by mature osteoblasts, which can bind the RANK-L.
Resorption
(+) Integrins, some interleukins, acidosis, vitamin A
(-) estrogen, calcitonin, interferon, TGF, other interleukins, sFRP-1
The mature osteoclasts resorb bone by forming a space on the matrix surface and secreting hydrogen ions and cathepsin into the space. As the BMU wanders, new osteoclasts are continuously activated and then start resorption. At any one spot on the surface the resorption lasts about two weeks. The osteoclasts then undergo programmed cell death or apoptosis, which is delayed by estrogen deficiency.
Osteoblast recruitment
Osteoblasts
Skeletal remodeling in health and disease 2007
(+) Wnt, BMPs, IGF, FGFs, PDGFs, CSF, PTH, calcitriol, Runx2, GST-RANK-Ligand,
TGF-beta
(-) ? leptin
Osteoblasts are derived from marrow stromal cells, which can differentiate into either adipocytes or osteoblasts; the transcription factor Runx2 (previously named Cbfa1) is necessary for osteoblastic differentiation. Osteoblasts are probably attracted by bone-derived growth factors.
Osteoid formation
(+) TGF-beta, BMPs, IGF
(-) FGFs, PDGFs, glucocorticoids
The active, secreting osteoblasts then make layers of osteoid and slowly refil the cavity. They also secrete growth factors, osteopontin, osteocalcin, osteoprotegerin and other proteins.
Mineralization
(+) calcium, phosphate
(-) pyrophosphate
When the osteoid is about 6 microns thick, it begins to mineralize. This process, also, is regulated by the osteoblasts. Osteoblasts also primarily regulate phosphate metabolism through PHEX and FGF-23, whose mechanisms of action are still uncertain. Osteoblast life-span is regulated by estrogens and other hormones.
Mineral maturation
Other ions
For months after the cavity has been filled with bone, the crystals of mineral are packed more closely and the density of the new bone increases.
Quiescence
The final osteoblasts turn into lining cells which participate in the minute-to-minute release of calcium from the bones. Some of the osteoblasts also turn into osteocytes which remain in the bone, connected by long cell processes which can sense mechanical stresses to the bones.
