14- General Hematology | Overview of RANK RANKL OPG Pathway
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RANKL / RANK / OPG
RANKL / RANK / OPG Signaling Pathway: Purpose and Mechanism. The RANKL-RANK-OPG Signaling pathway is an important pathway in bone remodelling and is important in various osteopathies such as osteoporosis. Osteoblasts are bone forming cells which express and release the protein RANK ligand (RANKL) and osteoprotegerin (OPG). RANK ligand binds to the RANK receptor which is located on bone absorbing cells known as osteoclasts. RANK ligand binding to RANK receptor leads to the differentiation and activation of osteoclasts. Activation of osteoclasts enables them to reabsorb bone to ensure bone remodelling occurs.
Hey everyone. In this lesson you will learn about the RANKL-RANK-OPG Signaling Pathway its purpose in bone remodelling and the various downstream signaling targets of the pathway including PI3K-AKT signaling JNK signaling and NFKB signaling.
I hope you find this video helpful.
The Receptor Activator for Nuclear Factor kappa B Ligand is believed to be an important molecule of bone metabolism. This is a natural and necessary surface-bound molecule on several types of cells and serves to activate osteoclasts.
Overproduction of RANKL is implicated in a variety of degenerative diseases. In patients with neuropathy the RANKL/OPG pathway is thought to mediate the development of Neuropathic Osteoarthropathy or "Charcot Joint"
An illustrative depiction of the RANKL pathway is as follows:
Cellular stress or injury may result in expression of RANK Ligand on the surface of activated ostoblasts and T cells. In this example an activated T cell is contacting a pre-osteoclast. Because this RANKL presenting cell is in an activated form RANKL will become expressed thus activate an uninhibited RANK receptor on the Surface of an Osteoclast.
What is important to note is that osteoprotegerin is a natural inhibitor of RANK and is thought to mediate a protective balance. Denosumab and several other drugs are being studied for their effects in preventing further transduction on the RANKL pathway and could prove to be useful in preventing disease progression.
As the transduction cascade continues IkB kinase is activated and subsequently phosphorylates the Inhibitor of kappa B leaving Nuclear Factor kappa B free to diffuse uninhibited. Upon entering the nuclear membrane Nuclear Factor kappa B will serve as a rapid-acting transcription factor and will contribute to a variety of changes in gene expression.
This gene expression is correlated with the progression of Preosteoclastic species in becoming activated as osteoclasts. When the overproduction and/or expression of RANKL is seen increased osteoclastogenesis will arise. Osteoclastogenesis is one of the fundamental elements in normal bone development and maturation.
However in Neuropathic Osteoarthropathy over abundance of osteoclastic activity will result in osteopenia or bone wasting. With compromised bone strength osteolysis and fragmentation will be observed.
One important note is that neuropathic osteoarthropathy or "Charcot Foot" is seen in nearly every sort of disease that results in peripheral neuropathy. The exact mechanisms of this correlation are still not entirely understood but neuropathic degeneration itself serves a presumable teleological role in permitting both an increase in blood flow and vascular permeability into the bone as well as a decreased sensation and detection of boney destruction in patients.
When considering the supporting evidence of these two factors the emergence of the indpendent Neurovascular (French theory) and the Neurotraumatic (German theory) may possibly hold a similar etiology which is reflective of a common underlying cause. Because of the varying causes of peripheral neuropathy the specific role the RANKL signal pathway merits more investigation at this time and is needed to fully understand the process of neuropathic osteoarthropathy.
Hey everyone. In this lesson you will learn about the RANKL-RANK-OPG Signaling Pathway its purpose in bone remodelling and the various downstream signaling targets of the pathway including PI3K-AKT signaling JNK signaling and NFKB signaling.
I hope you find this video helpful.
The Receptor Activator for Nuclear Factor kappa B Ligand is believed to be an important molecule of bone metabolism. This is a natural and necessary surface-bound molecule on several types of cells and serves to activate osteoclasts.
Overproduction of RANKL is implicated in a variety of degenerative diseases. In patients with neuropathy the RANKL/OPG pathway is thought to mediate the development of Neuropathic Osteoarthropathy or "Charcot Joint"
An illustrative depiction of the RANKL pathway is as follows:
Cellular stress or injury may result in expression of RANK Ligand on the surface of activated ostoblasts and T cells. In this example an activated T cell is contacting a pre-osteoclast. Because this RANKL presenting cell is in an activated form RANKL will become expressed thus activate an uninhibited RANK receptor on the Surface of an Osteoclast.
What is important to note is that osteoprotegerin is a natural inhibitor of RANK and is thought to mediate a protective balance. Denosumab and several other drugs are being studied for their effects in preventing further transduction on the RANKL pathway and could prove to be useful in preventing disease progression.
As the transduction cascade continues IkB kinase is activated and subsequently phosphorylates the Inhibitor of kappa B leaving Nuclear Factor kappa B free to diffuse uninhibited. Upon entering the nuclear membrane Nuclear Factor kappa B will serve as a rapid-acting transcription factor and will contribute to a variety of changes in gene expression.
This gene expression is correlated with the progression of Preosteoclastic species in becoming activated as osteoclasts. When the overproduction and/or expression of RANKL is seen increased osteoclastogenesis will arise. Osteoclastogenesis is one of the fundamental elements in normal bone development and maturation.
However in Neuropathic Osteoarthropathy over abundance of osteoclastic activity will result in osteopenia or bone wasting. With compromised bone strength osteolysis and fragmentation will be observed.
One important note is that neuropathic osteoarthropathy or "Charcot Foot" is seen in nearly every sort of disease that results in peripheral neuropathy. The exact mechanisms of this correlation are still not entirely understood but neuropathic degeneration itself serves a presumable teleological role in permitting both an increase in blood flow and vascular permeability into the bone as well as a decreased sensation and detection of boney destruction in patients.
When considering the supporting evidence of these two factors the emergence of the indpendent Neurovascular (French theory) and the Neurotraumatic (German theory) may possibly hold a similar etiology which is reflective of a common underlying cause. Because of the varying causes of peripheral neuropathy the specific role the RANKL signal pathway merits more investigation at this time and is needed to fully understand the process of neuropathic osteoarthropathy.
4 سال پیش
در تاریخ 1399/06/29 منتشر شده
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