- Charcot
-
by tmi
Tuesday, June 22, 2010
Overview of the RANKL OPG Pathway
Southern Arizona Limb Salvage Alliance (SALSA)
www.ToeAndFlow.com
Authorship:
Nicholas A. Giovinco
Julia Bernardini
David G. Armstrong
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.
In addition to osseous destruction, the RANKL pathway has been correlated with macroangiopathic disfunction. The RANKL signaling pathway serves a regulatory role in the expression of bone matrix proteins in Vascular smooth muscle cells. A phenomenon that is naturally observed in many patients with Charcot joint destruction is vascular smooth muscle calcification. This presentation is often referred to as Monckeberg’s arteriosclerosis.
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.
When observing Charcot foot on a macro anatomic level, evidence of destruction may be visualized on plain film xray. Vascular calcification is reported in nearly 90% of all diabetics with Charcot foot, and is often seen prior to joint or bone involvement. As Charcot joint progresses through the acute phase, destruction and dislocation will be observed with severe osteopenia. Although this phase will eventually subside, resulting in a coalescence of fragments and overall stability of architecture, the foot is often permanently deformed.
Deformations such as these, when accompanied by peripheral neuropathy and possible microangiopathological status, are often what lead to ulceration and infection. Although Neuropathic Osteoarthropathy is not directly responsible for the loss of limb or even death, the “Stairway to Amputation” is a perilous progression that must be curbed in all patients afflicted with this condition.
References:
Authorship:
Nicholas A. Giovinco
Julia Bernardini
David G. Armstrong
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.
In addition to osseous destruction, the RANKL pathway has been correlated with macroangiopathic disfunction. The RANKL signaling pathway serves a regulatory role in the expression of bone matrix proteins in Vascular smooth muscle cells. A phenomenon that is naturally observed in many patients with Charcot joint destruction is vascular smooth muscle calcification. This presentation is often referred to as Monckeberg’s arteriosclerosis.
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.
When observing Charcot foot on a macro anatomic level, evidence of destruction may be visualized on plain film xray. Vascular calcification is reported in nearly 90% of all diabetics with Charcot foot, and is often seen prior to joint or bone involvement. As Charcot joint progresses through the acute phase, destruction and dislocation will be observed with severe osteopenia. Although this phase will eventually subside, resulting in a coalescence of fragments and overall stability of architecture, the foot is often permanently deformed.
Deformations such as these, when accompanied by peripheral neuropathy and possible microangiopathological status, are often what lead to ulceration and infection. Although Neuropathic Osteoarthropathy is not directly responsible for the loss of limb or even death, the “Stairway to Amputation” is a perilous progression that must be curbed in all patients afflicted with this condition.
References:
- Jeffcoate W. Vascular calcification and osteolysis in diabetic neuropathy-is RANK-L the missing link? Diabetologia. Sep 2004;47(9):1488-1492.
- Lam J, Nelson CA, Ross FP, Teitelbaum SL, Fremont DH. Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity. J Clin Invest. Oct 2001;108(7):971-979.
- Whyte MP. The long and the short of bone therapy. N Engl J Med. Feb 23 2006;354(8):860-863.
- Buckley KA, Fraser WD. Receptor activator for nuclear factor kappaB ligand and osteoprotegerin: regulators of bone physiology and immune responses/potential therapeutic agents and biochemical markers. Ann Clin Biochem. Nov 2002;39(Pt 6):551-556.
- Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res. Nov 26 2004;95(11):1046-1057.
- Anandarajah AP, Schwarz EM. Anti-RANKL therapy for inflammatory bone disorders: Mechanisms and potential clinical applications. J Cell Biochem. Feb 1 2006;97(2):226-232.
- Baud’huin M, Duplomb L, Ruiz Velasco C, Fortun Y, Heymann D, Padrines M. Key roles of the OPG-RANK-RANKL system in bone oncology. Expert Rev Anticancer Ther. Feb 2007;7(2):221-232.
- Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther. 2007;9 Suppl 1:S1.
- McClung M. Role of RANKL inhibition in osteoporosis. Arthritis Res Ther. 2007;9 Suppl 1:S3.
- Yogo K, Ishida-Kitagawa N, Takeya T. Negative autoregulation of RANKL and c-Src signaling in osteoclasts. J Bone Miner Metab. 2007;25(4):205-210.