Role Of Wnt Signaling Pathway In The Pathogenesis Of Rheumatic Diseases
Mustafa Abdulrahman Mohammed;
Abstract
The Wnt signaling pathways are group of signal transduction pathways made of proteins that pass signals from outside of a cell through cell surface receptors to the inside of the cell.
Three main Wnt signaling pathways have been defined: the canonical Wnt pathway, the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway. The difference between the categories is that a canonical pathway involves the protein β-catenin while a noncanonical pathway operates independently of it.
All Wnt signaling pathways are activated by the binding of a Wnt-protein ligand to a Frizzled family receptor, which passes the biological signal to the protein Dishevelled inside the cell. However, to facilitate Wnt signaling, co-receptors may also be required alongside the interaction between the Wnt protein and Frizzled receptor. Examples include low density lipoprotein receptor-related protein (LRP)-5/6, receptor tyrosine kinase (Ryk), and ROR2.
The canonical Wnt pathway leads to regulation of gene transcription, the noncanonical planar cell polarity pathway regulates the cytoskeleton that is responsible for the shape of the cell, and the noncanonical Wnt/calcium pathway regulates calcium inside the cell.
Specific antagonists include Dickkopf (Dkk), Wnt inhibitory factor (WIF), secreted Frizzled-related proteins (SFRP), frizzled-related protein (Frzb), Wise, and Sclerostin. All of these constitute inhibitors of Wnt signaling.
However, other molecules have been shown to act as activators as well. For example, Norrin and R-Spondin have been shown to activate Wnt signaling.
The clinical importance of Wnt pathway has been demonstrated by disruptions of its components that lead to a variety of diseases, including rheumatic diseases, dermatological diseases, breast and prostate cancer, type II diabetes, and others.
It is clear that Wnt signaling is involved in joint development and postnatal joint homeostasis and remodeling.
There are two major patterns of joint pathology in rheumatic diseases. One of these is progressive bone and joint destruction leading to joint instability like rheumatoid arthritis (RA) and osteoarthritis (OA). In contrast, diseases such as ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are very different from rheumatoid arthritis and represent the second pattern of joint pathology, which is characterized by new bone formation.
In rheumatoid arthritis Wnt5a and FZD5 significantly contribute in induction of cytokines and chemokines which are characteristic of RA. While Wnt7B up regulated in RA and OA.
WISP3 is greater in synovium of RA patient than in that of OA patient or controlled individuals.WISP1 is over expressed in OA.
Wnt signaling inhibitors like (DKK , Sclerostin , Sfrp and FRZB) are elevated in RA and OA. While R-Spondin which is activates Wnt signaling is lowered.
In AS there will be increase activity of β_catenin which associated with up regulation of Wnt signaling. High Wnt3a with low DKK1 and sclerostin are observed in AS patients with syndesmophyte formation, while in AS patients without syndesmophyte formation showed higher level of DKK1 and sclerostin.
In PsA, changes in wnt signaling components is not clear, more information is required to explain the importance of Wnt signaling and its inhibitors in the process of new bone synthesis in PsA.
In Osteoporosis patients Wnt 10b and 7b deficiency cause decrease in bone mass. Wnt signaling inhibitors like (DKK , Sclerostin and SFRP) are increased. Mutation in LRP 5,6 (loss of function) leading to decrease bone formation.
It has been shown that the Wnt signaling pathway involved in many diseases, this pathway has arisen as an attractive therapeu¬tic target for treating several disorders. Wnt signaling contains multiple levels of regulation that can be manipulated to modulate the pathway; as Wnt receptors, secreted Wnt antago¬nists and intracellular mediators. Therefore, researchers have been working to develop drugs that target specific com¬ponents of Wnt signaling. Recently, a few agents have shown promising results and are currently undergoing clinical trials. Other drugs continue to be investigated at the preclinical stages.
Despite the therapeutic potential of manipulating the Wnt signaling pathway, caution must be taken. Any therapeutic intervention that modulates the Wnt signaling pathway should take into account the potential oncogenic risks associ¬ated with exogenous manipulation of the path¬way.
Three main Wnt signaling pathways have been defined: the canonical Wnt pathway, the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway. The difference between the categories is that a canonical pathway involves the protein β-catenin while a noncanonical pathway operates independently of it.
All Wnt signaling pathways are activated by the binding of a Wnt-protein ligand to a Frizzled family receptor, which passes the biological signal to the protein Dishevelled inside the cell. However, to facilitate Wnt signaling, co-receptors may also be required alongside the interaction between the Wnt protein and Frizzled receptor. Examples include low density lipoprotein receptor-related protein (LRP)-5/6, receptor tyrosine kinase (Ryk), and ROR2.
The canonical Wnt pathway leads to regulation of gene transcription, the noncanonical planar cell polarity pathway regulates the cytoskeleton that is responsible for the shape of the cell, and the noncanonical Wnt/calcium pathway regulates calcium inside the cell.
Specific antagonists include Dickkopf (Dkk), Wnt inhibitory factor (WIF), secreted Frizzled-related proteins (SFRP), frizzled-related protein (Frzb), Wise, and Sclerostin. All of these constitute inhibitors of Wnt signaling.
However, other molecules have been shown to act as activators as well. For example, Norrin and R-Spondin have been shown to activate Wnt signaling.
The clinical importance of Wnt pathway has been demonstrated by disruptions of its components that lead to a variety of diseases, including rheumatic diseases, dermatological diseases, breast and prostate cancer, type II diabetes, and others.
It is clear that Wnt signaling is involved in joint development and postnatal joint homeostasis and remodeling.
There are two major patterns of joint pathology in rheumatic diseases. One of these is progressive bone and joint destruction leading to joint instability like rheumatoid arthritis (RA) and osteoarthritis (OA). In contrast, diseases such as ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are very different from rheumatoid arthritis and represent the second pattern of joint pathology, which is characterized by new bone formation.
In rheumatoid arthritis Wnt5a and FZD5 significantly contribute in induction of cytokines and chemokines which are characteristic of RA. While Wnt7B up regulated in RA and OA.
WISP3 is greater in synovium of RA patient than in that of OA patient or controlled individuals.WISP1 is over expressed in OA.
Wnt signaling inhibitors like (DKK , Sclerostin , Sfrp and FRZB) are elevated in RA and OA. While R-Spondin which is activates Wnt signaling is lowered.
In AS there will be increase activity of β_catenin which associated with up regulation of Wnt signaling. High Wnt3a with low DKK1 and sclerostin are observed in AS patients with syndesmophyte formation, while in AS patients without syndesmophyte formation showed higher level of DKK1 and sclerostin.
In PsA, changes in wnt signaling components is not clear, more information is required to explain the importance of Wnt signaling and its inhibitors in the process of new bone synthesis in PsA.
In Osteoporosis patients Wnt 10b and 7b deficiency cause decrease in bone mass. Wnt signaling inhibitors like (DKK , Sclerostin and SFRP) are increased. Mutation in LRP 5,6 (loss of function) leading to decrease bone formation.
It has been shown that the Wnt signaling pathway involved in many diseases, this pathway has arisen as an attractive therapeu¬tic target for treating several disorders. Wnt signaling contains multiple levels of regulation that can be manipulated to modulate the pathway; as Wnt receptors, secreted Wnt antago¬nists and intracellular mediators. Therefore, researchers have been working to develop drugs that target specific com¬ponents of Wnt signaling. Recently, a few agents have shown promising results and are currently undergoing clinical trials. Other drugs continue to be investigated at the preclinical stages.
Despite the therapeutic potential of manipulating the Wnt signaling pathway, caution must be taken. Any therapeutic intervention that modulates the Wnt signaling pathway should take into account the potential oncogenic risks associ¬ated with exogenous manipulation of the path¬way.
Other data
| Title | Role Of Wnt Signaling Pathway In The Pathogenesis Of Rheumatic Diseases | Other Titles | دور مسار اشارات الونت في التسبب في الأمراض الروماتيزمية | Authors | Mustafa Abdulrahman Mohammed | Issue Date | 2014 |
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