Wnts talking with the TGF-β superfamily: WISPers about modulation of osteoarthritis (original) (raw)
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Rheumatology (Oxford, England), 2011
The study of primary hip OA is continuing to redefine what was once considered a stagnant pathology as one of dynamic change, occurring over a long period of time involving the many composite tissue types of the joint including the bone. Examination of the inverse relationships evident between OA and fracture cohorts, including individuals with osteoporosis (OP), indicates an imbalance in formation and resorption in the bony component of both pathologies. This review contains an overview of primary OA followed by an assessment of differential gene expression and altered cellular characteristics identified in the bony compartments of primary hip OA, with a focus on the wingless mouse mammary tumor virus integration (Wnt) and TGF-β signalling pathways. The studies reviewed here suggest that OA is a systemic disease involving the bone and validate the assessment of molecular changes to further investigate this complex disease.
CARTILAGE, 2011
Objective: It is well known that expression of markers for WNT signaling is dysregulated in osteoarthritic (OA) bone. However, it is still not fully known if the expression of these markers also is affected in OA cartilage. The aim of this study was therefore to examine this issue. Methods: Human cartilage biopsies from OA and control donors were subjected to genome-wide oligonucleotide microarrays. Genes involved in WNT signaling were selected using the BioRetis database, KEGG pathway analysis was searched using DAVID software tools, and cluster analysis was performed using Genesis software. Results from the microarray analysis were verified using quantitative real-time PCR and immunohistochemistry. In order to study the impact of cytokines for the dysregulated WNT signaling, OA and control chondrocytes were stimulated with interleukin-1 and analyzed with real-time PCR for their expression of WNT-related genes. Results: Several WNT markers displayed a significantly altered expressi...
International Journal of Molecular Sciences
Cartilage and the bordering subchondral bone form a functionally active regulatory interface with a prominent role in osteoarthritis pathways. The Wnt and the OPG-RANKL-RANK signaling systems, as key mediators, interact in subchondral bone remodeling. Osteoarthritic osteoblasts polarize into two distinct phenotypes: a low secretory and an activated, pro-inflammatory and anti-resorptive subclass producing high quantities of IL-6, PGE2, and osteoprotegerin, but low levels of RANKL, thus acting as putative effectors of subchondral bone sclerosis. Wnt agonists, Wnt5a, Wisp-1 initiate excessive bone remodeling, while Wnt3a and 5a simultaneously cause loss of proteoglycans and phenotype shift in chondrocytes, with decreased expression of COL2A, aggrecan, and Sox-9. Sclerostin, a Wnt antagonist possesses a protective effect for the cartilage, while DKK-1 inhibits VEGF, suspending neoangiogenesis in the subchondral bone. Experimental conditions mimicking abnormal mechanical load, the pro-in...
The American Journal of Pathology, 2015
Proteins from the Wnt signaling pathway are very important for joint development. Curiously, osteoarthritis (OA) is thought to be a recapitulation of developmental processes. Various members of the Wnt signaling pathway are overexpressed in the synovium during experimental OA. Here, we investigated the potency of specific Wnt proteins, when expressed in the synovium, to induce OA pathology. We overexpressed Wnt5a, Wnt8a, Wnt16, and WISP1 in the synovium using adenoviral vectors. We determined whether overexpression resulted in OA pathology by histology, and we measured whether Wnt signaling led to increased protease activity in the joint. Synovial overexpression of Wnt8a and Wnt16 led to canonical Wnt signaling in the cartilage, whereas overexpression of Wnt5a did not. Canonical Wnt signaling increased protease activity and induced cartilage damage shortly after overexpression. Specific blocking of the canonical Wnt signaling pathway with Dickkopf-1 reduced the Wnt-signalingeinduced cartilage damage. By contrast, the noncanonical signaling Wnt5a did not cause cartilage lesions. Overexpression of WISP1, a downstream protein of canonical Wnt signaling, resulted in increased cartilage damage. In conclusion, our data show that canonical Wnts and WISP1, which we found overexpressed in the synovium during experimental OA, may conduce to OA pathology.
JCI insight, 2018
Osteoarthritis (OA) is a degenerative joint disease involving both cartilage and synovium. The canonical Wnt/β-catenin pathway, which is activated in OA, is emerging as an important regulator of tissue repair and fibrosis. This study seeks to examine Wnt pathway effects on synovial fibroblasts and articular chondrocytes as well as the therapeutic effects of Wnt inhibition on OA disease severity. Mice underwent destabilization of the medial meniscus surgery and were treated by intra-articular injection with XAV-939, a small-molecule inhibitor of Wnt/β-catenin signaling. Wnt/β-catenin signaling was highly activated in murine synovial fibroblasts as well as in OA-derived human synovial fibroblasts. XAV-939 ameliorated OA severity associated with reduced cartilage degeneration and synovitis in vivo. Wnt inhibition using mechanistically distinct small-molecule inhibitors, XAV-939 and C113, attenuated the proliferation and type I collagen synthesis in synovial fibroblasts in vitro but did...
Wnt signaling in cartilage development and diseases: lessons from animal studies
Laboratory Investigation, 2015
Cartilage not only plays essential roles in skeletal development and growth during pre-and postnatal stages but also serves to provide smooth movement of skeletons throughout life. Thus, dysfunction of cartilage causes a variety of skeletal disorders. Results from animal studies reveal that β-catenin-dependent canonical and independent non-canonical Wnt signaling pathways have multiple roles in regulation of cartilage development, growth, and maintenance. β-Catenindependent signaling is required for progression of endochondral ossification and growth of axial and appendicular skeletons, while excessive activation of this signaling can cause severe inhibition of initial cartilage formation and growth plate organization and function in mice. In contrast, non-canonical Wnt signaling is important in columnar organization of growth plate chondrocytes. Manipulation of Wnt signaling causes or ameliorates articular cartilage degeneration in rodent osteoarthritis models. Human genetic studies indicate that Wnt/β-catenin signaling is a risk factor for osteoarthritis. Accumulative findings from analysis of expression of Wnt signaling molecules and in vivo and in vitro functional experiments suggest that Wnt signaling is a therapeutic target for osteoarthritis. The target tissues of Wnt signaling may be not only articular cartilage but also synovium and subchondral bone.
Wnt Signaling and Biological Therapy in Rheumatoid Arthritis and Spondyloarthritis
International Journal of Molecular Sciences, 2019
The Wnt signaling pathway plays a key role in several biological processes, such as cellular proliferation and tissue regeneration, and its dysregulation is involved in the pathogenesis of many autoimmune diseases. Several evidences support its role especially in bone complications of rheumatic diseases. In Rheumatoid Arthritis (RA), the Wnt signaling is implicated in systemic and localized bone loss, while available data of its role in Spondyloarthritis (SpA) are conflicting. In the last few decades, the quality of life of rheumatic patients has been dramatically improved by biological therapy, targeting cytokines involved in the pathogenesis of these diseases like tumor necrosis factor (TNF)α, interleukin (IL)-1, IL-6, IL-17. In this review, we reviewed the role of Wnt signaling in RA and SpA, focusing on the effect of biological therapy on this pathway and its possible clinical implications.
Osteoporosis International, 2010
Summary In comparison with hip fractures, increased expression of genes in the Wnt pathway and increased Wnt activity were found in bone samples and osteoblast cultures from patients with osteoarthritis, suggesting the involvement of this pathway in subchondral bone changes. No consistent differences were found in the genetic association study. Introduction This study aims to explore the allelic variations and expression of Wnt pathway genes in patients with osteoporosis and osteoarthritis. Methods The expression of 86 genes was studied in bone samples and osteoblast primary cultures from patients with hip fractures and hip or knee osteoarthritis. The Wnt-related activity was assessed by measuring AXIN2 and in transfection experiments. Fifty-five SNPs of the LRP5, LRP6, FRZB, and SOST genes were analyzed in 1,128 patients. Results Several genes were differentially expressed in bone tissue, with the lowest values usually found in hip fracture and the highest in knee osteoarthritis. Overall, seven genes were consistently upregulated both in tissue samples and in cell cultures from patients with knee osteoarthritis (BCL9, FZD5, DVL2, EP300, FRZB, LRP5, and TCF7L1). The increased expression of AXIN2 and experiments of transient transfection of osteoblasts with the TOP-Flash construct confirmed the activation of Wnt signaling. Three SNPs of the LRP5 gene and one in the LRP6 gene showed marginally significant differences in allelic frequencies across the patient groups, but they did not resist multiple-test adjustment. Conclusions Genes in the Wnt pathway are upregulated in the osteoarthritic bone, suggesting their involvement not only in cartilage distortion but also in subchondral bone changes.
TGF-β role in osteoarthritis. A review
Cytokines role in osteoarthritis is now well recognized and impact the normal function or homeostasis of hyaline articular cartilage. TGF-b altogether with another cytokines such as BMP are regulatory or anabolic cytokines interact with the chondrocyte in a paracrine pathaway. TGF-β usually signals through a pair of transmembrane serine/threonine kinases known as the type I and type II TGF-β receptors and the deregulation of its signalling is implicated in OA. Once TGF-β ligand bind to specific type II receptors, the Smad-dependent TGF-β signaling pathways initiate a cascade of events yielding to phosphorylation of their specific receptor-Smads (R-Smads); TGF-β signaling depends on Smad2 and Smad3 proteins. As a pharmacological target, the stimulation of TGF-b expression in articular chondrocytes by diacerhein, further to its inhibition of IL-1, could favour cartilage homeostasis promoting anabolic processes in the OA cartilage, therefore contributing to delay the progression of the disease. In conclusion, drugs acting in chondrocyte in the pathway of TGF-β could favour anabolic processes in the OA cartilage, contributing to delay the progression of the disease, and adjusting to the definition of disease-modifying osteoarthritic drug which interferes with the cartilage breakdown observed and improve symptoms.