Review Article: Is Wnt Signaling an Attractive Target for the Treatment of Osteoarthritis?

Abstract

Osteoarthritis is the most common chronic joint disease affecting millions of people worldwide and a leading cause of pain and disability. Increasing incidence of obesity and aging of the population are two factors that suggest that the impact of osteoarthritis will further increase at the society level. Currently, there are no drugs available that can manage both structural damage to the joint or the associated pain. Increasing evidence supports the view that the Wnt signaling pathway plays an important role in this disease. The current concept, based on genetic and functional studies, indicates that tight regulation of Wnt signaling in cartilage is essential to keep the joint healthy. In this review, we discuss how this concept has evolved, provide insights into the regulation of Wnt signaling, in particular by Wnt modulators such as frizzled-related protein and DOT1-like histone lysine methyltransferase, and summarize preclinical evidence and molecular mechanisms of lorecivivint, the first Wnt antagonist in clinical development for osteoarthritis.

Exploring the Crosstalk between Hydrostatic Pressure and Adipokines: An In Vitro Study on Human Osteoarthritic Chondrocytes

“…The pivotal role of the canonical Wnt/β-catenin signaling pathway in articular cartilage homeostasis and joint disease has been extensively reported [ 56 , 57 ].…”

Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases

“…A phase II study of CNTX-4975, a synthetic trans-capsaicin, showed that 1 mg of CNTX-4975 via local injection reduced pain associated with walking and improved knee stiffness and physical function in patients with OA knee pain [ 406 ]. An oral TRPV1 antagonist, NEO6860, did not show significant improvement compared to placebo in phase II study [ 407 ].…”

Arthritis and the role of endogenous glucocorticoids

“…Unfortunately, the study by Tu et al 252 did not investigate the mechanism of how osteoblasts facilitate pathological aspects of OA, although a potential pathway may be through Wnt/β-catenin signaling. 253 The Wnt/β-catenin pathway has been well described in OA pathogenesis and is known it play an important role in the disease (reviewed in 254 ). In fact, a small molecule Wnt inhibitor (Lorecivivint, SM04690) has provided encouraging results as a disease-modifying OA drug, improving pain, function, and joint space width, in recent phase I and II clinical trials (NCT02095548).…”

“…In fact, a small molecule Wnt inhibitor (Lorecivivint, SM04690) has provided encouraging results as a disease-modifying OA drug, improving pain, function, and joint space width, in recent phase I and II clinical trials (NCT02095548). 254,255 Wnt/β-catenin activity is increased in both OA subchondral bone and cartilage 256 Chondrocytes (Macfarlane et al 264 ) Synovial fibroblasts (Hardy et al 226 ) Myocytes (Hardy et al 226 ) Mast cells (Coutinho et al 236 ) Chondrocytes (Tu et al 238 ) Pro-inflammatory effects via Fig. 4 Endogenous glucocorticoid signaling in rheumatoid arthritis and osteoarthritis.…”

“…In fact, a small molecule Wnt inhibitor (Lorecivivint, SM04690) has provided encouraging results as a disease-modifying OA drug, improving pain, function, and joint space width, in recent phase I and II clinical trials (NCT02095548). 254 , 255 Wnt/β-catenin activity is increased in both OA subchondral bone and cartilage 256 and inhibition of Wnt signaling in menisectomized mice by transgenic expression of Dickkopf-1 (Dkk-1), a Wnt antagonist and known target of GCs, 256 , 257 can reduce OA severity. 256 In addition, evidence suggests that Dkk-1 can reduce cartilage degradation by inhibiting vascular endothelial growth factor (VEGF) expression in bone, 256 providing a possible “cross-talk” mechanism by which bone directly influences cartilage pathology.…”