Table 1

Overview of the roles of various elements of the Wnt signaling pathway in osteoarthritis development, as demonstrated by human genetic studies or animal models

Effect on

Element treatment/SNPs

Wnt signaling

Results

Conclusions


Receptor

LRP5

Haplotype (C-G-C-C-A) in LRP5

Inhibition

This haplotype predisposes to increased risk of OA

LRP5 variant may predispose patients to OA [56]

Lrp5 knockout in mice

Inhibition

Increased cartilage degradation, decreased bone mineral density

Loss of function of Lrp5 leads to OA [57]

Wnt ligands

Wnts (up-regulated in OA)

Mechanical injury

Activation

Up-regulation of Wnt16/WISP-1, down-regulation of FRZB, up- regulation of β-catenin, axin-2, C-JUN and LEF-1

Mechanical injury activates Wnt signaling [43]

Wnt antagonists

Frzb (up-regulated in OA)

Arg200Trp/Arg324Gly Frzb variants

Activation

These two variants are associated with female hip OA from an epidemiological viewpoint

These two variants confer genetic susceptibility to female hip OA [46,47]

Arg200Trp/Arg324Gly Frzb variants

Activation

These two variants are associated with other generalized OA by epidemiological analysis

These two variants contribute to female hip OA [50]

Frzb knockout mice

Activation

Increased cartilage damage, thicker cortical bone formation

Loss of function of Frzb contributes to the development of OA [51]

DKK1 (up-regulated in OA)

Inhibition of DKK1 by antibody

Activation

Blocks bone erosion, promotes bone formation, reverses RA to OA

Wnt signaling is a key regulator of joint remodeling [53]

OA rat knees were treated with end-capped phosphorothioate Dkk-1 antisense oligonucleotide (Dkk-1-AS)

Inhibition

Alleviated Mankin score, cartilage fibrillation, and serum cartilage degradation markers

Dkk1 expression prevents OA cartilage destruction and subchondral bone damage [54]

Transcription factor

β-Catenin (up- regulated in OA)

Activation of β-catenin in articular chondrocytes

Activation

OA-like cartilage degradation, osteophyte formation, accelerated chondrocyte maturation and MMP13 expression

Wnt/β-catenin activation promotes OA development by accelerating chondrocyte maturation [58]

Suppression of β-catenin in articular chondrocytes

Inhibition

OA-like cartilage degradation, increased chondrocyte apoptosis

Wnt/β-catenin inhibition promotes OA development by increasing chondrocyte apoptosis [59]


LEF, lymphoid enhancing factor; MMP, matrix metalloproteinase; OA, osteoarthritis; RA, rheumatoid arthritis.

Zhu et al. Arthritis Research & Therapy 2013 15:217   doi:10.1186/ar4240