Articular cartilage and biomechanical properties of the long bones in Frzb ‐knockout mice

108

Objective. Dkk is a family of canonical Wnt antagonists with 4 members (Dkk-1, Dkk-2, Dkk-3, and Dkk-4). We undertook this study to explore the roles of Dkk-1 and Dkk-2 in osteoarthritic (OA) cartilage destruction in mice.Methods. Expression of Dkk and other catabolic factors was determined at the messenger RNA and protein levels in human and mouse OA cartilage. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM) or by intraarticular injection of Epas1 adenovirus (AdEPAS-1). The role of Dkk in OA pathogenesis was examined by intraarticular injection of AdDkk-1 or by using chondrocyte-specific Dkk1 (Col2a1-Dkk1)-transgenic mice and Dkk2 (Col2a1-Dkk2)-transgenic mice. Primary culture mouse chondrocytes were also treated with recombinant Dkk proteins.Results. We found opposite patterns of Dkk1 and Dkk2 expression in human and mouse experimental OA cartilage: Dkk1 was up-regulated and Dkk2 was downregulated. Overexpression of Dkk1 by intraarticular injection of AdDkk-1 significantly inhibited DMMinduced experimental OA. DMM-induced OA was also significantly inhibited in Col2a1-Dkk1-transgenic mice compared with their wild-type littermates. However, Col2a1-Dkk2-transgenic mice showed no significant difference in OA pathogenesis. Wnt-3a, which activates the canonical Wnt pathway, induced Mmp13 and Adamts4 expression in primary culture chondrocytes, an effect that was significantly inhibited by Dkk-1 pretreatment or Dkk1 overexpression.Conclusion. Our findings indicate that expression of Dkk1, but not Dkk2, in chondrocytes inhibits OA cartilage destruction. The protective effect of Dkk-1 appears to be associated with its capacity to inhibit Wnt-mediated expression of catabolic factors, such as Mmp13, providing evidence that Dkk-1 might serve as a therapeutic target for OA treatment.

Section: Dkk-1 Inhibits Experimental Oa 2575supporting

confidence: 90%

mentioning

confidence: 99%

Dkk‐1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice

Oh¹,

Chun²,

Chun³

2012

108

“…It is, however, generally known that meta-analyses have little power to detect relatively rare variants with a modest effect that confer risk in a specific subset of OA cases. Furthermore, functional studies in Frzb-knockout mice showed increased cortical bone thickness and density, resulting in stiffer bones upon mechanical loading, which may increase OA susceptibility and stresses developmental aspects (8).…”

mentioning

confidence: 99%

Osteoarthritis susceptibility genes influence the association between hip morphology and osteoarthritis

Waarsing

Kloppenburg

Slagboom

et al. 2011

Objective. The identified osteoarthritis (OA) susceptibility genes are mainly active in skeletal development and could thus affect joint geometry. Because nonoptimal joint geometry is a risk factor for the development of OA, we investigated if and how the path that leads from nonoptimal joint geometry to OA of the hip is influenced by these genes.Methods. The shape of the hips of subjects in the Genetics, Osteoarthritis and Progression Study, consisting of sibling pairs with symptomatic OA at multiple joint locations, was quantified by applying a statistical shape model to radiographs. Shape aspects (modes) were correlated to OA characteristics. We then tested for the association of shape modes with OA susceptibility single-nucleotide polymorphisms (SNPs) of GDF5, FRZB, and DIO2.Results. Four of 23 shape modes (mode 1, mode 17, mode 18, and mode 21) were strongly associated with OA characteristics. We observed a significant interaction between carrier status of DIO2 rs12885300 and hip OA characteristics for mode 1 (P ‫؍‬ 0.005). This indicates that this specific aspect of hip shape correlates with OA characteristics only in carriers of the susceptibility allele.Conclusion. Our results suggest that it is more likely that the rs12885300 SNP of DIO2 increases the vulnerability of cartilage to nonoptimal bone shapes rather than directly influencing the formation of these shapes.The genetic predisposition for osteoarthritis (OA) (1) may reflect the result of multiple interacting genes with small effects (2). The identification of such genes should be considered essential to obtain a better understanding of OA and the underlying biologic events preceding its onset (3). One path leading to OA in which genes might play a role starts with the causal effect of hip morphology on the development of OA and may explain part of the heritability of hip OA. The life-long biomechanical stress caused by a nonoptimal shape of the bones in the joint leads to recurrent damage of cartilage, which eventually triggers the onset of OA (4).What is interesting in this respect is the fact that genes that are mainly active in skeletal development, such as FRZB and GDF5, are identified as OA susceptibility genes (5,6). These genes are involved in the orchestration of growth plate chondrocytes that results in formation of cartilage and eventually bone during endochondral ossification (7). A recent large-scale metaanalysis (6) did not provide evidence for the relatively rare FRZB OA risk alleles, indicating that these variants do not confer susceptibility to common OA. It is, however, generally known that meta-analyses have little power to detect relatively rare variants with a modest effect that confer risk in a specific subset of OA cases. Furthermore, functional studies in Frzb-knockout mice showed increased cortical bone thickness and density, resulting in stiffer bones upon mechanical loading, which may increase OA susceptibility and stresses developmental aspects (8).

“…Through its influence on Wnt signaling, FRZB is a powerful and direct modulator of chondrocyte maturation (6). Accelerated cartilage breakdown has been shown to develop in knockout mice deficient in this gene (7). The original study in which an association of FRZB with hip OA was reported involved a cohort of women (8); that study showed that the associated alleles at FRZB reduced the activity of the protein encoded.…”

mentioning

confidence: 99%

Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee

Valdes

Loughlin

Oene

et al. 2007

180

118

Objective. To assess whether the association of genetic polymorphisms with osteoarthritis (OA) in other populations could be replicated in a large, multicenter, mixed-sex, case-control study of clinical knee OA.Methods. Genetic polymorphisms in OA candidate genes were genotyped in 298 men and 305 women, ages 50-86 years, all of whom had a diagnosis of knee OA as assessed clinically and radiographically, and in 300 male and 299 female control subjects matched for age and ethnicity. Allele and haplotype frequencies for 5 genes (ASPN, CALM1, COL2A1, COMP, and FRZB) previously tested for association with hip and/or knee OA in other populations were compared between patients and control subjects, analyzing men and women separately.Results. The same FRZB 2-marker single-nucleotide polymorphism (SNP) haplotype associated with hip OA in other populations of Caucasian women was shown to increase the risk of knee OA among the women (but not the men) in the current study (odds ratio [OR] 2.87, P < 0.04). The CALM1 SNP, which affects the risk of hip OA in Japanese individuals, was not shown to be associated with susceptibility to OA in men or women. COL2A1 haplotypes were demonstrated to be associated with a decreased risk of knee OA in men (OR 0.68, P < 0.005) but not in women. COMP haplotypes that were associated with susceptibility to knee OA were different in men and women (P < 0.014 and P < 0.032, respectively). A meta-analysis of these data and those from previously published reports indicated a strong association between the FRZB G324 allele (P < 0.0003) and suggested that an ASPN allele is protective against the risk of knee OA in Caucasians (P < 0.02).Conclusion. Our results indicate that genetic polymorphisms affecting knee OA vary between populations (Japanese versus Caucasian) and sexes and indicate a role for ASPN, COMP, FRZB, and COL2A1 in Caucasians.