2q32.1

FRE,FRITZ,FRP-3,FRZB-1,FRZB-PEN,FRZB1,FZRB,OS1,SFRP3,SRFP3,hFIZ

Osteoarthritis

Osteoarthritis is a chronic degenerative joint disease without underlying autoimmune or autoinflammatory mechanisms. The disease leads to pain and disability and affects millions of people worldwide. Although once considered as a disease of the articular cartilage, the current concept holds that the whole joint is involved, including the subchondral bone, menisci, ligaments, periarticular muscle, capsule and synovium. Osteoarthritis is a complex disorder to which both genetic and acquired factors contribute (Hunter et al., 2006).
Polymorphisms in FRZB (Arg200Trp and Arg324Gly) have been associated with osteoarthritis (Loughlin et al., 2004; Min et al., 2005; Lories et al., 2005; Lane et al., 2006; Valdes et al., 2007). However, the results from a recent meta-analysis showing no overall effect of FRZB genetic variants on hip or knee OA debated this association (Evangelou et al., 2009). Recently, a transcriptomics analysis in Frzb^-/- mice provided evidence for a tight regulation of WNT signalling and highlighted the complex role for FRZB in joint homeostasis (Lodewyckx et al., 2012). Moreover, Frzb^-/- mice show increased cartilage damage when challenged by different models of acute and short-term joint, suggesting a role for FRZB in osteoarthritis. The observed cartilage damage was associated with increased WNT signalling and matrix metalloproteinase 3 (MMP-3) expression and activity. Additionally, Frzb^-/- mice have increased cortical bone thickness and density without changes in the trabecular bone (Lories et al., 2007).

The haplotype coding for substitutions of two highly conserved arginine residues (Arg200Trp and Arg324Gly) in FRZB are associated with hip osteoarthritis in females. Moreover, transfection studies indicated that substitutions of these positively charged residues reduced the ability of FRZB to inhibit WNT signalling (Loughlin et al., 2004). Additionally, an association analysis confirmed that the R324G variant of the FRZB gene is involved in osteoarthritis and indicates a role of this variant in several generalized OA phenotypes (Min et al., 2005). Next, evidence was found for a differential association of the FRZB Arg200Trp polymorphism with hip osteoarthritis and osteoporosis (Lories et al., 2005). Lane et al. confirmed the earlier finding that a rare haplotype with both Arg200Trp and Arg324Gly FRZB variants contributes to hip osteoarthritis in women. Further, an association of genetic polymorphisms of FRZB and knee osteoarthritis was found (Valdes et al., 2007). In contrast, Rodriguez-Lopez et al. could not find an association of FRZB polymorphisms with either generalised osteoarthritis or hip OA. But, their results suggest that the Arg324Gly SNP may have an effect in the development of osteoarthritis in multiple joints. Furthermore, a large-scale meta-analysis of individual-level data does not support the association of SNPs of FRZB with osteoarthritis (Evangelou et al., 2009).

Colorectal cancer

The functional genetic variant Arg324Gly of FRZB was shown to be associated with colorectal cancer risk (Shanmugam et al., 2007). However, Berndt et al. observed no association for either polymorphisms (Arg324Gly and Arg200Trp) or any haplotypes with colorectal adenoma or colorectal cancer.

Gastric cancer

Overexpression of FRZB in gastric cancer cell suppresses proliferation and modulates the balance between proliferation and differentiation in gastric cancer (Qu et al., 2008c). Additionally, FRZB exhibits anti-tumor ability in gastric cancer cell line SGC-7901 in vitro and in vivo, and decreases the expression of MMP-2, MMP-7 and MMP-9 leading to a reduced invasion ability of the tumor cells (Qu et al., 2008b).

Prostate cancer

Ectopic expression of FRZB in an androgen-independent prostate cancer cellular model results in the suppression of tumor growth and cellular invasiveness. This provides evidence that FRZB can act as a tumor suppressor gene (Zi et al., 2005).

Micro-array analysis shows that FRZB has virtually no mRNA expression in osteogenic sarcoma-derived specimens compared to control (Mandal et al., 2007).

Breast cancer

Expression of FRZB is turned off in breast carcinomas (versus normal breasts). These results suggest that FRZB is a candidate gene for malignancies (Ugolini et al., 1999).

Renal cancer

A kidney tissue microarray and analysis of FRZB overexpression in a renal cancer cell line shows that sFRP3 expression promotes cell growth, invasion, and inhibition of apoptosis in renal cancer cells (Hirata et al., 2010).

Bladder cancer

Methylation of HOXB2, KRT13 and FRZB are associated with aggressive invasive bladder cancer (Marsit et al., 2010).

Malignant pleural mesothelioma

The transcription of the SFRP family is frequently down-regulated in human malignant pleural mesothelioma (Lee et al., 2004).

Soft tissue sarcomas

FRZB overexpression in fibrosarcoma and liposarcoma cell lines reduces cell motility, invasiveness and tumorigenesis. These results implicate an important tumor suppressive function for FRZB in sarcomas (Guo et al., 2008).

Melanoma

FRZB expression is reduced in malignant melanoma tissues and cell lines compared to normal cells and this down-regulation is related to methylation of the FRZB gene. Additionally, recombinant FRZB decreases migration and invasion of melanoma cells (Ekström et al., 2011).