FrzB-2: a human secreted frizzled-related protein with a potential role in chondrocyte apoptosis

James, Ian E.; Kumar, Sanjay; Barnes, Michael R.; Gress, Catherine J.; Hand, Annalisa T.; Dodds, Robert A.; Connor, J.T.H.; Bradley, B.R.; Campbell, David A.; Grabill, S.E.; Williams, Ken; Blake, S; Gowen, Maxine; Lark, Michael W.

doi:10.1053/joca.1999.0321

Cited by 55 publications

(48 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These data indicate that sFRP-4 has phosphatonin-like properties, promoting phosphaturia and hypophosphatemia, and may therefore control bone mineralization. Finally, James et al [2000] have reported that sFRP-4 is highly expressed in chondrocytes from patients with sFRP-1 Controls Osteoblast and Osteocyte Apoptosisosteoarthritis, while its expression is negligible in cells from normal cartilage. Moreover, the authors observed a correlation between sFRP-4 expression and chondrocyte apopotosis.…”

Section: Discussionmentioning

confidence: 98%

The Wnt antagonist secreted frizzled‐related protein‐1 controls osteoblast and osteocyte apoptosis

Bodine¹,

Billiard²,

Moran³

et al. 2005

J of Cellular Biochemistry

157

113

View full text Add to dashboard Cite

Mechanisms controlling human bone formation remain to be fully elucidated. We have used differential display-polymerase chain reaction analysis to characterize osteogenic pathways in conditionally immortalized human osteoblasts (HOBs) representing distinct stages of differentiation. We identified 82 differentially expressed messages and found that the Wnt antagonist secreted frizzled-related protein (sFRP)-1 was the most highly regulated of these. Transient transfection of HOBs with sFRP-1 suppressed canonical Wnt signaling by 70% confirming its antagonistic function in these cells. Basal sFRP-1 mRNA levels increased 24-fold during HOB differentiation from pre-osteoblasts to pre-osteocytes, and then declined in mature osteocytes. This expression pattern correlated with levels of cellular viability such that the preosteocytes, which had the highest levels of sFRP-1 mRNA, also had the highest rate of cell death. Basal sFRP-1 mRNA levels also increased 29-fold when primary human mesenchymal stem cells were differentiated to osteoblasts supporting the developmental regulation of the gene. Expression of sFRP-1 mRNA was induced 38-fold following prostaglandin E 2 (PGE 2 ) treatment of pre-osteoblasts and mature osteoblasts that had low basal message levels. In contrast, sFRP-1 expression was down-regulated by as much as 80% following transforming growth factor (TGF)-b1 treatment of preosteocytes that had high basal mRNA levels. Consistent with this, treatment of pre-osteoblasts and mature osteoblasts with PGE 2 increased apoptosis threefold, while treatment of pre-osteocytes with TGF-b1 decreased cell death by 50%. Likewise, over-expression of sFRP-1 in HOBs accelerated the rate of cell death threefold. These results establish sFRP-1 as an important negative regulator of human osteoblast and osteocyte survival.

show abstract

Section: Discussionmentioning

confidence: 98%

The Wnt antagonist secreted frizzled‐related protein‐1 controls osteoblast and osteocyte apoptosis

Bodine¹,

Billiard²,

Moran³

et al. 2005

J of Cellular Biochemistry

157

113

View full text Add to dashboard Cite

show abstract

“…Inhibition of Wnt proteins promotes programmed cell death in different types of cancer cells (50,51). In human OA cartilage, FrzB-2 is highly expressed and is associated with chondrocyte apoptosis (52). In Col2a1-ICAT-transgenic mice in which ␤-catenin signaling is selectively blocked in chondrocytes, apoptosis is increased (27).…”

Section: Discussionmentioning

confidence: 99%

Chromatin protein HMGB2 regulates articular cartilage surface maintenance via β-catenin pathway

Taniguchi

Caramés

Kawakami

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The superficial zone (SZ) of articular cartilage is critical in maintaining tissue function and homeostasis and represents the site of the earliest changes in osteoarthritis. Mechanisms that regulate the unique phenotype of SZ chondrocytes and maintain SZ integrity are unknown. We recently demonstrated that expression of the chromatin protein high mobility group box (HMGB) protein 2 is restricted to the SZ in articular cartilage suggesting a transcriptional regulation involving HMGB2 in SZ. Here, we show that an interaction between HMGB2 and the Wnt/␤-catenin pathway regulates the maintenance of the SZ. We found that the Wnt/␤-catenin pathway is active specifically in the SZ in normal mouse knee joints and colocalizes with HMGB2. Both Wnt signaling and HMGB2 expression decrease with aging in mouse joints. Our molecular studies show that HMGB2 enhances the binding of Lef-1 to its target sequence and potentiates transcriptional activation of the Lef-1-␤-catenin complex. The HMG domain within HMGB2 is crucial for interaction with Lef-1, suggesting that both HMGB2 and HMGB1 may be involved in this function. Furthermore, conditional deletion of ␤-catenin in cultured mouse chondrocytes induced apoptosis. These findings define a pathway where protein interactions of HMGB2 and Lef-1 enhance Wnt signaling and promote SZ chondrocyte survival. Loss of the HMGB2-Wnt signaling interaction is a new mechanism in aging-related cartilage pathology.aging ͉ osteoarthritis ͉ apoptosis ͉ superficial zone A rticular cartilage is a tissue that provides biomechanical properties that allow near frictionless joint movement and dispersion of mechanical loads. Cartilage is composed of a single cell lineage but differences in the organization, phenotype and function of cells in the various layers of cartilage have been recognized (1-4). The superficial zone (SZ) is the most unique. SZ cells produce lubricin, also termed proteoglycan-4 (PRG4) or superficial zone protein (SZP), an important joint lubricant (5-7), and are more responsive to stimulation by catabolic cytokines such as IL-1 (8). Recent studies also suggest that the SZ contains cells that express mesenchymal stem cell markers (9-11).Articular cartilage is among the tissues that undergo profound aging-related changes and aging represents the major risk factor for osteoarthritis (OA), the most prevalent joint disease (12). Agingrelated changes in cartilage include reduced cellularity, increased apoptosis and altered cellular responses to growth factors, cytokines and mechanical stress (13-15). Cartilage changes in aging and OA begin in the SZ and once the SZ is disrupted this is followed by progressive erosion of the remaining cartilage layers (16).To address mechanisms that maintain the unique phenotype of SZ cells we performed gene expression analyses and observed that expression of the chromatin protein HMGB2 is restricted to the SZ (17). Joint aging in humans and mice leads to loss of HMGB2 expression and this is correlated with the onset of OA-like changes. Mice deficient in Hm...

show abstract

“…OA cartilage displays signs of Wnt/catenin activation and expresses FRP (7,32,33). Ectopic canonical Wnt signaling leads to enhanced ossification and suppression of chondrocyte formation (34).…”

Section: Discussionmentioning

confidence: 99%

Frizzled‐related protein variants are risk factors for hip osteoarthritis

Lane

Lian

Nevitt

et al. 2006

Arthritis & Rheumatism

121

View full text Add to dashboard Cite

Objective. To examine the association of the Arg200Trp and Arg324Gly variants of FRZB with the risk and phenotype of radiographic osteoarthritis (OA) of the hip and serum levels of Frizzled-related protein (FRP) in a prospective cohort of elderly Caucasian women.Methods. Radiographic hip OA status of patients was defined by the presence of severe joint space narrowing (JSN) (feature grade >3), a summary grade >3, or definite osteophytes (grade >2) and JSN (grade >2) in the same hip. Genotypes were obtained in 569 patients with radiographic OA of the hip and in 1,317 and 4,136 controls for the Arg200Trp and Arg324Gly variants, respectively. Serum FRP levels were measured by enzyme-linked immunosorbent assay. Multivariate logistic regression was performed.Results. The minor allele frequency for the Arg200Trp polymorphism was 0.12 in the control group compared with 0.14 in the group with radiographic OA of the hip (P ‫؍‬ 0.12), and the minor allele frequency for the Arg324Gly variant was 0.083 in the control group compared with 0.088 in the group with radiographic OA of the hip (P ‫؍‬ 0.63). The multilocus genotypes available in 1,886 subjects suggested that inheritance of both minor alleles was a risk factor for developing OA characterized by JSN (P < 0.01). Patients with radiographic OA of the hip who were homozygous for the Arg200Trp minor allele had higher serum FRP levels than controls who were homozygous for the major allele.Conclusion. Our data confirm findings of another study, that a rare haplotype with both Arg200Trp and Arg324Gly FRZB variants contributes to the genetic susceptibility to hip OA among Caucasian women, and that these polymorphisms may contribute to increased serum levels of proteins as biomarkers of OA.

show abstract

FrzB-2: a human secreted frizzled-related protein with a potential role in chondrocyte apoptosis

Abstract: These data suggest that FrzB-2 may play a role in apoptosis and that the expression of this protein may be important in the pathogenesis of human OA.

Cited by 55 publications

References 27 publications

The Wnt antagonist secreted frizzled‐related protein‐1 controls osteoblast and osteocyte apoptosis

The Wnt antagonist secreted frizzled‐related protein‐1 controls osteoblast and osteocyte apoptosis

Chromatin protein HMGB2 regulates articular cartilage surface maintenance via β-catenin pathway

Frizzled‐related protein variants are risk factors for hip osteoarthritis

Contact Info

Product

Resources

About