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Molecular mechanisms involved in a differential association of Frzb biology with osteoarthritis and osteoporosis
Arthritis Research & Therapy volume 9, Article number: P37 (2007)
Background
Nonsynonymous polymorphisms in the human FRZB gene have been associated with osteoarthritis (OA). In addition, a differential association between OA and osteoporosis (OP) has been reported. We have demonstrated that genetic deletion of the Frzb gene in mice increases cartilage damage in different models of OA. In addition, Frzb-/- mice show increased cortical bone density.
Objective
To study the underlying molecular mechanisms involved in cartilage damage and increased bone density in Frzb-/- mice.
Methods
Active Wnt signaling in the articular cartilage was studied in normal and methylated bovine serum albumin, collagenase and papain-induced arthritis using β-catenin (CTNNB1) immunohistochemistry. Gene expression patterns of components of the Wnt signaling pathway, its antagonist and target genes, were studied using multigene cDNA arrays (Superarray) in microdissected articular cartilage and soft tissues of healthy and affected knees from Frzb-/- and wild-type mice. Gene expression of tissue destructive enzymes in the cartilage was studied by real-time PCR. Matrix metalloproteinase-3 activity was tested in vitro. Cortical bone stiffness was estimated by compression of the ulnae. Mechanical loading-induced bone adaptation was studied by compression of the ulnae of 17-week-old mice, followed by microcomputed tomography analysis at a resolution of 5 μm. Subchondral bone properties were studied with histomorphometry, peripheral quantitative computed tomography and microcomputed tomography.
Results
In healthy cartilage of Frzb-/- mice, four genes were consistently expressed at lower levels than in the wild-type mice: Ctnnb1, Ctbp1, Fosl1 and Myc. In contrast, Wnt8b expression was upregulated in healthy cartilage in 2/3 samples from Frzb-/- versus wild-type mice and in all samples in affected versus healthy wild-type cartilage. Ctbp1 and Fosl1 were also downregulated in all samples from arthritic wild-type mice versus healthy ones. In addition, Wnt8b appears to be downregulated in arthritic versus healthy joints of Frzb-/- mice, suggesting a distinct regulation of Wnt ligand expression in the genetic model as compared with the wild-type mice. Cartilage damage in Frzb-/- mice is associated with increased canonical Wnt signaling, matrix metalloproteinase-3 expression and activity. In addition, the Frzb-/- mice have an increased cortical bone thickness and density, resulting in stiffer bones as demonstrated by a different stress–strain relationship in Frzb-/- mice. Moreover, the periosteal anabolic response to mechanical loading is significantly greater in Frzb-/- mice than in wild-type mice. FRZB is expressed in the periosteum.
Conclusion
The preinduction gene expression profile in Frzb-/- mice shows similarities with arthritic cartilage in wild-type mice. Loss of Frzb may contribute to cartilage damage by increased expression and activity of matrix metalloproteinase in both a Wnt-dependent and Wnt-independent manner. FRZB deficiency also results in thicker cortical bone with increased stiffness and higher cortical appositional bone formation after loading. This may contribute to OA by producing increased strain on the articular cartilage during locomotion. Increased cortical density of long bones in Frzb-/- mice supports our earlier observation that polymorphisms in the human FRZB gene are differentially associated with hip OA and OP hip fractures. The role of FRZB in cartilage and bone biology may therefore provide a mechanistic basis for the longstanding clinical observation that OA and OP show an inverse relationship.
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Lories, R.J., Schrooten, J., Derese, I. et al. Molecular mechanisms involved in a differential association of Frzb biology with osteoarthritis and osteoporosis. Arthritis Res Ther 9, P37 (2007). https://doi.org/10.1186/ar2263
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Keywords
- Articular Cartilage
- Cartilage Damage
- Microcomputed Tomography
- Cortical Bone Thickness
- Healthy Cartilage
