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Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice
Rik J U Lories1, Jenny Peeters, Astrid Bakker
1Laboratory for Skeletal Development and Joint Disorders, Department of Rheumatology, University Hospitals Leuven, Katholieke Universiteit Leuven, Herestraat 49, Leuven, Belgium.
Objective:
Ligands and antagonists of the WNT pathway are linked to osteoporosis and osteoarthritis. In particular, polymorphisms in the FRZB gene, a secreted WNT antagonist, have been associated with osteoarthritis. The aim of this study was to examine cartilage and bone in Frzb(-/-) mice.
Methods:
The Frzb gene in mice was inactivated using a Cre/loxP strategy. Three models of osteoarthritis were used: collagenase, papain, and methylated bovine serum albumin induced. Bone biology was studied using density measurements and microfocal computed tomography. Bone stiffness and mechanical loading-induced bone adaptation were studied by compression of the ulnae.
Results:
Targeted deletion of the Frzb gene in mice increased articular cartilage loss during arthritis triggered by instability, enzymatic injury, or inflammation. Cartilage damage in Frzb(-/-) mice was associated with increased WNT signaling and matrix metalloproteinase 3 (MMP-3) expression and activity. Frzb(-/-) mice had increased cortical bone thickness and density, resulting in stiffer bones, as demonstrated by stress-strain relationship analyses. Moreover, Frzb(-/-) mice had an increased periosteal anabolic response to mechanical loading as compared with wild-type mice.
Conclusion:
The genetic association between osteoarthritis and FRZB polymorphisms is corroborated by increased cartilage proteoglycan loss in 3 different models of arthritis in Frzb(-/-) mice. Loss of Frzb may contribute to cartilage damage by increasing the expression and activity of MMPs, in a WNT-dependent and WNT-independent manner. FRZB deficiency also resulted in thicker cortical bone, with increased stiffness and higher cortical appositional bone formation after loading. This may contribute to the development of osteoarthritis by producing increased strain on the articular cartilage during normal locomotion but may protect against osteoporotic fractures.
Insights
Loss of the secreted WNT antagonist, Frzb, exacerbates cartilage damage in osteoarthritis models. Frzb deficiency also leads to denser, stiffer bones, potentially increasing osteoarthritis risk but protecting against fractures.
Area of Science:
- Molecular biology
- Skeletal biology
- Rheumatology
Background:
- WNT pathway ligands and antagonists are implicated in osteoporosis and osteoarthritis.
- Genetic variations in FRZB, a WNT antagonist, are linked to osteoarthritis development.
Purpose of the Study:
- To investigate the role of the Frzb gene in cartilage and bone.
- To examine the effects of Frzb deficiency on osteoarthritis pathogenesis and bone properties.
Main Methods:
- Frzb gene knockout mice were generated using Cre/loxP technology.
- Osteoarthritis was induced using collagenase, papain, and methylated bovine serum albumin models.
- Bone density, microarchitecture, stiffness, and mechanical loading responses were assessed.
Main Results:
- Frzb(-/-) mice exhibited increased articular cartilage loss across all osteoarthritis models.
- Cartilage damage correlated with elevated WNT signaling and matrix metalloproteinase 3 (MMP-3) activity.
- Frzb deficiency resulted in increased cortical bone thickness, density, and stiffness, with enhanced periosteal response to mechanical loading.
Conclusions:
- The study confirms the association between FRZB and osteoarthritis, showing Frzb deficiency worsens cartilage degradation.
- Loss of Frzb contributes to cartilage damage via increased MMP expression and activity, potentially through WNT-dependent and independent pathways.
- Frzb deficiency leads to denser, stiffer bones and increased bone formation, which may influence osteoarthritis progression and fracture risk.
