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


CONCLUSIONS
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.
Lories
Rik J U
RJ
Laboratory for Skeletal Development and Joint Disorders, Department of Rheumatology, University Hospitals Leuven, Katholieke Universiteit Leuven, Herestraat 49, Leuven, Belgium.
Peeters
Jenny
J
Bakker
Astrid
A
Tylzanowski
Przemko
P
Derese
Inge
I
Schrooten
Jan
J
Thomas
J Terrig
JT
Luyten
Frank P
FP
D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000502:physiology; D002357:Cartilage Diseases / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D017364:Collagenases; D004195:Disease Models, Animal; D005269:Femur / Q000378:metabolism* / Q000473:pathology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010024:Osteoporosis / Q000378:metabolism / Q000473:pathology; D010206:Papain; D013977:Tibia / Q000378:metabolism* / Q000473:pathology; D051153:Wnt Proteins / Q000378:metabolism*; D000099274:Frizzled-Related Proteins
D017364:Collagenases; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D019278:Matrix Metalloproteinase 3; D010206:Papain; D051153:Wnt Proteins; D000099274:Frizzled-Related Proteins