The Skeletal Phenotype of Chondroadherin Deficient Mice

Abstract

Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their α2β1 integrin as well as via cell surface proteoglycans, providing for different sets of signals to the cell. Additionally, the protein acts as an anchor to the matrix by binding tightly to collagens type I and II as well as type VI. We generated mice with inactivated chondroadherin gene to provide integrated studies of the role of the protein. The null mice presented distinct phenotypes with affected cartilage as well as bone. At 3–6 weeks of age the epiphyseal growth plate was widened most pronounced in the proliferative zone. The proteome of the femoral head articular cartilage at 4 months of age showed some distinct differences, with increased deposition of cartilage intermediate layer protein 1 and fibronectin in the chondroadherin deficient mice, more pronounced in the female. Other proteins show decreased levels in the deficient mice, particularly pronounced for matrilin-1, thrombospondin-1 and notably the members of the α1-antitrypsin family of proteinase inhibitors as well as for a member of the bone morphogenetic protein growth factor family. Thus, cartilage homeostasis is distinctly altered. The bone phenotype was expressed in several ways. The number of bone sialoprotein mRNA expressing cells in the proximal tibial metaphysic was decreased and the osteoid surface was increased possibly indicating a change in mineral metabolism. Micro-CT revealed lower cortical thickness and increased structure model index, i.e. the amount of plates and rods composing the bone trabeculas. The structural changes were paralleled by loss of function, where the null mice showed lower femoral neck failure load and tibial strength during mechanical testing at 4 months of age. The skeletal phenotype points at a role for chondroadherin in both bone and cartilage homeostasis, however, without leading to altered longitudinal growth.

The C-Terminal Domain of Chondroadherin: A New Regulator of Osteoclast Motility Counteracting Bone Loss

“…(34) Therefore, unbalance of these phases is observed in bone diseases in which, when bone resorption overwhelms bone formation, bone loss occurs, increasing bone fragility and risk of fractures. (35) In line with our recent report showing that CHAD is critical for preserving skeletal structure and strength, (36) this study demonstrates that cyclicCHAD increased bone mass in healthy mice through its anti-osteoclastic effect, and was active in preventing and curing osteoporosis in OVX mice and in increasing bone mass in elderly mice. In vivo, the mechanism of action appears be associated, at least in part, to the suppression of NO metabolism as well, because it was mimicked, although with a lower efficacy, by treatment with the NO inhibitor L-NIL.…”

Gene network and canonical pathway analysis in canine myxomatous mitral valve disease: A microarray study

“…KERA is a small leucine rich PG and plays a pivotal role in ECM assembly in the cornea to maintain translucency, while CHAD is an anchor to the matrix by binding tightly to collagens I, II, and VI in cartilage (Liu et al, 2003;Hessle et al, 2013). Nevertheless, the role of CHAD and KERA in the mitral valve is unknown.…”

Osteoarthritis year in review 2015: mechanics

“…70 used nanoindentation to quantify the biomechanical properties of femoral condyle cartilage in mice with deletion of chondroadherin (CHAD), a small leucine rich protein in the ECM. Deletion of CHAD previously revealed no observable OA-like phenotype 72 . However, nanoindentation revealed a ~70–80% reduction in the effective indentation modulus of CHAD−/− superficial zone cartilage compared to wild type (WT) controls at ages 11 weeks, 4 months and 1 year.…”