OBJECTIVE: The wingless-type MMTV integration site family (WNT) signalling pathway plays an important role in embryonic joint and bone development and has been associated with osteoporosis and osteoarthritis (OA). Loss-of-function mutations in low-density lipoprotein receptor-related protein 5 (LRP5), a WNT co-receptor, result in low bone mass. Lrp5(-)(/)(-) mice also have low bone mass phenotypes. Recently an OA-susceptibility locus containing the LRP5 gene was suggested. We investigated the effects of loss of Lrp5 in joint biology in three different mouse models of OA. METHODS: Total body bone mineral parameters were measured by dual-energy X-ray absorptiometry. Trabecular and cortical bone parameters of tibia and femur were assessed ex vivo by peripheral quantitative CT. Osteoarthritic changes were induced in Lrp5(-)(/)(-) and wild-type C57Bl/6J mice using the surgically induced destabilization of the medial meniscus model and the chemically induced papain and collagenase model. The severity of joint disease was investigated by histological analysis of the knee joints. RESULTS: Bone mineral density and weight were significantly decreased in Lrp5(-)(/)(-) C57Bl/6J mice compared with their wild-type littermates. Surgically induced destabilization of the knee joint resulted in significantly increased cartilage degradation in the medial tibia of Lrp5(-)(/)(-) mice compared with wild-type control mice. In the medial femur, a similar trend was found but did not reach statistical significance. In the papain- and collagenase-induced models, these differences were not observed. Inflammation scores were comparable between wild-type and Lrp5(-)(/)(-) mice. CONCLUSION: These data show that loss of function of Lrp5 increases cartilage degradation in mild instability-induced OA models in mice. Low bone mass density could have contributed to this effect.
OBJECTIVE: The wingless-type MMTV integration site family (WNT) signalling pathway plays an important role in embryonic joint and bone development and has been associated with osteoporosis and osteoarthritis (OA). Loss-of-function mutations in low-density lipoprotein receptor-related protein 5 (LRP5), a WNT co-receptor, result in low bone mass. Lrp5(-)(/)(-) mice also have low bone mass phenotypes. Recently an OA-susceptibility locus containing the LRP5 gene was suggested. We investigated the effects of loss of Lrp5 in joint biology in three different mouse models of OA. METHODS: Total body bone mineral parameters were measured by dual-energy X-ray absorptiometry. Trabecular and cortical bone parameters of tibia and femur were assessed ex vivo by peripheral quantitative CT. Osteoarthritic changes were induced in Lrp5(-)(/)(-) and wild-type C57Bl/6J mice using the surgically induced destabilization of the medial meniscus model and the chemically induced papain and collagenase model. The severity of joint disease was investigated by histological analysis of the knee joints. RESULTS: Bone mineral density and weight were significantly decreased in Lrp5(-)(/)(-) C57Bl/6J mice compared with their wild-type littermates. Surgically induced destabilization of the knee joint resulted in significantly increased cartilage degradation in the medial tibia of Lrp5(-)(/)(-) mice compared with wild-type control mice. In the medial femur, a similar trend was found but did not reach statistical significance. In the papain- and collagenase-induced models, these differences were not observed. Inflammation scores were comparable between wild-type and Lrp5(-)(/)(-) mice. CONCLUSION: These data show that loss of function of Lrp5increases cartilage degradation in mild instability-induced OA models in mice. Low bone mass density could have contributed to this effect.
Authors: B A Christiansen; F Guilak; K A Lockwood; S A Olson; A A Pitsillides; L J Sandell; M J Silva; M C H van der Meulen; D R Haudenschild Journal: Osteoarthritis Cartilage Date: 2015-05-21 Impact factor: 6.576