W R Parrish1, B A Byers2, D Su3, J Geesin4, U Herzberg5, S Wadsworth6, A Bendele7, B Story8. 1. DePuy Synthes Mitek Sports Medicine, Raynham, MA, USA. Electronic address: wparrish@its.jnj.com. 2. DePuy Synthes Mitek Sports Medicine, Raynham, MA, USA. Electronic address: bbyers@its.jnj.com. 3. Advanced Therapeutics and Regenerative Medicine, Johnson & Johnson, Somerville, NJ, USA. Electronic address: sudongling@yahoo.com. 4. Advanced Therapeutics and Regenerative Medicine, Johnson & Johnson, Somerville, NJ, USA. Electronic address: jeffrey@geesinconsulting.com. 5. Advanced Therapeutics and Regenerative Medicine, Johnson & Johnson, Somerville, NJ, USA. Electronic address: uherzberg@celgene.com. 6. Advanced Therapeutics and Regenerative Medicine, Johnson & Johnson, Somerville, NJ, USA. Electronic address: scottawadsworth@comcast.net. 7. Bolder BioPATH, Boulder, CO, USA. Electronic address: Alison@bolderbiopath.com. 8. DePuy Synthes Mitek Sports Medicine, Raynham, MA, USA. Electronic address: bstory1@its.jnj.com.
Abstract
OBJECTIVE: Investigation of osteoarthritis (OA) risk alleles suggests that reduced levels of growth and differentiation factor-5 (GDF5) may be a precipitating factor in OA. We hypothesized that intra-articular recombinant human GDF5 (rhGDF5) supplementation to the OA joint may alter disease progression. METHODS: A rat medial meniscus transection (MMT) joint instability OA model was used. Animals received either one intra-articular injection, or two or three bi-weekly intra-articular injections of either 30 μg or 100 μg of rhGDF5 beginning on day 21 post surgery after structural pathology had been established. Nine weeks after MMT surgery, joints were processed for histological analysis following staining with toluidine blue. Control groups received intra-articular vehicle injections, comprising a glycine-buffered trehalose solution. OA changes in the joint were evaluated using histopathological end points that were collected by a pathologist who was blinded to treatment. RESULTS: Intra-articular rhGDF5 supplementation reduced cartilage lesions on the medial tibial plateau in a dose-dependent manner when administered therapeutically to intercept OA disease progression. A single 100 μg rhGDF5 injection on day 21 slowed disease progression at day 63. A similar effect was achieved with two bi-weekly injections of 30 μg. Two bi-weekly injections of 100 μg or three bi-weekly injections of 30 μg stopped progression of cartilage lesions. Importantly, three biweekly injections of 100 μg rhGDF5 stimulated significant cartilage repair. CONCLUSIONS: Intra-articular rhGDF5 supplementation can prevent and even reverse OA disease progression in the rat MMT OA model. Collectively, these results support rhGDF5 supplementation as an intra-articular disease modifying OA therapy.
OBJECTIVE: Investigation of osteoarthritis (OA) risk alleles suggests that reduced levels of growth and differentiation factor-5 (GDF5) may be a precipitating factor in OA. We hypothesized that intra-articular recombinant humanGDF5 (rhGDF5) supplementation to the OA joint may alter disease progression. METHODS: A rat medial meniscus transection (MMT) joint instability OA model was used. Animals received either one intra-articular injection, or two or three bi-weekly intra-articular injections of either 30 μg or 100 μg of rhGDF5 beginning on day 21 post surgery after structural pathology had been established. Nine weeks after MMT surgery, joints were processed for histological analysis following staining with toluidine blue. Control groups received intra-articular vehicle injections, comprising a glycine-buffered trehalose solution. OA changes in the joint were evaluated using histopathological end points that were collected by a pathologist who was blinded to treatment. RESULTS: Intra-articular rhGDF5 supplementation reduced cartilage lesions on the medial tibial plateau in a dose-dependent manner when administered therapeutically to intercept OA disease progression. A single 100 μg rhGDF5 injection on day 21 slowed disease progression at day 63. A similar effect was achieved with two bi-weekly injections of 30 μg. Two bi-weekly injections of 100 μg or three bi-weekly injections of 30 μg stopped progression of cartilage lesions. Importantly, three biweekly injections of 100 μg rhGDF5 stimulated significant cartilage repair. CONCLUSIONS: Intra-articular rhGDF5 supplementation can prevent and even reverse OA disease progression in the ratMMT OA model. Collectively, these results support rhGDF5 supplementation as an intra-articular disease modifying OA therapy.
Authors: Kamil Slowikowski; Hung N Nguyen; Erika H Noss; Daimon P Simmons; Fumitaka Mizoguchi; Gerald F M Watts; Michael F Gurish; Michael B Brenner; Soumya Raychaudhuri Journal: Proc Natl Acad Sci U S A Date: 2020-02-20 Impact factor: 12.779
Authors: Xiao-Ning Fu; Hui-Wu Li; Na Du; Xu Liang; Shi-Hao He; Kuang-Jin Guo; Tian-Fang Li Journal: Am J Transl Res Date: 2020-10-15 Impact factor: 4.060