Yuki Etani1, Kosuke Ebina2, Makoto Hirao1, Kazuma Kitaguchi3, Masafumi Kashii3, Takuya Ishimoto4, Takayoshi Nakano4, Gensuke Okamura1, Akira Miyama1, Kenji Takami1, Atsushi Goshima1, Takashi Kanamoto5, Ken Nakata5, Hideki Yoshikawa3. 1. Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. 2. Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. Electronic address: k-ebina@umin.ac.jp. 3. Department of Orthopaedic Surgery, Toyonaka Municipal Hospital, 4-14-1 Shibaharacho, Toyonaka, Osaka 560-8565, Japan. 4. Division of Materials and Manufacturing Science, Osaka University Graduate School of Engineering, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan. 5. Department of Health and Sport Sciences, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Abstract
OBJECTIVE: The purpose of this study was to examine the effect of single or combination therapy of teriparatide (TPTD) and a monoclonal antibody against the murine receptor activator of nuclear factor κB ligand (anti-RANKL Ab) on cancellous and cortical bone regeneration in a mouse model of glucocorticoid-induced osteoporosis (GIOP). METHODS: C57BL/6 J mice (24 weeks of age) were divided into five groups: (1) the SHAM group: sham operation + saline; (2) the prednisolone (PSL) group: PSL + saline; (3) the TPTD group: PSL + TPTD; (4) the Ab group: PSL + anti-RANKL Ab; and (5) the COMB group: PSL + TPTD + anti-RANKL Ab (n = 8 per group). With the exception of the SHAM group, 7.5 mg of PSL was inserted subcutaneously into mice, to generate a mouse model of GIOP. Four weeks after insertion, bone defects with a diameter of 0.9 mm were created to assess bone regeneration on both femoral metaphysis (cancellous bone) and diaphysis (cortical bone). After surgery, therapeutic intervention was continued for 4 weeks. Saline (200 μl) or TPTD (40 μg/kg) was injected subcutaneously five times per week, whereas the anti-RANKL Ab (5 mg/kg) was injected subcutaneously once on the day after surgery. Subsequently, the following analyses were performed: microstructural assessment of bone regeneration and bone mineral density (BMD) measurement via micro-computed tomography, and histological, histomorphometrical, and biomechanical analyses with nanoindentation. RESULTS: The COMB group showed the highest lumbar spine BMD increase (vs. the PSL, TPTD, and Ab groups). The volume of regenerated cancellous bone at the bone defect site was higher in the COMB group compared with the PSL, TPTD, and Ab group. The volume of the regenerated cortical bone was significantly higher in the COMB group compared with the PSL group, and its hardness was significantly higher in the COMB group compared with the PSL and TPTD groups. CONCLUSION: In a mouse model of glucocorticoid-induced osteoporosis, the combination therapy of TPTD plus the anti-RANKL Ab increased bone mineral density in the lumbar spine and regenerated cancellous bone volume compared with single administration of each agent, and also increased regenerated cortical bone strength compared with single administration of TPTD.
OBJECTIVE: The purpose of this study was to examine the effect of single or combination therapy of teriparatide (TPTD) and a monoclonal antibody against the murine receptor activator of nuclear factor κB ligand (anti-RANKL Ab) on cancellous and cortical bone regeneration in a mouse model of glucocorticoid-induced osteoporosis (GIOP). METHODS: C57BL/6 J mice (24 weeks of age) were divided into five groups: (1) the SHAM group: sham operation + saline; (2) the prednisolone (PSL) group: PSL + saline; (3) the TPTD group: PSL + TPTD; (4) the Ab group: PSL + anti-RANKL Ab; and (5) the COMB group: PSL + TPTD + anti-RANKL Ab (n = 8 per group). With the exception of the SHAM group, 7.5 mg of PSL was inserted subcutaneously into mice, to generate a mouse model of GIOP. Four weeks after insertion, bone defects with a diameter of 0.9 mm were created to assess bone regeneration on both femoral metaphysis (cancellous bone) and diaphysis (cortical bone). After surgery, therapeutic intervention was continued for 4 weeks. Saline (200 μl) or TPTD (40 μg/kg) was injected subcutaneously five times per week, whereas the anti-RANKL Ab (5 mg/kg) was injected subcutaneously once on the day after surgery. Subsequently, the following analyses were performed: microstructural assessment of bone regeneration and bone mineral density (BMD) measurement via micro-computed tomography, and histological, histomorphometrical, and biomechanical analyses with nanoindentation. RESULTS: The COMB group showed the highest lumbar spine BMD increase (vs. the PSL, TPTD, and Ab groups). The volume of regenerated cancellous bone at the bone defect site was higher in the COMB group compared with the PSL, TPTD, and Ab group. The volume of the regenerated cortical bone was significantly higher in the COMB group compared with the PSL group, and its hardness was significantly higher in the COMB group compared with the PSL and TPTD groups. CONCLUSION: In a mouse model of glucocorticoid-induced osteoporosis, the combination therapy of TPTD plus the anti-RANKL Ab increased bone mineral density in the lumbar spine and regenerated cancellous bone volume compared with single administration of each agent, and also increased regenerated cortical bone strength compared with single administration of TPTD.
Authors: Christian Horst Tonk; Sarah Hani Shoushrah; Patrick Babczyk; Basma El Khaldi-Hansen; Margit Schulze; Monika Herten; Edda Tobiasch Journal: Int J Mol Sci Date: 2022-01-26 Impact factor: 5.923