title: The effect of dose on rhBMP-2 signaling, delivered via collagen sponge, on osteoclast activation and in vivo bone resorption.
abstract: While recombinant human bone morphogenetic protein (rhBMP)-2-based bone therapy presents potential osteoinductivity, it also leads concern due to transient osteoclast activation during early healing periods, ultimately limiting its clinical use. Therefore, we investigated in vivo and in vitro rhBMP-2 signaling which mediates early bone resorbing effect, depending on the dose, and attempted to inhibit this resorption phenomenon using NFAT inhibitor as a target molecule. High-dose of rhBMP-2 (20 μg/defect) enhanced osteoclast activation and the expression of bone resorption markers, compared to low dose (5 μg/defect) at one week after surgery in collagen sponge-delivered rat calvarial defect models. Interestingly, this trend was also observed in the expression of bone formation markers. In particular, rhBMP-2 upregulated RANKL expression, while it downregulated osteoprotegerin (OPG) expression, resulting in a dose-dependent increase in the ratio of RANKL to OPG. NFAT inhibitor (150 μm) treatment in vivo suppressed the high-dose effect of rhBMP-2 on both resorption and formation. In vitro results of rhBMP-2 signaling and NFAT inhibitor effects in rat mesenchymal stem cells showed similar trends as in vivo results. Microcomputer tomography-based evaluation at 4 weeks showed that combined treatment of NFAT inhibitor with 20 μg rhBMP-2 in vivo increased bone volume (BV) more than 20 μg rhBMP-2 alone, which showed little difference in BV compared to 5 μg of rhBMP-2. These results demonstrated that rhBMP-2 implantation concurrently signalized into enhanced osteoclastogenesis and osteoblastogenesis in vivo, dose-dependently. Ratio of RANKL/OPG might be an index for early bone resorbing activity of implanted rhBMP-2. A local cocktail treatment of NFAT inhibitor and high-dose rhBMP-2 might be an alternative to overcome early bone resorbing effects, thereby accelerating bone formation.
authors: Department of Maxillofacial Cell and Developmental Biology, School of Dentistry, Seoul National University, BK21 Plus, Seoul 110-749, Republic of Korea.
authors: Ri Youn
authors: RY
authors: Kim
authors: Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
authors: Ji Hye
authors: JH
authors: Oh
authors: Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
authors: Beom Seok
authors: BS
authors: Lee
authors: Department of Medical Biotechnology, Dongguk University, Seoul 100-715, Republic of Korea.
authors: Young-Kwon
authors: YK
authors: Seo
authors: Department of Maxillofacial Cell and Developmental Biology, School of Dentistry, Seoul National University, BK21 Plus, Seoul 110-749, Republic of Korea; Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea; Department of Oral and Maxillofacial Surgery, School of Dentistry, Seoul National University, BK21 Plus, Seoul 110-749, Republic of Korea. Electronic address: sjhwang@snu.ac.kr.
authors: Soon Jung
authors: SJ
authors: Hwang
authors: Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea. Electronic address: ishwkim@snu.ac.kr.
authors: In Sook
authors: IS
authors: Kim
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology* / Q000627:therapeutic use; D001862:Bone Resorption / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000627:therapeutic use; D014945:Wound Healing / Q000187:drug effects
chemical_list: D055396:Bone Morphogenetic Protein 2; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D003094:Collagen
keywords: Bone formation; High-dose; NFATc1; Osteoclast activation; RANKL; rhBMP-2