title: Exaggerated inflammatory environment decreases BMP-2/ACS-induced ectopic bone mass in a rat model: implications for clinical use of BMP-2.
abstract: OBJECTIVE
  Numerous recent reports have observed a low osteoinductive efficacy property of bone morphogenetic protein-2 (BMP-2) and disappointing long-term outcomes in clinical cases. An alternative hypothesis, that these observations are caused by an exaggerated inflammatory environment, needs experimental evidence.
  
  
  METHODS
  Thirty-seven Sprague Dawley (SD) rats were administrated with Lipopolysaccharide (LPS) injections and BMP-2/absorbable collagen sponge (ACS) implantation to respectively mimic pre-operative and post-operative inflammatory responses. Blood samples and BMP-2/ACS implants were analyzed by enzyme-linked immunosorbent assay (ELISA), real-time polymerase chain reaction (PCR), micro-computed tomography (μCT) and histological examination.
  
  
  RESULTS
  LPS injections and BMP-2/ACS implantation provoked a significant elevation of inflammatory cytokines in serum and an obvious infiltration of inflammatory cells around BMP-2/ACS implants. The bone volume, mineral content and mineral density of the BMP-2/ACS implants from LPS-injected rats were significantly decreased, indicating that attenuated BMP-2-induced bone mass might be associated with down-regulated bone formation activity and up-regulated bone resorption activity. Furthermore, histological examination of the rhBMP-2/ACS implants showed a decreased expression of osteocalcin (OCN) and an increased number of osteoclasts in LPS-injected rats at 8 weeks; the expression level of bone turnover markers in serum and BMP-2/ACS implants revealed inhibited osteoblastogenesis activity and activated osteoclastogenesis activity in LPS-injected rats. Among the top three elevated pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) showed a suppressive effect on BMP-2-induced osteoblastic differentiation in vitro.
  
  
  CONCLUSIONS
  These data indicate that an exaggerated inflammatory environment may decrease BMP-2/ACS-induced bone mass in vivo by suppressing BMP-2-induced osteoblastic differentiation and by increasing the number or activity of osteoclasts. The negative role of exaggerated inflammation deserves consideration for future clinical use of BMP-2 in inducing bone regeneration.
authors: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China; Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.
authors: R-L
authors: RL
authors: Huang
authors: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China; Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.
authors: Y
authors: Y
authors: Yuan
authors: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China; Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.
authors: J
authors: J
authors: Tu
authors: Shanghai Cancer Institute, Shanghai Jiao Tong University, 800 Dong Chuan Road, Wenxuan Medicine Bldg, Room 442, Shanghai 200240, China. Electronic address: gzou2003@yahoo.com.
authors: G-M
authors: GM
authors: Zou
authors: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China. Electronic address: dr.liqingfeng@shsmu.edu.cn.
authors: Q
authors: Q
authors: Li
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D001861:Bone Regeneration / Q000187:drug effects* / Q000276:immunology; D001862:Bone Resorption / Q000276:immunology*; D003094:Collagen; D004797:Enzyme-Linked Immunosorbent Assay; D007249:Inflammation / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009999:Ossification, Heterotopic / Q000276:immunology*; D015675:Osteocalcin / Q000378:metabolism; D010010:Osteoclasts; D010012:Osteogenesis / Q000187:drug effects* / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D055114:X-Ray Microtomography
chemical_list: C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D015675:Osteocalcin; D003094:Collagen
keywords: BMP-2; Bone regeneration; Bone resorption; Inflammation; Lipopolysaccharide