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Exaggerated inflammatory environment decreases BMP-2/ACS-induced ectopic bone mass in a rat model: implications for
1Department 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.
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.
Method:
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.
Conclusion:
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.
Insights
An exaggerated inflammatory environment, triggered by lipopolysaccharide (LPS), significantly reduces bone morphogenetic protein-2 (BMP-2)-induced bone mass. This inflammation suppresses bone formation and enhances bone resorption, impacting BMP-2 efficacy in bone regeneration.
Area of Science:
- Biomaterials Science
- Regenerative Medicine
- Orthopedic Research
Background:
- Recent studies report diminished osteoinductive efficacy of bone morphogenetic protein-2 (BMP-2).
- Clinical outcomes with BMP-2 have been disappointing, prompting investigation into underlying causes.
- An exaggerated inflammatory environment is hypothesized to be a key factor affecting BMP-2 performance.
Purpose of the Study:
- To experimentally investigate the impact of an exaggerated inflammatory environment on BMP-2/absorbable collagen sponge (ACS)-induced bone regeneration.
- To elucidate the mechanisms by which inflammation affects BMP-2 efficacy in vivo and in vitro.
Main Methods:
- Lipopolysaccharide (LPS) injections were used to mimic pre-operative inflammation in Sprague Dawley rats.
- BMP-2/absorbable collagen sponge (ACS) implants were used to assess bone regeneration post-LPS administration.
- Analyses included ELISA, PCR, micro-computed tomography (μCT), and histological examination of serum and implants.
Main Results:
- LPS administration significantly increased inflammatory cytokines and inflammatory cell infiltration around BMP-2/ACS implants.
- Bone volume, mineral content, and density were significantly reduced in LPS-treated rats.
- Inflammation suppressed osteoblastogenesis and enhanced osteoclastogenesis, with TNF-α and IL-1β inhibiting osteoblastic differentiation in vitro.
Conclusions:
- Exaggerated inflammation negatively impacts BMP-2/ACS-induced bone mass by inhibiting osteoblastic differentiation and promoting osteoclast activity.
- The findings highlight the critical role of inflammation in modulating BMP-2 efficacy for bone regeneration.
- Consideration of inflammatory status is crucial for optimizing the clinical application of BMP-2.
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