Inflammatory Characteristics of rhBMP-2 In Vitro and in an In Vivo Rodent Model

Lee, Kwang-Bok; Taghavi, Cyrus E.; Song, Kyung-Jin; Sintuu, Chananit; Yoo, Jeong Hyun; Keorochana, Gun; Tzeng, Shia-Tzu; Fei, Zhiqiang; Liao, Jen‐Chung; Wang, Jeffrey C.

doi:10.1097/brs.0b013e3181f2d1ec

Cited by 72 publications

(77 citation statements)

References 18 publications

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“…Exogenous BMP2 has been demonstrated to induce bone formation, but adverse effects including ectopic bone formation, osteolysis, and seroma formation have been reported [11,12]. Soft tissue inflammation was seen as early as 3 hours after subcutaneous BMP2 implantation in a rat model, an effect dependent on BMP2 dose [39,40]. We previously reported that exogenous BMP2 induced pro-inflammatory interleukin production by osteoblast-like cells on microstructured Ti surfaces in a TAB/TAK-dependent manner [13].…”

Section: Discussionmentioning

confidence: 99%

Coordinated regulation of mesenchymal stem cell differentiation on microstructured titanium surfaces by endogenous bone morphogenetic proteins

Olivares-Navarrete¹,

Hyzy²,

Haithcock³

et al. 2015

Bone

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Human mesenchymal stem cells (MSCs) differentiate into osteoblasts on microstructured titanium (Ti) surfaces without addition of medium supplements, suggesting that surface-dependent endogenous mechanisms are involved. They produce bone morphogenetic proteins (BMPs), which regulate MSC differentiation and bone formation via autocrine/paracrine mechanisms that are modulated by changes in BMP mRNA and protein, receptors, and inhibitors (Noggin, Cerberus, Gremlin 1, and Chordin). We examined expression of BMPs, their receptors and their inhibitors over time and used BMP2-silenced cells to determine how modulating endogenous BMP signaling can affect the process. MSCs were cultured on tissue culture polystyrene or Ti [PT (Ra<0.4μm); sandblasted/acid-etched Ti (SLA, Ra=3.2μm); or hydrophilic-SLA (modSLA)]. BMP mRNAs and proteins increased by day 4 of culture. Exogenous BMP2 increased differentiation whereas differentiation was decreased in BMP2-silenced cells. Noggin was regulated by day 2 whereas Gremlin 1 and Cerberus were regulated after 6 days. Osteoblastic differentiation increased in cells cultured with blocking antibodies against Noggin, Gremlin 1, and Cerberus. Endogenous BMPs enhance an osteogenic microenvironment whereas exogenous BMPs are inhibitory. Antibody blocking of the BMP2 inhibitor Cerberus resulted in IL-6 and IL-8 levels that were similar to those observed when treating cells with exogenous BMP2, while antibodies targeting the inhibitors Gremlin or Noggin did not. These results suggest that microstructured titanium implants supporting therapeutic stem cells may be treated with appropriately selected agents antagonistic to extracellular BMP inhibitors in order to enhance BMP2 mediated bone repair while avoiding undesirable inflammatory side effects observed with exogenous BMP2 treatment.

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Section: Discussionmentioning

confidence: 99%

Coordinated regulation of mesenchymal stem cell differentiation on microstructured titanium surfaces by endogenous bone morphogenetic proteins

Olivares-Navarrete¹,

Hyzy²,

Haithcock³

et al. 2015

Bone

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“…In summary, this study accepted the hypothesis proposed and demonstrated the following: First, recombinant BGN devoid of posttranslational modifications specifically and predictably enhances BMP-2 function in vitro and in vivo; second, the bone formed by a low dose of BMP-2 combined with GST-BGN was well organized and mature when compared with that formed by a low or high dose of BMP-2 alone at 2 wk post-surgery; last, Smad pathway is consistently activated by BMP-2 and BGNassisted BMP-2 osteogenesis in vitro. The data suggest that by utilizing a BMP-2 functional effector such as recombinant BGN, smaller quantities of BMP-2 could be used to possibly minimize adverse side effects, such as ectopic bone formation and robust inflammation (Shields et al, 2006;Lee et al, 2011;Zara et al, 2011), and effectively regenerate craniofacial bone.…”

Section: Discussionmentioning

confidence: 99%

Recombinant Biglycan Promotes Bone Morphogenetic Protein-induced Osteogenesis

et al. 2014

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The aim of this study was to determine the effects of glutathione-S-transferase-fused recombinant biglycan (GST-BGN) on craniofacial bone regeneration. We recently demonstrated a positive effect of tissue-derived BGN on bone morphogenetic protein 2 (BMP-2) function, which is exerted likely via the BGN core protein. Here, we investigated the effects of GST-BGN lacking any posttranslational modifications on BMP-2 function in vitro and in vivo. In the C2C12 cell culture system, BMP-2-induced Smad 1/5/8 phosphorylation and alkaline phosphatase activity were both enhanced by the addition of GST-BGN. For the in vivo effect, we employed a Sprague-Dawley rat mandible defect model utilizing 1 µg (optimal) or 0.1 µg (suboptimal) of BMP-2 combined with 0, 2, 4, or 8 µg of GST-BGN. At 2 weeks post-surgery, newly formed bone was evaluated by microcomputed tomography and histologic analyses. The results revealed that the greatest amounts of bone within the defect were formed in the groups of suboptimal BMP-2 combined with 4 or 8 µg of GST-BGN. Also, bone was well organized versus that formed by the optimal dose of BMP. These results indicate that recombinant BGN is an efficient substrate to promote low-dose BMP-induced osteogenesis.

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“…Following BMP-2/ACS implantation, the inflammatory response is characterized by the recruitment of both inflammatory cells and stem cells to the implantation site and by the presence of inflammatory cytokines in the sera, such as TNF-a, IL1b, and IL-6, in clinical patients as well as experimental animals [8,15,16]. Among these inflammatory cytokines, TNF-a and IL-1b have been reported to play an inhibitory role on BMP-2-induced osteogenic differentiation of BMSCs [17e21].…”

Section: Introductionmentioning

confidence: 99%

Synergy between IL-6 and soluble IL-6 receptor enhances bone morphogenetic protein-2/absorbable collagen sponge-induced bone regeneration via regulation of BMPRIA distribution and degradation

et al. 2015

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Inflammatory Characteristics of rhBMP-2 In Vitro and in an In Vivo Rodent Model

Abstract: Swelling and inflammation after rhBMP-2 use are dose-dependent. Swelling may be due to direct contact as well as spread in the plane of access. The causes are a robust inflammatory reaction as well as sterile seroma and encapsulated hematoma formation.

Cited by 72 publications

References 18 publications

Coordinated regulation of mesenchymal stem cell differentiation on microstructured titanium surfaces by endogenous bone morphogenetic proteins

Coordinated regulation of mesenchymal stem cell differentiation on microstructured titanium surfaces by endogenous bone morphogenetic proteins

Recombinant Biglycan Promotes Bone Morphogenetic Protein-induced Osteogenesis

Synergy between IL-6 and soluble IL-6 receptor enhances bone morphogenetic protein-2/absorbable collagen sponge-induced bone regeneration via regulation of BMPRIA distribution and degradation

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