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Article: Transient brown adipocyte-like cells derive from peripheral nerve progenitors in response to bone morphogenetic protein 2.

Salisbury, Elizabeth A / Lazard, Zawaunyka W / Ubogu, Eroboghene E / Davis, Alan R / Olmsted-Davis, Elizabeth A

2012 Volume 1, Issue 12, Page(s) 874–885

Abstract: Perineurial-associated brown adipocyte-like cells were rapidly generated during bone morphogenetic protein 2 (BMP2)-induced sciatic nerve remodeling in the mouse. Two days after intramuscular injection of transduced mouse fibroblast cells expressing BMP2 ...

Abstract	Perineurial-associated brown adipocyte-like cells were rapidly generated during bone morphogenetic protein 2 (BMP2)-induced sciatic nerve remodeling in the mouse. Two days after intramuscular injection of transduced mouse fibroblast cells expressing BMP2 into wild-type mice, there was replication of beta-3 adrenergic receptor(+) (ADRB3(+)) cells within the sciatic nerve perineurium. Fluorescence-activated cell sorting and analysis of cells isolated from these nerves confirmed ADRB3(+) cell expansion and their expression of the neural migration marker HNK1. Similar analysis performed 4 days after BMP2 delivery revealed a significant decrease in ADRB3(+) cells from isolated sciatic nerves, with their concurrent appearance within the adjacent soft tissue, suggesting migration away from the nerve. These soft tissue-derived cells also expressed the brown adipose marker uncoupling protein 1 (UCP1). Quantification of ADRB3-specific RNA in total hind limb tissue revealed a 3-fold increase 2 days after delivery of BMP2, followed by a 70-fold increase in UCP1-specific RNA after 3 days. Expression levels then rapidly returned to baseline by 4 days. Interestingly, these ADRB3(+) UCP1(+) cells also expressed the neural guidance factor reelin. Reelin(+) cells demonstrated distinct patterns within the injected muscle, concentrated toward the area of BMP2 release. Blocking mast cell degranulation-induced nerve remodeling resulted in the complete abrogation of UCP1-specific RNA and protein expression within the hind limbs following BMP2 injection. The data collectively suggest that local BMP2 administration initiates a cascade of events leading to the expansion, migration, and differentiation of progenitors from the peripheral nerve perineurium to brown adipose-like cells in the mouse, a necessary prerequisite for associated nerve remodeling.
MeSH term(s)	Adenoviridae/genetics ; Adipocytes, Brown/cytology ; Adipocytes, Brown/physiology ; Age Factors ; Animals ; Bone Morphogenetic Protein 2/genetics ; Cell Adhesion Molecules, Neuronal/genetics ; Cell Differentiation/physiology ; Cell Division/physiology ; Cell Lineage/physiology ; Cell Movement/physiology ; Cells, Cultured ; Extracellular Matrix Proteins/genetics ; Fibroblasts/cytology ; Fibroblasts/physiology ; Humans ; Ion Channels/genetics ; Mast Cells/cytology ; Mast Cells/physiology ; Mice ; Mitochondrial Proteins/genetics ; Nerve Regeneration/physiology ; Nerve Tissue Proteins/genetics ; Norepinephrine/metabolism ; Peripheral Nerves/cytology ; Peripheral Nerves/physiology ; Receptors, Adrenergic, beta-3/genetics ; Serine Endopeptidases/genetics ; Stem Cell Transplantation/methods ; Stem Cells/cytology ; Stem Cells/physiology ; Transgenes/genetics ; Uncoupling Protein 1
Chemical Substances	BMP2 protein, human ; Bone Morphogenetic Protein 2 ; Cell Adhesion Molecules, Neuronal ; Extracellular Matrix Proteins ; Ion Channels ; Mitochondrial Proteins ; Nerve Tissue Proteins ; Receptors, Adrenergic, beta-3 ; UCP1 protein, human ; Ucp1 protein, mouse ; Uncoupling Protein 1 ; Serine Endopeptidases (EC 3.4.21.-) ; reelin protein (EC 3.4.21.-) ; Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2012-11-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2642270-0
ISSN	2157-6580 ; 2157-6564
ISSN (online)	2157-6580
ISSN	2157-6564
DOI	10.5966/sctm.2012-0090
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Article ; Online: Location-dependent heterotopic ossification in the rat model: The role of activated matrix metalloproteinase 9.

Davis, Eleanor L / Sonnet, Corinne / Lazard, ZaWaunyka W / Henslee, Gabrielle / Gugala, Zbigniew / Salisbury, Elizabeth A / Strecker, Edward V / Davis, Thomas A / Forsberg, Jonathan A / Davis, Alan R / Olmsted-Davis, Elizabeth A

Journal of orthopaedic research : official publication of the Orthopaedic Research Society

2016 Volume 34, Issue 11, Page(s) 1894–1904

Abstract: Extremity amputation or traumatic injury can often lead to the formation of heterotopic ossification (HO). Studies to induce HO in rat muscle using cell-based gene therapy show that this process appears to be location dependent. In the present study, HO ... ...

Abstract	Extremity amputation or traumatic injury can often lead to the formation of heterotopic ossification (HO). Studies to induce HO in rat muscle using cell-based gene therapy show that this process appears to be location dependent. In the present study, HO was induced in mice and rats through injection of immunologically matched cells transduced with either a replication-defective adenovirus possessing bone morphogenetic protein 2 (BMP2) or an empty adenovirus vector (control). Injection in rat near the skeletal bone resulted in HO, whereas cells injected into the same muscle group but distal from the bone did not result in bone formation. When cells were injected in the same limb at both locations at the same time, HO was formed at both sites. Characterization of the bone formation in rats versus mice demonstrated that different sources of osteogenic progenitors were involved, which may account for the location dependent bone formation observed in the rat. Further experimentation has shown that a potential reason for this difference may be the inability of rat to activate matrix metalloproteinase 9 (MMP9), an essential protease in mice necessary for recruitment of progenitors. Inhibition of active MMP9 in mice led to a significant decrease in HO. The studies reported here provide insight into the mechanisms and pathways leading to bone formation in different animals and species. It appears that not all animal models are appropriate for testing HO therapies, and our studies also challenge the conventional wisdom that larger animal models are better for testing treatments affecting bone. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1894-1904, 2016.
MeSH term(s)	Adenoviridae ; Animals ; Cells, Cultured ; Disease Models, Animal ; Gene Transfer Techniques ; Humans ; Matrix Metalloproteinase 9/physiology ; Mesenchymal Stem Cell Transplantation ; Mice, Inbred C57BL ; Ossification, Heterotopic ; Rats, Nude ; Rats, Wistar
Chemical Substances	Matrix Metalloproteinase 9 (EC 3.4.24.35)
Language	English
Publishing date	2016-03-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	605542-4
ISSN	1554-527X ; 0736-0266
ISSN (online)	1554-527X
ISSN	0736-0266
DOI	10.1002/jor.23216
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Article ; Online: Osteoblasts Have a Neural Origin in Heterotopic Ossification.

Lazard, ZaWaunyka W / Olmsted-Davis, Elizabeth A / Salisbury, Elizabeth A / Gugala, Zbigniew / Sonnet, Corrine / Davis, Eleanor L / Beal, Eric / Ubogu, Eroboghene E / Davis, Alan R

Clinical orthopaedics and related research

2015 Volume 473, Issue 9, Page(s) 2790–2806

Abstract: Background: Heterotopic ossification (HO) is the process of bone formation at a nonskeletal site. Recently, we showed that the earliest steps occur in sensory nerves. We now extend these studies by identifying unique osteogenic progenitors within the ... ...

Abstract	Background: Heterotopic ossification (HO) is the process of bone formation at a nonskeletal site. Recently, we showed that the earliest steps occur in sensory nerves. We now extend these studies by identifying unique osteogenic progenitors within the endoneurial compartment of sensory nerves. Questions/purposes: We asked: (1) What is the nature of the osteoprogenitor in the endoneurium of peripheral nerves? (2) How do osteoprogenitors travel from the nerve to the site of new bone formation? Methods: HO was induced by intramuscular injection of Ad5BMP-2-transduced cells in mice. Osteoprogenitors were identified through immunohistochemistry and then quantified and further characterized by fluorescence-activated cell sorting and immunocytochemistry. The kinetics of the appearance of markers of extravasation was determined by quantitative reverse transcription-polymerase chain reaction. In each experiment mice were injected with bone morphogenetic protein-2 (BMP-2)-producing cells (experimental) or with cells transduced with empty vector or, in some cases, a group receiving no injection (control). Results: Induction of HO leads to the expression, within 24 hours, of osteoblast-specific transcription factors in cells in the endoneurium followed by their coordinate disappearance from the nerve at 48 hours. They reappear in blood also at 48 hours after induction. During vessel entrance they begin to express the tight junction molecule, claudin 5. The cells expressing both the osteoblast-specific transcription factor, osterix, as well as claudin 5, then disappear from circulation at approximately 3 to 4 days by extravasation into the site of new bone formation. These endoneurial osteoprogenitors express neural markers PDGFRα, musashi-1, and the low-affinity nerve growth factor receptor p75(NTR) as well as the endothelial marker Tie-2. In a key experiment, cells that were obtained from mice that were injected with cells transduced with an empty vector, at 2 days after injection, contained 0.83% (SD, 0.07; 95% confidence interval [CI], 0.59-1.05) cells expressing claudin 5. However, cells that were obtained from mice 2 days after injection of BMP-2-producing cells contained 4.5% cells expressing claudin 5 (SD, 0.72%; 95% CI, 2.01-6.94; p < 0.0015). Further analysis revealed that all of the cells expressing claudin 5 were found to be positive for osteoblast-specific markers, whereas cells not expressing claudin 5 were negative for these same markers. Conclusions: The findings suggest that the endoneurial progenitors are the major osteogenic precursors that are used for HO. They exit the nerve through the endoneurial vessels, flow through vessels to the site of new bone formation, and then extravasate out of the vessels into this site. Clinical relevance: The biogenesis of osteoblasts in HO is very different than expected and shows that HO is, at least in part, a neurological disorder. This could result in a major shift in orthopaedic methodologies to prevent or treat this disease. The fact that nerves are intimately involved in the process may also provide clues that will lead to an explanation of the clinical fact that HO often occurs as a result of traumatic brain injury.
MeSH term(s)	Adenoviridae/genetics ; Animals ; Biomarkers/metabolism ; Bone Morphogenetic Protein 2/biosynthesis ; Bone Morphogenetic Protein 2/genetics ; Cell Lineage ; Cell Movement ; Disease Models, Animal ; Gene Expression Regulation ; Genetic Vectors ; Kinetics ; Male ; Mice ; Mice, Inbred C57BL ; Neural Stem Cells/metabolism ; Neural Stem Cells/pathology ; Ossification, Heterotopic/genetics ; Ossification, Heterotopic/metabolism ; Ossification, Heterotopic/pathology ; Osteoblasts/metabolism ; Osteoblasts/pathology ; RNA, Messenger/metabolism ; Sensory Receptor Cells/metabolism ; Sensory Receptor Cells/pathology ; Signal Transduction ; Transduction, Genetic
Chemical Substances	Biomarkers ; Bone Morphogenetic Protein 2 ; RNA, Messenger
Language	English
Publishing date	2015-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80301-7
ISSN	1528-1132 ; 0009-921X
ISSN (online)	1528-1132
ISSN	0009-921X
DOI	10.1007/s11999-015-4323-9
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Article ; Online: Far-red fluorescence gene reporter tomography for determination of placement and viability of cell-based gene therapies.

Lu, Yujie / Darne, Chinmay D / Tan, I-Chih / Zhu, Banghe / Hall, Mary A / Lazard, Zawaunyka W / Davis, Alan R / Simpson, Lashan / Sevick-Muraca, Eva M / Olmsted-Davis, Elizabeth A

Optics express

2013 Volume 21, Issue 20, Page(s) 24129–24138

Abstract: Non-invasive injectable cellular therapeutic strategies based on sustained delivery of physiological levels of BMP-2 for spinal fusion are emerging as promising alternatives, which could provide sufficient fusion without the associated surgical risks. ... ...

Abstract	Non-invasive injectable cellular therapeutic strategies based on sustained delivery of physiological levels of BMP-2 for spinal fusion are emerging as promising alternatives, which could provide sufficient fusion without the associated surgical risks. However, these injectable therapies are dependent on bone formation occurring only at the specific target region. In this study, we developed and deployed fluorescence gene reporter tomography (FGRT) to provide information on in vivo cell localization and viability. This information is sought to confirm the ideal placement of the materials with respect to the area where early bone reaction is required, ultimately providing three dimensional data about the future fusion. However, because almost all conventional fluorescence gene reporters require visible excitation wavelengths, current in vivo imaging of fluorescent proteins is limited by high tissue absorption and confounding autofluorescence. We previously administered fibroblasts engineered to produce BMP-2, but is difficult to determine 3-D information of placement prior to bone formation. Herein we used the far-red fluorescence gene reporter, IFP1.4 to report the position and viability of fibroblasts and developed 3-D tomography to provide placement information. A custom small animal, far-red fluorescence tomography system integrated into a commercial CT scanner was used to assess IFP1.4 fluorescence and to demark 3-D placement of encapsulated fibroblasts with respect to the vertebrae and early bone formation as assessed from CT. The results from three experiments showed that the placement of the materials within the spine could be detected. This work shows that in vivo fluorescence gene reporter tomography of cell-based gene therapy is feasible and could help guide cell-based therapies in preclinical models.
MeSH term(s)	Animals ; Bone Morphogenetic Protein 2/genetics ; Bone Morphogenetic Protein 2/therapeutic use ; Cell Survival ; Fluorescence ; Genes, Reporter ; Genetic Therapy ; Humans ; Image Processing, Computer-Assisted ; Mice ; Optical Imaging ; Spinal Fusion ; Tomography, X-Ray Computed/methods
Chemical Substances	Bone Morphogenetic Protein 2
Language	English
Publishing date	2013-10-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1491859-6
ISSN	1094-4087 ; 1094-4087
ISSN (online)	1094-4087
ISSN	1094-4087
DOI	10.1364/OE.21.024129
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Article ; Online: Cell-based gene therapy for repair of critical size defects in the rat fibula.

Lazard, Zawaunyka W / Heggeness, Michael H / Hipp, John A / Sonnet, Corinne / Fuentes, Angie S / Nistal, Rita P / Davis, Alan R / Olabisi, Ronke M / West, Jennifer L / Olmsted-Davis, Elizabeth A

Journal of cellular biochemistry

2011 Volume 112, Issue 6, Page(s) 1563–1571

Abstract: More than a decade has passed since the first experiments using adenovirus-transduced cells expressing bone morphogenetic protein 2 were performed for the synthesis of bone. Since this time, the field of bone gene therapy has tackled many issues ... ...

Abstract	More than a decade has passed since the first experiments using adenovirus-transduced cells expressing bone morphogenetic protein 2 were performed for the synthesis of bone. Since this time, the field of bone gene therapy has tackled many issues surrounding safety and efficacy of this type of strategy. We present studies examining the parameters of the timing of bone healing, and remodeling when heterotopic ossification (HO) is used for bone fracture repair using an adenovirus gene therapy approach. We use a rat fibula defect, which surprisingly does not heal even when a simple fracture is introduced. In this model, the bone quickly resorbs most likely due to the non-weight bearing nature of this bone in rodents. Using our gene therapy system robust HO can be introduced at the targeted location of the defect resulting in bone repair. The HO and resultant bone healing appeared to be dose dependent, based on the number of AdBMP2-transduced cells delivered. Interestingly, the HO undergoes substantial remodeling, and assumes the size and shape of the missing segment of bone. However, in some instances we observed some additional bone associated with the repair, signifying that perhaps the forces on the newly forming bone are inadequate to dictate shape. In all cases, the HO appeared to fuse into the adjacent long bone. The data collectively indicates that the use of BMP2 gene therapy strategies may vary depending on the location and nature of the defect. Therefore, additional parameters should be considered when implementing such strategies.
MeSH term(s)	Adenoviridae/genetics ; Animals ; Bone Morphogenetic Protein 2/genetics ; Bone Morphogenetic Protein 2/metabolism ; Bone and Bones/abnormalities ; Cell Line ; Cell- and Tissue-Based Therapy/methods ; Fibula/abnormalities ; Genetic Therapy/methods ; Humans ; Mice ; Osteogenesis/physiology ; Rats ; Wound Healing/physiology
Chemical Substances	Bone Morphogenetic Protein 2
Language	English
Publishing date	2011-02-23
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	392402-6
ISSN	1097-4644 ; 0730-2312
ISSN (online)	1097-4644
ISSN	0730-2312
DOI	10.1002/jcb.23068
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Article: Characterization of chemical, radiochemical and optical properties of a dual-labeled MMP-9 targeting peptide

Azhdarinia, Ali / Wilganowski, Nathaniel / Robinson, Holly / Ghosh, Pradip / Kwon, Sunkuk / Lazard, ZaWaunyka W / Davis, Alan R / Olmsted-Davis, Elizabeth / Sevick-Muraca, Eva M

Bioorganic & medicinal chemistry. 2011 June 15, v. 19, no. 12

2011

Abstract: Optical imaging possesses similar sensitivity to nuclear imaging and has led to the emergence of multimodal approaches with dual-labeled nuclear/near-infrared (NIR) agents. The growing impact of ⁶⁸Ga (t₁/₂=68min) labeled peptides on preclinical and ... ...

Abstract	Optical imaging possesses similar sensitivity to nuclear imaging and has led to the emergence of multimodal approaches with dual-labeled nuclear/near-infrared (NIR) agents. The growing impact of ⁶⁸Ga (t₁/₂=68min) labeled peptides on preclinical and clinical research offers a promising opportunity to merge the high spatial resolution of NIR imaging with the clinically-accepted positron emission tomography (PET). Previously, dual-labeled agents have been prepared with longer-lived radiometals and showed no detrimental effects on optical properties as a result of radiolabeling. In this study, we selected a peptide (M₂) that targets MMP-2/9 and is dual-labeled with IRDye 800CW and ⁶⁸Ga. Since ⁶⁸Ga chelation typically requires low pH (3.5–4) and elevated heating temperatures (95°C), we sought to evaluate the impact of ⁶⁸Ga labeling on the optical properties of M₂. An efficient method for preparation of ⁶⁸Ga-M₂ was developed and reaction conditions were optimized. Stability studies in PBS, DTPA, and serum were performed and high levels of intact agent were evident under each condition. The addition of multiple reporters to a targeting agent adds further complexity to the characterization and validation and thus requires not only testing to ensure the agent is stable chemically and radiochemically, but also optically. Therefore, fluorescence properties were evaluated using a spectrofluorometer as well as by fluorescence detection via HPLC. It was determined that ⁶⁸Ga-labeling conditions did not impair the fluorescent properties of the agent. The agent was then used for in vivo imaging in a mouse model of heterotopic ossification (HO) with activated MMP-9 expression as an early biomarker which precedes mineralization. Although ⁶⁸Ga-complexation greatly reduced binding affinity of the peptide and negated tracer uptake on PET, NIR imaging showed consistent fluorescent signal that correlated to MMP-9 expression. This attests to the feasibility of using ⁶⁸Ga/NIR for dual-labeling of other peptides or small molecules for multimodality molecular imaging.
Keywords	animal models ; binding capacity ; biomarkers ; blood serum ; bone formation ; chelation ; fluorescence ; heat ; high performance liquid chromatography ; image analysis ; mineralization ; optical properties ; pH ; peptides ; positron-emission tomography ; radiolabeling ; temperature
Language	English
Dates of publication	2011-0615
Size	p. 3769-3776.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1161284-8
ISSN	1464-3391 ; 0968-0896
ISSN (online)	1464-3391
ISSN	0968-0896
DOI	10.1016/j.bmc.2011.04.054
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Matrix metalloproteinase-9 is a diagnostic marker of heterotopic ossification in a murine model.

Rodenberg, Eric / Azhdarinia, Ali / Lazard, ZaWaunyka W / Hall, Mary / Kwon, Sun Kuk / Wilganowski, Nathaniel / Salisbury, Elizabeth A / Merched-Sauvage, Maria / Olmsted-Davis, Elizabeth A / Sevick-Muraca, Eva M / Davis, Alan R

Tissue engineering. Part A

2011 Volume 17, Issue 19-20, Page(s) 2487–2496

Abstract: Heterotopic ossification (HO) is a serious disorder that occurs when there is aberrant bone morphogenic protein (BMP) signaling in soft tissues. Currently, there are no methods to detect HO before mineralization occurs. Yet once mineralization occurs, ... ...

Abstract	Heterotopic ossification (HO) is a serious disorder that occurs when there is aberrant bone morphogenic protein (BMP) signaling in soft tissues. Currently, there are no methods to detect HO before mineralization occurs. Yet once mineralization occurs, there are no effective treatments, short of surgery, to reverse HO. Herein, we used in vivo molecular imaging and confirmatory ex vivo tissue analyses of an established murine animal model of BMP-induced HO to show that matrix metalloproteinase-9 (MMP-9) can be detected as an early-stage biomarker before mineralization. Ex vivo analyses show that active MMP-9 protein is significantly elevated within tissues undergoing HO as early as 48 h after BMP induction, with its expression co-localizing to nerves and vessels. In vivo molecular imaging with a dual-labeled near-infrared fluorescence and micro-positron emission tomography (μPET) agent specific to MMP-2/-9 expression paralleled the ex vivo observations and reflected the site of HO formation as detected from microcomputed tomography 7 days later. The results suggest that the MMP-9 is a biomarker of the early extracellular matrix (ECM) re-organization and could be used as an in vivo diagnostic with confirmatory ex vivo tissue analysis for detecting HO or conversely for monitoring the success of tissue-engineered bone implants that employ ECM biology for engraftment.
MeSH term(s)	Amino Acid Sequence ; Animals ; Biomarkers/metabolism ; Disease Models, Animal ; Fluorescent Antibody Technique ; Gene Expression Regulation, Enzymologic/drug effects ; Hindlimb/drug effects ; Hindlimb/pathology ; Humans ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/genetics ; Matrix Metalloproteinase 9/metabolism ; Mice ; Molecular Imaging ; Molecular Sequence Data ; Multimodal Imaging ; Ossification, Heterotopic/diagnosis ; Ossification, Heterotopic/enzymology ; Peptides, Cyclic/chemistry ; Peptides, Cyclic/pharmacology ; Positron-Emission Tomography ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Spectroscopy, Near-Infrared ; Tomography, X-Ray Computed
Chemical Substances	Biomarkers ; Peptides, Cyclic ; RNA, Messenger ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; Mmp9 protein, mouse (EC 3.4.24.35)
Language	English
Publishing date	2011-10
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2420582-5
ISSN	1937-335X ; 1937-3341
ISSN (online)	1937-335X
ISSN	1937-3341
DOI	10.1089/ten.TEA.2011.0007
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Article ; Online: Characterization of chemical, radiochemical and optical properties of a dual-labeled MMP-9 targeting peptide.

Azhdarinia, Ali / Wilganowski, Nathaniel / Robinson, Holly / Ghosh, Pradip / Kwon, Sunkuk / Lazard, Zawaunyka W / Davis, Alan R / Olmsted-Davis, Elizabeth / Sevick-Muraca, Eva M

Bioorganic & medicinal chemistry

2011 Volume 19, Issue 12, Page(s) 3769–3776

Abstract: Optical imaging possesses similar sensitivity to nuclear imaging and has led to the emergence of multimodal approaches with dual-labeled nuclear/near-infrared (NIR) agents. The growing impact of (68)Ga (t(1/2)=68 min) labeled peptides on preclinical and ... ...

Abstract	Optical imaging possesses similar sensitivity to nuclear imaging and has led to the emergence of multimodal approaches with dual-labeled nuclear/near-infrared (NIR) agents. The growing impact of (68)Ga (t(1/2)=68 min) labeled peptides on preclinical and clinical research offers a promising opportunity to merge the high spatial resolution of NIR imaging with the clinically-accepted positron emission tomography (PET). Previously, dual-labeled agents have been prepared with longer-lived radiometals and showed no detrimental effects on optical properties as a result of radiolabeling. In this study, we selected a peptide (M(2)) that targets MMP-2/9 and is dual-labeled with IRDye 800 CW and (68)Ga. Since (68)Ga chelation typically requires low pH (3.5-4) and elevated heating temperatures (95 °C), we sought to evaluate the impact of (68)Ga labeling on the optical properties of M(2). An efficient method for preparation of (68)Ga-M(2) was developed and reaction conditions were optimized. Stability studies in PBS, DTPA, and serum were performed and high levels of intact agent were evident under each condition. The addition of multiple reporters to a targeting agent adds further complexity to the characterization and validation and thus requires not only testing to ensure the agent is stable chemically and radiochemically, but also optically. Therefore, fluorescence properties were evaluated using a spectrofluorometer as well as by fluorescence detection via HPLC. It was determined that (68)Ga-labeling conditions did not impair the fluorescent properties of the agent. The agent was then used for in vivo imaging in a mouse model of heterotopic ossification (HO) with activated MMP-9 expression as an early biomarker which precedes mineralization. Although (68)Ga-complexation greatly reduced binding affinity of the peptide and negated tracer uptake on PET, NIR imaging showed consistent fluorescent signal that correlated to MMP-9 expression. This attests to the feasibility of using (68)Ga/NIR for dual-labeling of other peptides or small molecules for multimodality molecular imaging.
MeSH term(s)	Animals ; Chromatography, High Pressure Liquid ; Drug Delivery Systems ; Fluorescent Dyes/chemistry ; Gallium Radioisotopes/chemistry ; Humans ; Matrix Metalloproteinase 9/chemistry ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Molecular Structure ; Peptides/chemistry
Chemical Substances	Fluorescent Dyes ; Gallium Radioisotopes ; Peptides ; Matrix Metalloproteinase 9 (EC 3.4.24.35)
Language	English
Publishing date	2011-05-06
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1161284-8
ISSN	1464-3391 ; 0968-0896
ISSN (online)	1464-3391
ISSN	0968-0896
DOI	10.1016/j.bmc.2011.04.054
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Article ; Online: Hydrogel microsphere encapsulation of a cell-based gene therapy system increases cell survival of injected cells, transgene expression, and bone volume in a model of heterotopic ossification.

Olabisi, Ronke M / Lazard, Zawaunyka W / Franco, Christy L / Hall, Mary A / Kwon, Sun Kuk / Sevick-Muraca, Eva M / Hipp, John A / Davis, Alan R / Olmsted-Davis, Elizabeth A / West, Jennifer L

Tissue engineering. Part A

2010 Volume 16, Issue 12, Page(s) 3727–3736

Abstract: Bone morphogenetic proteins (BMPs) are well known for their osteoinductive activity, yet harnessing this capacity remains a high-priority research focus. We present a novel technology that delivers high BMP-2 levels at targeted locations for rapid ... ...

Abstract	Bone morphogenetic proteins (BMPs) are well known for their osteoinductive activity, yet harnessing this capacity remains a high-priority research focus. We present a novel technology that delivers high BMP-2 levels at targeted locations for rapid endochondral bone formation, enhancing our preexisting cell-based gene therapy system by microencapsulating adenovirus-transduced cells in nondegradable poly(ethylene glycol) diacrylate (PEGDA) hydrogels before intramuscular delivery. This study evaluates the in vitro and in vivo viability, gene expression, and bone formation from transgenic fibroblasts encapsulated in PEGDA microspheres. Fluorescent viability and cytotoxicity assays demonstrated >95% viability in microencapsulated cells. ELISA and alkaline phosphatase assays established that BMP-2 secretion and specific activity from microencapsulated AdBMP2-transduced fibroblasts were not statistically different from monolayer. Longitudinal transgene expression studies of AdDsRed-transduced fibroblasts, followed through live animal optical fluorescent imaging, showed that microencapsulated cells expressed longer than unencapsulated cells. When comparable numbers of microencapsulated AdBMP2-transduced cells were intramuscularly injected into mice, microcomputed tomography evaluation demonstrated that the resultant heterotopic bone formation was approximately twice the volume of unencapsulated cells. The data suggest that microencapsulation protects cells and prolongs and spatially distributes transgene expression. Thus, incorporation of PEGDA hydrogels significantly advances current gene therapy bone repair approaches.
MeSH term(s)	Alkaline Phosphatase/metabolism ; Animals ; Bone Morphogenetic Protein 2/genetics ; Bone Morphogenetic Protein 2/metabolism ; Cell Line ; Cell Survival/genetics ; Cell Survival/physiology ; Enzyme-Linked Immunosorbent Assay ; Female ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Humans ; Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry ; Mice ; Mice, SCID ; Microspheres ; Tissue Engineering/methods ; Transgenes/genetics ; Transgenes/physiology ; X-Ray Microtomography
Chemical Substances	BMP2 protein, human ; Bone Morphogenetic Protein 2 ; Hydrogel, Polyethylene Glycol Dimethacrylate (25852-47-5) ; Alkaline Phosphatase (EC 3.1.3.1)
Language	English
Publishing date	2010-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2420582-5
ISSN	1937-335X ; 1937-3341
ISSN (online)	1937-335X
ISSN	1937-3341
DOI	10.1089/ten.TEA.2010.0234
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Article ; Online: Vessel formation is induced prior to the appearance of cartilage in BMP-2-mediated heterotopic ossification.

Dilling, Christine Fouletier / Wada, Aya M / Lazard, Zawaunyka W / Salisbury, Elizabeth A / Gannon, Francis H / Vadakkan, Tegy J / Gao, Liang / Hirschi, Karen / Dickinson, Mary E / Davis, Alan R / Olmsted-Davis, Elizabeth A

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

2009 Volume 25, Issue 5, Page(s) 1147–1156

Abstract: Heterotopic ossification (HO), or endochondral bone formation at nonskeletal sites, often results from traumatic injury and can lead to devastating consequences. Alternatively, the ability to harness this phenomenon would greatly enhance current ... ...

Abstract	Heterotopic ossification (HO), or endochondral bone formation at nonskeletal sites, often results from traumatic injury and can lead to devastating consequences. Alternatively, the ability to harness this phenomenon would greatly enhance current orthopedic tools for treating segmental bone defects. Thus, understanding the earliest events in this process potentially would allow us to design more targeted therapies to either block or enhance this process. Using a murine model of HO induced by delivery of adenovirus-transduced cells expressing bone morphogenetic protein 2 (BMP-2), we show here that one of the earliest stages in this process is the establishment of new vessels prior to the appearance of cartilage. As early as 48 hours after induction of HO, we observed the appearance of brown adipocytes expressing vascular endothelial growth factors (VEGFs) simultaneous with endothelial progenitor replication. This was determined by using a murine model that possesses the VEGF receptor 2 (Flk1) promoter containing an endothelial cell enhancer driving the expression of nuclear-localized yellow fluorescent protein (YFP). Expression of this marker has been shown previously to correlate with the establishment of new vasculature, and the nuclear localization of YFP expression allowed us to quantify changes in endothelial cell numbers. We found a significant increase in Flk1-H2B::YFP cells in BMP-2-treated animals compared with controls. The increase in endothelial progenitors occurred 3 days prior to the appearance of early cartilage. The data collectively suggest that vascular remodeling and growth may be essential to modify the microenvironment and enable engraftment of the necessary progenitors to form endochondral bone.
MeSH term(s)	Adipocytes, Brown/metabolism ; Animals ; Bone Morphogenetic Protein 2/pharmacology ; Cartilage/blood supply ; Ki-67 Antigen/biosynthesis ; Mice ; Ossification, Heterotopic/metabolism ; RNA, Messenger/metabolism ; Vascular Endothelial Growth Factor A/biosynthesis ; Vascular Endothelial Growth Factor Receptor-2/biosynthesis ; von Willebrand Factor/biosynthesis
Chemical Substances	Bone Morphogenetic Protein 2 ; Ki-67 Antigen ; RNA, Messenger ; Vascular Endothelial Growth Factor A ; vascular endothelial growth factor A, rat ; von Willebrand Factor ; Vascular Endothelial Growth Factor Receptor-2 (EC 2.7.10.1)
Language	English
Publishing date	2009-10-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	632783-7
ISSN	1523-4681 ; 0884-0431
ISSN (online)	1523-4681
ISSN	0884-0431
DOI	10.1359/jbmr.091031
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