Vessel formation is induced prior to the appearance of cartilage in BMP-2-mediated heterotopic ossification

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

doi:10.1359/jbmr.091031

Cited by 71 publications

(81 citation statements)

References 34 publications

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“…We previously showed the rapid expansion of new vessels after delivery of the AdBMP-2-transduced cells [7] and in the current study, an extensive vascular plexus can be seen surrounding the claudin 5 + osterix + cells. Furthermore, at the same time, extravasation factors (CXCR4, CD44, and E-selectin) were significantly elevated in these tissues consistent with the appearance, through the circulation, of the cells at this site.…”

Section: Discussionsupporting

confidence: 77%

“…We therefore propose that the exact location of extravasation of the osteoprogenitors is determined by induction of HIF1 in tBAT [27] because of the ability of UCP1 to rapidly generate a hypoxic microenvironment [27]. This process induces vascular endothelial growth factor [7], which then induces new vessel formation. These new vessels are actually the small venules that are required for extravasation [43].…”

Section: Discussionmentioning

confidence: 99%

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Osteoblasts Have a Neural Origin in Heterotopic Ossification

Lazard

Olmsted-Davis

Salisbury

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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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 123Clin Orthop Relat Res (2015) 473:2790-2806 DOI 10.1007 Clinical Orthopaedics and Related Research ® A Publication of The Association of Bone and Joint Surgeons® 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 PDGFRa, 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 par...

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Osteoblasts Have a Neural Origin in Heterotopic Ossification

Lazard

Olmsted-Davis

Salisbury

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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“…However, MSCs are defined as multipotent cells capable of adipogenic differentiation, and, as such, their contribution to brown adipose tissue formation during the early stages of HO cannot be ruled out. Brown adipocytes formed at the onset of HO have been shown to express vascular endothelial growth factors, concurrent with endothelial progenitor proliferation [43]. Consequently, the presence of brown adipocytes within the lesion reduces the oxygen tension in the adjacent tissue, due to oxidative metabolism [42].…”

Section: Mesoderm Mesenchymal Stem Cellsmentioning

confidence: 99%

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

et al. 2015

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“…We then quantified whether this led to new vessel formation, and found a 2 fold enhancement in new vessels in tissues receiving the BMP2 transduced cells (Fouletier-Dilling et al, 2010). We also demonstrated that cells expressing the VEGFs were the brown adipose (Fouletier- Dilling et al, 2010), and that the adipose appears to be generated rapidly, and involved in patterning of the newly forming bone. From these studies we have identified a novel mechanism which shows the molecular pathway induced directly by BMP2, which leads to production of brown adipose, new vessels, peripheral nerve ingrowth, and ultimately cartilage and bone (Olmsted-Davis et al, 2007).…”

Section: B Engineer Cellular Binding Sights Within the Hydrogel To Dmentioning

confidence: 76%

Cellular Therapy to Obtain Spine Fusion

Davis¹

2012

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Surgery of the spine to fuse the vertebral bones is one of the most commonly performed operations with an estimated 350,000 Americans undergoing this surgery annually with estimated costs of $60 billion. Current procedures are highly invasive with limited success. The goal of this study is to develop a safe efficacious system for inducing spine fusion which will eliminate the need for invasive surgery. We have currently developed a cell based gene therapy system that can induce rapid bone formation at a targeted location which is independent of immune status of the model. This system relies on adenovirus transduced cells expressing bone morphogenetic protein 2 to induce bone formation leading to vertebral fusion after delivery into the paraspinous musculature. To prolong cell survival and insure cells are maintained at the target site, we have encapsulated them in a nondegradable hydrogel material. This provides additional safety by eliminating direct injection of the virus through cell delivery, and prevention of cell diffusion, through encapsulation. Here we provide preliminary data; demonstrating spine fusion using this system at 6 weeks after induction. This is the first step in demonstrating efficacy, a critical component of preclinical testing. Thus with validation of our hypothesis, this approach can now be developed as a safe and efficacious gene therapy system for spine fusion, thus circumventing the need for costly invasive surgery. Introduction: Surgery of the spine to fuse the vertebral bones is one of the most commonly performed operations with some 400,000 Americans undergoing this type of surgery annually in the United States. The estimated cost associated with such procedures exceeding $60 billion annually demonstrating this to be a significant problem. In the most common form, posterolateral fusion, the paraspinous musculature is stripped and the bone decorticated, resulting in significant pain, reduced stability afforded by these muscles, and disruption of the blood supply to both bone and muscle. Further, success rates for fusion range from 50-70% depending on how many levels are fused and the number and types of attendant complications. We recently demonstrated that transduced cells expressing high levels of bone morphogenetic protein 2 (BMP2) in skeletal muscle could rapidly recruit and expand endogenous cell populations to initiate all stages of endochondral bone formation, with mineralized bone forming within one week of implantation. The central hypothesis of this applicati...

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Vessel formation is induced prior to the appearance of cartilage in BMP-2-mediated heterotopic ossification

Cited by 71 publications

References 34 publications

Osteoblasts Have a Neural Origin in Heterotopic Ossification

Osteoblasts Have a Neural Origin in Heterotopic Ossification

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

Cellular Therapy to Obtain Spine Fusion

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