Multipotent progenitors resident in the skeletal muscle interstitium exhibit robust BMP-dependent osteogenic activity and mediate heterotopic ossification

Wosczyna, Michael N.; Biswas, Arpita; Cogswell, Catherine A.; Goldhamer, David J.

doi:10.1002/jbmr.1562

Cited by 281 publications

(394 citation statements)

References 54 publications

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“…On the surface, as noted above, it appear that groups have claimed widely disparate progenitors ranging from those from the nerve described in this manuscript, to endothelial cells [4], or progenitors residing in muscle [5]. However, as shown in the model of HO presented in Figure 7, each of these precursors or cells very much like them, is present during HO.…”

Section: Discussionmentioning

confidence: 61%

“…Although these reports do not agree on its origin, surprisingly they agree on several markers associated with the osteoprogenitor phenotype. These markers include PDGFRα, Tie-2, and SP7 [4, 5, 7]. Even studies of human osteoprogenitors involved in HO induced by traumatic injury, although passaged in vitro , confirm the presence of these markers on the cells [8–10].…”

Section: Introductionmentioning

confidence: 99%

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Progenitors in Peripheral Nerves Launch Heterotopic Ossification

Olmsted-Davis

Salisbury²,

Hoang³

et al. 2017

Stem Cells Translational Medicine

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Studies presented here, using a murine model of bone morphogenetic protein type 2 (BMP2)-induced HO show that the protein initiates HO by signaling through progenitors in the endoneurium of peripheral nerves. In the mouse, these cells were identified in the endoneurium one day after BMP2 induction using antibody against phosphoSMAD (PS) 1, 5, and 8. Studies conducted in a tracking mouse that contains a tamoxifen-regulated Wnt1-Cre recombinase crossed with a td Tomato red (TR) reporter (Wnt1CreErt:Ai9Tm) confirmed their neural origin. In this model both BMP2 induction and tamoxifen are absolutely required to induce TR. SP7+(osterix+)TR+ cells were found in the endoneurium on day 1 and associated with bone on day 7. Quantification of TR+ and TR− cells isolated by FACS showed that all SP7+ cells were found in the TR+ population, whereas only about 80 percent of the TR+ cells expressed SP7. Pre-chondrocytes (Sox 9+) and transient brown fat (tBAT, UCP1+) also co-expressed TR, suggesting that the progenitor in nerves is multi-potential. The endoneurium of human nerves near the site of HO contained many PS+ cells, and SP7+ cells were found in nerves and on bone in tissue from patients with HO. Control tissues and nerves did not contain these PS+ and SP7+ cells. Some osteoblasts on bone from patients with HO were positive for PS, suggesting the continued presence of BMP during bone formation. The data suggests that the progenitors for HO are derived from the endoneurium in both the mouse model of HO and in humans with HO.

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Progenitors in Peripheral Nerves Launch Heterotopic Ossification

Olmsted-Davis

Salisbury²,

Hoang³

et al. 2017

Stem Cells Translational Medicine

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“…The presence of PDGF receptors as a marker of mesenchymal cells closely associated with the vasculature correlates with work conducted by Wosczyna et al (2012). This work showed that a population of non-endothelial Tie2 + PDGFRα + Sca-1 + cells in the muscle interstitium was found to be consistently incorporated into chondrogenic and osteogenic lesions [94]. However, the expression of PDGFα also draws a direct comparison with bone marrowderived pericyte progenitors (PDGFRα + Sca-1 + ) previously identified by Uezumi et al (2010) [62] (see Table 1).…”

Section: Endoderm Endothelial Cellsmentioning

confidence: 66%

“…For example, a study by Kirton et al (2007) has shown that the chondrogenic differentiation pathway of pericytes can be activated by Wnt/betacatenin signalling in the presence of TGF-β3 [98]. Additionally, a recent study by Kan et al (2013) identified that cells presenting the glutamate transporter GLAST were found to contribute to the formation of ectopic bone, and that these GLAST + cells appeared to be distinct from the Tie2 + population identified by Woscyzna et al (2012) [94]. Pericyte populations have been shown to express GLAST [99], and consequently this information further highlighted the potential role of these cells during HO.…”

Section: Neural Crest Pericytesmentioning

confidence: 99%

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

et al. 2015

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“…There have been publications suggesting that osteoprogenitors are derived from either mesenchymal stem cells in the bone marrow [29] or from the interstitial cells between the muscle fibers [45] or from fully differentiated endothelial cells [19], which then undergo an endothelial to mesenchymal transition [18]. It has also been suggested that the osteoprogenitors can be found in the circulation [39].…”

Section: Introductionmentioning

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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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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Multipotent progenitors resident in the skeletal muscle interstitium exhibit robust BMP-dependent osteogenic activity and mediate heterotopic ossification

Cited by 281 publications

References 54 publications

Progenitors in Peripheral Nerves Launch Heterotopic Ossification

Progenitors in Peripheral Nerves Launch Heterotopic Ossification

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

Osteoblasts Have a Neural Origin in Heterotopic Ossification

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