Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

Davies, Owen G.; Grover, Liam M.; Eisenstein, Neil; Lewis, Mark P.; Liu, Yang

doi:10.1007/s00223-015-0034-1

Cited by 33 publications

(28 citation statements)

References 109 publications

(142 reference statements)

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“…In fact, although a few cases of ossification have been reported in Peutz-Jeghers polyposis or colorectal cancer, ossification in the gastrointestinal tract is extremely rare [7, 8]. Since heterotopic ossification commonly occurs as a complication of trauma [9], the process of wound healing after traumatic injury at the anastomotic region may have induced heterotopic ossification, as well as the incorporation of rectal mucosa into the bone and surrounding stromal tissues in our patient. We had knowledge of the patient’s clinical history of long hospitalization after high anterior resection, in addition to the findings from the second low anterior resection of strong adhesion between the anastomotic region and the surrounding intestines.…”

Section: Discussionmentioning

confidence: 80%

Rectal cancer developing from an anastomotic site 18 years after resection due to intussusception caused by Peutz-Jeghers polyposis in a 31-year-old man: a case report

et al. 2018

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BackgroundPeutz-Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by hamartomatous polyposis of the gastrointestinal tract. It is associated with a high risk of malignancy in the gastrointestinal tract, as well as in other organs. We report a case of colon cancer at the anastomotic site that occurred 18 years after high anterior resection of the rectum for intussusception caused by Peutz-Jeghers polyposis.Case presentationA 31-year-old man with PJS, who had undergone high anterior resection of the rectum for intussusception at the age of 12, presented to our hospital complaining of hematochezia. Colonoscopy revealed a hemorrhagic tumor protruding from the anastomotic site, which was histologically diagnosed as an adenocarcinoma. We performed a low anterior resection of the rectum including the anastomotic site, with combined resection of the strongly adherent ileum. Histological examination revealed that the adenocarcinoma had developed from the submucosal area, where the normal rectal mucosa had been incorporated into the stromal and bone tissues, resulting in heterotopic ossification in the anastomotic region. These findings suggested that the reconstructive surgical procedure or postoperative complications, such as anastomotic leakage, had formed the cavity where the cancer had developed.ConclusionsWe concluded that the cancer might be derived from the rectal mucosa with malignant potential that was present in the anastomotic region and exacerbated by the presence of chronic inflammation in the cavity after the patient’s initial operation.

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Section: Discussionmentioning

confidence: 80%

Rectal cancer developing from an anastomotic site 18 years after resection due to intussusception caused by Peutz-Jeghers polyposis in a 31-year-old man: a case report

et al. 2018

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“…More recent evidence points to the fact that the adipogenic population is likely to be of fibroblast rather than myogenic origin, with the intramuscular injection BMP-2 expressing fibroblasts causing an accumulation of brown adipocytes after just 24 h (Olmsted-Davis et al, 2007). However, in addition to fibroblasts, numerous other endogenous and migratory cell types have shown a capacity for adipogenesis (Davies et al, 2015) (Figure 3). For instance MSCs, hypothesized to migrate from the bone marrow following trauma (Pignolo and Shore, 2013), have a well-defined adipogenic capacity.…”

Section: Adipogenesismentioning

confidence: 99%

“…Current prophylaxis and treatments have varying levels of success and include the use of non-steroidal anti-inflammatories (NSAIDs), bisphosphonates, and single dose radiotherapy. A thorough discussion of the benefits and drawbacks of these clinical methods can be found in a previous review (Davies et al, 2015). Currently, the underlying mechanisms governing acquired HO are not well understood, with the osteoinductive action of certain BMPs, implicated in genetic forms of the condition, such as fibrodysplasia ossificans progressiva (FOP), likely to be only partly responsible.…”

Section: Introductionmentioning

confidence: 99%

Defining the Balance between Regeneration and Pathological Ossification in Skeletal Muscle Following Traumatic Injury

et al. 2017

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Heterotopic ossification (HO) is characterized by the formation of bone at atypical sites. This type of ectopic bone formation is most prominent in skeletal muscle, most frequently resulting as a consequence of physical trauma and associated with aberrant tissue regeneration. The condition is debilitating, reducing a patient's range of motion and potentially causing severe pathologies resulting from nerve and vascular compression. Despite efforts to understand the pathological processes governing HO, there remains a lack of consensus regarding the micro-environmental conditions conducive to its formation, and attempting to define the balance between muscle regeneration and pathological ossification remains complex. The development of HO is thought to be related to a complex interplay between factors released both locally and systemically in response to trauma. It develops as skeletal muscle undergoes significant repair and regeneration, and is likely to result from the misdirected differentiation of endogenous or systemically derived progenitors in response to biochemical and/or environmental cues. The process can be sequentially delineated by the presence of inflammation, tissue breakdown, adipogenesis, hypoxia, neo-vasculogenesis, chondrogenesis and ossification. However, exactly how each of these stages contributes to the formation of HO is at present not well understood. Our previous review examined the cellular contribution to HO. Therefore, the principal aim of this review will be to comprehensively outline changes in the local tissue micro-environment following trauma, and identify how these changes can alter the balance between skeletal muscle regeneration and ectopic ossification. An understanding of the mechanisms governing this condition is required for the development and advancement of HO prophylaxis and treatment, and may even hold the key to unlocking novel methods for engineering hard tissues.

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“…The formation of bone at atypical sites can have serious consequences such as neurovascular entrapment, and has a significant impact on an individual's quality of life (Colachis et al ., ). Acquired HO is associated with severe trauma that can result as a consequence of injuries, burns or changes in local biomechanics following reparative surgeries (Davies et al ., ). Despite continued efforts to determine the cellular and molecular events governing HO, the underlying mechanisms remain elusive.…”

Section: Introductionmentioning

confidence: 99%

PDGF is a potent initiator of bone formation in a tissue engineered model of pathological ossification

Davies

Grover

Lewis

et al. 2017

J Tissue Eng Regen Med

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Heterotopic ossification (HO) is a debilitating condition defined by the rapid formation of bone in soft tissues. What makes HO fascinating is first the rate at which bone is deposited, and second the fact that this bone is structurally and compositionally similar to that of a healthy adult. If the mechanisms governing HO are understood, they have the potential to be exploited for the development of potent osteoinductive therapies. With this aim, a tissue‐engineered skeletal muscle was used model to better understand the role of inflammation on this debilitating phenomenon. It was shown that myoblasts could be divided into two distinct populations: myogenic cells and undifferentiated ‘reserve’ cells. Gene expression analysis of myogenic and osteoregulatory markers confirmed that ‘reserve’ cells were primed for osteogenic differentiation but had a reduced capacity for myogenesis. Osteogenic differentiation was significantly enhanced in the presence of platelet‐derived growth factor (PDGF)‐BB and bone morphogenetic protein 2 (BMP2), and correlated with conversion to a Sca‐1+/CD73+ phenotype. Alizarin red staining showed that PDGF‐BB promoted significantly more mineral deposition than BMP2. Finally, it was shown that PDGF‐induced mineralization was blocked in the presence of the pro‐inflammatory cytokines tumour necrosis factor‐α and interleukin 1. In conclusion, the present study identified that PDGF‐BB is a potent osteoinductive factor in a model of tissue‐engineered skeletal muscle, and that the osteogenic capacity of this protein was modulated in the presence of pro‐inflammatory cytokines. These findings reveal a possible mechanism by which HO develops following trauma. Importantly, these findings have implications for the induction and control of bone formation for regenerative medicine. © 2016 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd.

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Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

Cited by 33 publications

References 109 publications

Rectal cancer developing from an anastomotic site 18 years after resection due to intussusception caused by Peutz-Jeghers polyposis in a 31-year-old man: a case report

Rectal cancer developing from an anastomotic site 18 years after resection due to intussusception caused by Peutz-Jeghers polyposis in a 31-year-old man: a case report

Defining the Balance between Regeneration and Pathological Ossification in Skeletal Muscle Following Traumatic Injury

PDGF is a potent initiator of bone formation in a tissue engineered model of pathological ossification

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