Heterotopic ossification and the elucidation of pathologic differentiation

Cholok, David; Chung, Michael T.; Ranganathan, Kavitha; Ucer, Serra; Day, Devaveena; Davis, Thomas A.; Mishina, Yuji; Lévi, Benjamin

doi:10.1016/j.bone.2017.09.019

Cited by 58 publications

(51 citation statements)

References 117 publications

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“…Much progress has been made in the past few years in better understanding the cellular and molecular causes of NHO and traumatic HO that involve progenitor cells, specific molecular signals directing the progenitor cell fate and a permissive environment [4, 6, 21, 46, 47]. For example, Kan et al recently reported that Gli1-creERT-labeled cells contribute significantly to all stages of HO in adult triple transgenic mice (Nse-BMP4/Gli1-creERT-Zsgreen) and that these cells are also co-labeled by mesenchymal progenitor/stem cell markers, confirming that local tissue-resident mesenchymal progenitors/stem cells are involved in traumatic HO [48].…”

Section: Discussionmentioning

confidence: 99%

Muscle injury-induced hypoxia alters the proliferation and differentiation potentials of muscle resident stromal cells

et al. 2019

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Background: Trauma-induced heterotopic ossification (HO) is a complication that develops under three conditions: the presence of an osteogenic progenitor cell, an inducing factor, and a permissive environment. We previously showed that a mouse multipotent Sca1 + CD31 − Lin − muscle resident stromal cell (mrSC) population is involved in the development of HO in the presence of inducing factors, members of the bone morphogenetic protein family. Interestingly, BMP9 unlike BMP2 causes HO only if the muscle is damaged by injection of cardiotoxin. Because acute trauma often results in blood vessel breakdown, we hypothesized that a hypoxic state in damaged muscles may foster mrSCs activation and proliferation and trigger differentiation toward an osteogenic lineage, thus promoting the development of HO. Methods: Three-to-six-month-old male C57Bl/6 mice were used to induce muscle damage by injection of cardiotoxin intramuscularly into the tibialis anterior and gastrocnemius muscles. mrSCs were isolated from damaged (hypoxic state) and contralateral healthy muscles and counted, and their osteoblastic differentiation with or without BMP2 and BMP9 was determined by alkaline phosphatase activity measurement. The proliferation and differentiation of mrSCs isolated from healthy muscles was also studied in normoxic incubator and hypoxic conditions. The effect of hypoxia on BMP synthesis and Smad pathway activation was determined by qPCR and/or Western blot analyses. Differences between normally distributed groups were compared using a Student's paired t test or an unpaired t test. Results: The hypoxic state of a severely damaged muscle increased the proliferation and osteogenic differentiation of mrSCs. mrSCs isolated from damaged muscles also displayed greater sensitivity to osteogenic signals, especially BMP9, than did mrSCs from a healthy muscle. In hypoxic conditions, mrSCs isolated from a control muscle were more proliferative and were more prone to osteogenic differentiation. Interestingly, Smad1/5/8 activation was detected in hypoxic conditions and was still present after 5 days, while Smad1/5/8 phosphorylation could not be detected after 3 h of normoxic incubator condition. BMP9 mRNA transcripts and protein levels were higher in mrSCs cultured in hypoxic conditions. Our results suggest that low-oxygen levels in damaged muscle influence mrSC behavior by facilitating their differentiation into osteoblasts. This effect may be mediated partly through the activation of the Smad pathway and the expression of osteoinductive growth factors such as BMP9 by mrSCs. Conclusion: Hypoxia should be considered a key factor in the microenvironment of damaged muscle that triggers HO.

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Section: Discussionmentioning

confidence: 99%

Muscle injury-induced hypoxia alters the proliferation and differentiation potentials of muscle resident stromal cells

et al. 2019

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“…Acquired HO is closely related to tissue trauma and can be seen after joint surgery, musculoskeletal trauma, central nervous system injury, and even burns 2. HO develops in up to 44% of patients undergoing hip arthroscopy or replacement, 10-20% of those with CNS injury, and 4% of those with burns covering greater than 30% of body surface 3, 4, 5, 6, 7, 8, 9, 10. Many cases of HO lead an indolent course, however severe cases can cause inflammation, pain, immobility and functional impairment 11.…”

Section: Introductionmentioning

confidence: 99%

Heterotopic ossification: radiological and pathological review

Mujtaba

Taher

Fiala

et al. 2019

Radiology and Oncology

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Background Heterotopic Ossification (HO) is a common condition referring to ectopic bone formation in soft tissues. It has two major etiologies, acquired (more common) and genetic. The acquired form is closely related to tissue trauma. The exact pathogenesis of this disease remains unclear; however, there is ongoing research in prophylactic and therapeutic treatments that is promising. Conclusions Due to HO potential to cause disability, it is so important to differentiate it from other causes in order to establish the best possible management.

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“…The exact mechanism of OM of the cervix is not known although several have been proposed. It has been suggested that inflammation and trauma leading to chronic tissue injury stimulate undifferentiated stromal mesenchymal cells to undergo OM [ 17 ]. In case of OM of the cervix, inflammation and trauma are in the form of cervical infections, cervical intraepithelial neoplasia, or cervical biopsy [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

Osseous Metaplasia of the Cervix: A Rare Transformation Can Mimic a Tumor—Literature Review

Alsaqobi

Al-Brahim

2018

Case Reports in Pathology

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Background The transformation of nonosseous soft tissue into bone is known as osseous metaplasia (OM). This condition most commonly affects the musculoskeletal and central nervous systems and it is a well-known phenomenon in different soft tissue organs. Rarely, OM can affect the uterus, which can extend into the cervix. OM affecting the cervix alone is a more rare condition that has multiple different clinical presentations. The presentation can be similar to that of a tumor in extremely rare cases. Case Summary A 23-year-old nulligravida was complaining of irregular vaginal bleeding for one-month duration. Speculum examination revealed a foul-smelling bloody purulent discharge, tender cervix, and a brownish growth located at the posterior cervical lip. A punch biopsy of the growth was performed. Histological examination of the tissue revealed multiple bone fragments with necrosis and an inflammatory exudate. Because of the unusual findings, a repeat biopsy was performed. The biopsy yielded the same findings, which confirmed the diagnosis of osseous metaplasia of the cervix. Conclusion Although osseous metaplasia is a known phenomenon in different soft tissues, it is extremely rare in the uterine cervix and can mimic malignancy. Therefore, clinicians should be aware of it.

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Heterotopic ossification and the elucidation of pathologic differentiation

Cited by 58 publications

References 117 publications

Muscle injury-induced hypoxia alters the proliferation and differentiation potentials of muscle resident stromal cells

Muscle injury-induced hypoxia alters the proliferation and differentiation potentials of muscle resident stromal cells

Heterotopic ossification: radiological and pathological review

Osseous Metaplasia of the Cervix: A Rare Transformation Can Mimic a Tumor—Literature Review

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