Inflammation in Fibrodysplasia Ossificans Progressiva and Other Forms of Heterotopic Ossification

Matsuo, Koji; Chavez, Robert Dalton; Barruet, Emilie; Hsiao, Edward C.

doi:10.1007/s11914-019-00541-x

Cited by 47 publications

(46 citation statements)

References 83 publications

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“…In the general pathological process of HO, multipotent cells unexpectedly accumulate in the soft tissue lesion region and differentiate into mature bone cells through an endochondral ossification process under relevant induction signals. This aberrant permissive microenvironment formation, according to our current knowledge, is often initiated and aggravated by inflammatory cues ( 14 ). Upon injury, circulating monocytes from peripheral blood respond and infiltrate the injury site, where they undergo the monocyte-to-macrophage transition and polarization, secreting a plethora of proinflammatory mediators, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor β (TGF-β), creating an osteogenesis-promoting niche ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

Quercetin Attenuates Trauma-Induced Heterotopic Ossification by Tuning Immune Cell Infiltration and Related Inflammatory Insult

Sun

Luo

et al. 2021

Front. Immunol.

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Heterotopic ossification (HO) is one of the most intractable disorders following musculoskeletal injury and is characterized by the ectopic presence of bone tissue in the soft tissue leading to severe loss of function in the extremities. Recent studies have indicated that immune cell infiltration and inflammation are involved in aberrant bone formation. In this study, we found increased monocyte/macrophage and mast cell accumulation during early HO progression. Macrophage depletion by clodronate liposomes and mast cell stabilization by cromolyn sodium significantly impeded HO formation. Therefore, we proposed that the dietary phytochemical quercetin could also suppress immune cell recruitment and related inflammatory responses to prevent HO. As expected, quercetin inhibited the monocyte-to-macrophage transition, macrophage polarization, and mast cell activation in vitro in a dose-dependent manner. Using a murine burn/tenotomy model, we also demonstrated that quercetin attenuated inflammatory responses and HO in vivo. Furthermore, elevated SIRT1 and decreased acetylated NFκB p65 expression were responsible for the mechanism of quercetin, and the beneficial effects of quercetin were reversed by the SIRT1 antagonist EX527 and mimicked by the SIRT agonist SRT1720. The findings in this study suggest that targeting monocyte/macrophage and mast cell activities may represent an attractive approach for therapeutic intervention of HO and that quercetin may serve as a promising therapeutic candidate for the treatment of trauma-induced HO by modulating SIRT1/NFκB signaling.

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Section: Introductionmentioning

confidence: 99%

Quercetin Attenuates Trauma-Induced Heterotopic Ossification by Tuning Immune Cell Infiltration and Related Inflammatory Insult

Sun

Luo

et al. 2021

Front. Immunol.

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“…Although animal studies have shown that Activin A inhibition could be highly effective in blocking progressive HO, this mutation alone is not sufficient for HO, since disease flare-ups are triggered by inflammation and activation of the innate immune system [ 3 ]. Studies have shown that innate immunity and cytokines are of great importance for HO occurrence and progression, furthermore, various cytokines have been implicated in HO pathogenesis [ 4 , 5 ]. Previous research hypothesized that for the induction of HO in FOP patients an increase in at least one pro-inflammatory cytokine is both essential and sufficient to trigger the entire process of inflammatory cell influx [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Post-COVID-19 exacerbation of fibrodysplasia ossificans progressiva with multiple flare-ups and extensive heterotopic ossification in a 45-year-old female patient

et al. 2021

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Fibrodyplasia ossificans progressiva (FOP) is a rare hereditary disease, which has a variable course characterized by occasional flare-ups of heterotopic ossification (HO) in soft tissues that are followed by swelling, stiffness, pain and warmth. Here, we report for the first time a case of a 45-year-old female patient with known FOP recovering from COVID-19 with disease progression potentially linked with the viral illness. In December 2020 the patient contracted a mild form of COVID-19 infection without need for hospital admission. Since January 2021, the patient felt unwell, with occasional abdominal pain which progressively intensified. In March 2021 she presented with new onset of HO, complaining of pain, swelling and thickening sensation in the lower abdomen and left part of the neck. Computerized tomography (CT) and cytokine analysis were performed. CT scan revealed new heterotopic bone formation in multiple soft tissue areas of the neck indicating clear radiological progression. Radiotherapy, which has proven to be an efficient tool to control HO in this patient, was not able to halt HO formation after COVID-19 infection. Cytokine analysis of a plasma sample obtained during a flare-up after COVID-19 infection showed a significantly elevated pro-inflammatory cytokines compared to a flare-up panel prior to infection. Of the 23 analyzed levels of cytokines, a staggering number of 21 were above normal levels. This case is the first confirmation of uncontrolled post-COVID-19 effects in a FOP patient, which manifested with flare-ups followed by progressive HO, possibly caused by a thus far, never described form of post-COVID syndrome.

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“…Aberrant repair after muscle injury can results in scarring, fibrosis, lipid infiltration, or heterotopic ossification (HO; bone formation in an inappropriate site). Although HO is a relatively uncommon complication, it can form after trauma, burns, spinal cord injuries, and surgical procedures such as hip arthroplasty (Agarwal et al, 2016;Matsuo, Chavez, Barruet, & Hsiao, 2019;Meyers et al, 2019;Sullivan, Torres, Mehta, & Ahn, 2013). Recently, HO has been reported in patients with severe COVID-19, suggesting a critical role for inflammation and muscle damage (Aziz, Choudhari, Alexander, & Allam, 2021).…”

Section: Introductionmentioning

confidence: 99%

Modeling the ACVR1R206H mutation in human skeletal muscle stem cells

Barruet

Garcia

et al. 2021

eLife

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Abnormalities in skeletal muscle repair can lead to poor function and complications such as scarring or heterotopic ossification (HO). Here, we use fibrodysplasia ossificans progressiva (FOP), a disease of progressive HO caused by ACVR1R206H (Activin receptor type-1 receptor) mutation, to elucidate how ACVR1 affects skeletal muscle repair. Rare and unique primary FOP human muscle stem cells (Hu-MuSCs) isolated from cadaveric skeletal muscle demonstrated increased ECM marker expression, showed skeletal muscle-specific impaired engraftment and regeneration ability. Human induced pluripotent stem cell (iPSC)-derived muscle stem/progenitor cells (iMPCs) single cell transcriptome analyses from FOP also revealed unusually increased ECM and osteogenic marker expression compared to control iMPCs. These results show that iMPCs can recapitulate many aspects of Hu-MuSCs for detailed in vitro study, that ACVR1 is a key regulator of Hu-MuSC function and skeletal muscle repair; and that ACVR1 activation in iMPCs or Hu-MuSCs may contribute to HO by changing the local tissue environment.

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Inflammation in Fibrodysplasia Ossificans Progressiva and Other Forms of Heterotopic Ossification

Cited by 47 publications

References 83 publications

Quercetin Attenuates Trauma-Induced Heterotopic Ossification by Tuning Immune Cell Infiltration and Related Inflammatory Insult

Quercetin Attenuates Trauma-Induced Heterotopic Ossification by Tuning Immune Cell Infiltration and Related Inflammatory Insult

Post-COVID-19 exacerbation of fibrodysplasia ossificans progressiva with multiple flare-ups and extensive heterotopic ossification in a 45-year-old female patient

Modeling the ACVR1R206H mutation in human skeletal muscle stem cells

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