Elevated plasma RANTES in fibrodysplasia ossificans progressiva – A novel therapeutic target?

Grgurević, Lovorka; Novak, Ruđer; Trkulja, Vladimir; Hamzić, Lejla Ferhatović; Hrkač, Stela; Grazio, Simeon; Santini, Marija

doi:10.1016/j.mehy.2019.109313

Cited by 9 publications

(7 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, the EVs of both FOP groups were significantly associated with immune response. This finding further confirms the importance of immune regulation in FOP pathogenesis, as inflammation established and sustained by the innate immune system seems to be a key trigger of disease flare-ups ( Grgurević et al, 2019 ; Kaplan et al, 2011 ; Haviv et al, 2019 ). Due to the fact that the ratio of involved proteins is comparable in participants with and without an ongoing flare-up, it could be argued that immune system activity is upregulated in FOP even in between flare-ups, although this needs to be further explored on a larger sample size.…”

Section: Discussionsupporting

confidence: 74%

“…Disease flare-ups are reported to be triggered by several factors, such as small tissue injuries, intramuscular injections, muscle fatigue and even viral infections ( Kaplan et al, 2008 ; Scarlett et al, 2004 ; Lanchoney et al, 1995 ; Grgurevic et al, 2021 ). As inflammation is an important component of HO, innate and adaptive immunity, as well as inflammatory cytokines have an important role in HO occurrence and progression ( Matsuo et al, 2019 ; Grgurević et al, 2019 ). Furthermore, the signaling pathways related to bone physiology, such as BMP/TGF-β, are believed to have a central role in the HO of FOP ( Kan et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Heterotopic ossification vs. fracture healing: Extracellular vesicle cargo proteins shed new light on bone formation

et al. 2022

Self Cite

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Heterotopic ossification vs. fracture healing: Extracellular vesicle cargo proteins shed new light on bone formation

et al. 2022

Self Cite

View full text Add to dashboard Cite

“…Furthermore, MCP-1 signaling has shown to be essential for the recruitment of MSCs during early stages of fracture healing in animals models (23). RANTES (CCL5) acts as a chemoattractant for immune cells as well as for osteoblasts and has previously been hypothesized to be a culprit-trigger molecule for the induction of heterotopic ossification in a rare bone disease -fibrodysplasia ossificans progressiva (FOP) (26,27). Moreover, increased RANTES expression was observed locally, at the site of hematoma formation as well as in the surrounding bone marrow in human specimens (27,28).…”

Section: Discussionmentioning

confidence: 99%

Different cytokine expression profiles in metaphyseal and diaphyseal fracture healing may provide new insights in the field of bone regeneration

Hrkač¹,

Novak²,

Salai³

et al. 2022

Rad Hrvatske akademije znanosti i umjetnosti

Self Cite

View full text Add to dashboard Cite

Introduction Fractures are traumatic injuries that mainly occur in bone metaphysis, however most studies of bone healing have focused on diaphyseal bone. This is important because the healing process of trabecular metaphyseal bone has different healing characteristics from the diaphyseal area. Inflammation is thought to play an important, but different role in these two bone fracture types: diaphyseal fractures heal slowly through the formation of callus tissue, and metaphyseal trabecular bone heals faster, with no, or limited callus formation. As cytokines are key modulators of inflammation, the aim of the present study was to define the cytokine profiles at the core of these two conditions with possible implications for the bone healing process. Materials and Methods This study included sixteen patients with long bone metaphyseal and diaphyseal fractures and a healthy control group. Blood samples were taken at two timepoints: i) between the 1 st (the day of the fracture) and the 6 th day after fracture occurrence; ii) between the 7 th and the 21 st day after fracture occurrence. Fractures were treated either conservatively or surgically, depending on specific clinical indications. All participants with diaphyseal fractures were treated surgically. The control group provided blood samples on one occasion. The obtained plasma samples were pooled into 5 different experimental groups and analysed using commercial cytokine arrays. Results Marked differences in cytokine expression profiles were found between the fracture groups and the control group. The diaphyseal group had an "activated" pro-inflammatory cytokine profile with markedly higher levels of cytokines at both timepoints compared to the metaphyseal group, which in contrast had a "silenced" cytokine expression profile. Single cytokine analysis revealed that in both metaphyseal and diaphyseal fracture groups MCP-1 and RANTES showed the most prominent fold change at both timepoints. IL-6 and TNF-α also show similarly elevated levels in both timepoints in the diaphyseal fracture group, whereas this is not observed in the metaphyseal group. Furthermore, IL-3 expression was also elevated in the diaphyseal group, but only in the first timepoint. Conclusion This pilot study indicated chemokines which might be potential crucial drivers of bone healing, as well as painted distinct cytokine plasma profiles evident in metaphyseal and diaphyseal healing.

show abstract

“…Previous research shows that involvement of immune cells, such as macrophages and mast cells, as well as various cytokines are of great importance in the process of HO [ 5 ]. In a previous study of plasma cytokine levels in FOP patients, it was hypothesized that RANTES (Regulated on activation, normal T-cell expressed and secreted/CCL5) might be a potential trigger and/or indicator of HO [ 6 ]. Cytokine analysis of a sample obtained during a flare-up prior to COVID-19 infection from the same patient, showed a significantly lower amount of elevated pro-inflammatory cytokines compared to the post-COVID-19 panel.…”

Section: Discussionmentioning

confidence: 99%

“…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 ]. Coronavirus disease (COVID-19) is caused by SARS-CoV-2 and represents a global public health concern [ 7 ].…”

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Elevated plasma RANTES in fibrodysplasia ossificans progressiva – A novel therapeutic target?

Cited by 9 publications

References 18 publications

Heterotopic ossification vs. fracture healing: Extracellular vesicle cargo proteins shed new light on bone formation

Heterotopic ossification vs. fracture healing: Extracellular vesicle cargo proteins shed new light on bone formation

Different cytokine expression profiles in metaphyseal and diaphyseal fracture healing may provide new insights in the field of bone regeneration

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

Contact Info

Product

Resources

About