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

Hrkač, Stela; Novak, Ruđer; Salai, Grgur; Grazio, Simeon; Vlahović, Tomislav; Grgurević, Lovorka

doi:10.1016/j.bonr.2022.101177

Cited by 4 publications

(3 citation statements)

References 55 publications

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“…[58]. After isolation of EVs of fibrodysplasia ossificans progressiva patients, analysis of the liquid chromatography/mass spectrometry results revealed that the heterotopic ossification occurs via the Ephrin B signaling pathway by aiding in Mφ chemotaxis and activation [59].…”

Section: Msc-ob-derived Evs Regulate Mφmentioning

confidence: 99%

Extracellular Vesicles in Bone Homeostasis: Emerging Mediators of Osteoimmune Interactions and Promising Therapeutic Targets

Huang¹,

Lan²,

Shen³

et al. 2022

Int. J. Biol. Sci.

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An imbalance in bone homeostasis results in bone loss and poor healing in bone diseases and trauma. Osteoimmune interactions, as a key contributor to bone homeostasis, depend on the crosstalk between mesenchymal stem cell-osteoblast (MSC-OB) and monocyte-macrophage (MC-Mφ) lineages. Currently, extracellular vesicles (EVs) are considered to be involved in cell-to-cell communication and represent a novel avenue to enhance our understanding of bone homeostasis and to develop novel diagnostic and therapeutic options. In this comprehensive review, we aim to present recent advances in the study of the effect of MC-Mφ-derived EVs on osteogenesis and the regulatory effects of MSC-OB-derived EVs on the differentiation, recruitment and efferocytosis of Mφ. Furthermore, we discuss the role of EVs as crucial mediators of the communication between these cell lineages involved in the development of common bone diseases, with a focus on osteoporosis, osteoarthritis, bone fracture, and periodontal disease. Together, this review focuses on the apparent discrepancies in current research findings and future directions for translating fundamental insights into clinically relevant EV-based therapies for improving bone health.

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Section: Msc-ob-derived Evs Regulate Mφmentioning

confidence: 99%

Extracellular Vesicles in Bone Homeostasis: Emerging Mediators of Osteoimmune Interactions and Promising Therapeutic Targets

Huang¹,

Lan²,

Shen³

et al. 2022

Int. J. Biol. Sci.

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“…Lees-Shepard et al [17] have shown that fibroadipogenic progenitor cells that reside in skeletal muscle interstitium contribute to injury-induced HO in a genetically correct mouse model of FOP as well as in non-FOP mice. In addition, a recent report on extracellular vesicle cargo proteins suggests there are sizeable differences between fracture healing in a non-FOP context and HO in patients with FOP [8].…”

Section: Discussionmentioning

confidence: 99%

Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility

Lindborg

Mukaddam²,

Baujat

et al. 2023

Clin Orthop Relat Res

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Background Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder with episodic and progressive heterotopic ossification. Tissue trauma is a major risk factor for flareups, heterotopic ossification (HO), and loss of mobility in patients with FOP. The International Clinical Council on FOP generally recommends avoiding surgery in patients with FOP unless the situation is life-threatening, because soft tissue injury can trigger an FOP flareup. Surprisingly little is known about flareups, HO formation, and loss of mobility after fractures of the normotopic (occurring in the normal place, distinct from heterotopic) skeleton when treated nonoperatively in patients with FOP. Questions/purposes (1) What proportion of fractures had radiographic evidence of union (defined as radiographic evidence of healing at 6 weeks) or nonunion (defined as the radiographic absence of a bridging callus at 3 years after the fracture)? (2) What proportion of patients had clinical symptoms of an FOP flareup because of the fracture (defined by increased pain or swelling at the fracture site within several days after closed immobilization)? (3) What proportion of patients with fractures had radiographic evidence of HO? (4) What proportion of patients lost movement after a fracture? Methods We retrospectively identified 36 patients with FOP from five continents who sustained 48 fractures of the normotopic skeleton from January 2001 to February 2021, who were treated nonoperatively, and who were followed for a minimum of 18 months after the fracture and for as long as 20 years, depending on when they sustained their fracture during the study period. Five patients (seven fractures) were excluded from the analysis to minimize cotreatment bias because these patients were enrolled in palovarotene clinical trials (NCT02190747 and NCT03312634) at the time of their fractures. Thus, we analyzed 31 patients (13 male, 18 female, The institution of one or more of the authors (MA, RJP) has received, during the study period, funding from the Radiant Hope Foundation.

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“…Bone fracture healing is an extremely complex physiological mechanism which employs a plethora of factors including a vast array of different cell types which are tightly regulated through different mediators -namely, hormones, growth factors and cytokines, as well as other molecules. These mediators can either act locally in the tissue (paracrine signaling), or they can be plasma soluble; additionally, they could be transported with other modes of transportation, as protein cargo inside extracellular vesicles, whose role in bone healing is emerging (21). Since cytokines are crucial messengers that govern cell communication, which in turn enable basic cellular functions and coordination of multiple-cell actions; we focused on the systemic axis of bone fracture healing.…”

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

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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.

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

Cited by 4 publications

References 55 publications

Extracellular Vesicles in Bone Homeostasis: Emerging Mediators of Osteoimmune Interactions and Promising Therapeutic Targets

Extracellular Vesicles in Bone Homeostasis: Emerging Mediators of Osteoimmune Interactions and Promising Therapeutic Targets

Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility

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

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