The effects of soluble activin type IIB receptor on bone formation and body composition

Bone tissue is a dynamic organ which undergoes constant remodeling through a coupled series of events in order to maintain proper skeletal structure and calcium-phosphate homeostasis. In addition to its mechanical properties, extensive research has revealed bone to modulate multiple metabolic processes as well, and it is wide-ly accepted that bone tissue engages in active crosstalk with different tissue types. Activins are pleiotropic growth factors belonging to the transforming growth factor β-superfamily and have recently been associated with numerous pathologic states affecting the musculoskeletal system. As activins are highly expressed in bone, the clarification of the true roles of activins in the pathogenesis of skeletal disorders could lead to the development of novel therapeutics targeting these growth factors. To address this, we investigated the effect of soluble activin type IIB receptor (ActRIIB-Fc), an activin-signaling inhibitor, on bone formation and body composi-tion in different animal models. In this series of translational studies we show that treatment with ActRIIB-Fc im-proves bone mass and strength as well as induces an increase in muscle mass in a mouse model of Duchenne muscular dystrophy. We also demonstrate that ActRIIB-Fc enhances fracture healing in a closed, diaphyseal fracture mouse mod-el. Finally, we showed that treatment with ActRIIB-Fc rescues bone loss and fat gain induced by estrogen deficiency in an ovariectomy-mouse model. Our novel results propose that ActRIIB-Fc affects multiple tissue types in clinically relevant models and could be a potential therapeutic approach in different musculoskeletal and metabolic disorders, in which bone, fat and muscle are affected.Liukoisen tyypin IIB aktiviinireseptorin vaikutus luun muodostumiseen ja kehon koostumukseen Luu on dynaaminen elin, joka säätelee monia biologisia prosesseja. Luukudos uusiutuu jatkuvasti luuta muodostavien osteoblastien ja luuta hajottavien osteoklastien yhteistoiminnan avulla. Tämän uudistumisen tarkoituksena on ylläpitää luun biomekaanisia ominaisuuksia ja kalsium- ja fosfaattitasapainoa. Viimeaikaiset tutkimustulokset ovat osoittaneet, että luu säätelee myös useita aineenvaihdunnan mekanismeja ja luukudos on suorassa vuorovaikutuksessa useiden eri kudostyyppien kanssa. Aktiviinit ovat transformoiva kasvutekijä β-kasvutekijäperheen jäseniä, jotka on viimeaikaisissa tutkimuksissa yhdistetty erilaisiin tukikudosten häiriöihin kuten postmenopausaaliseen osteoporoosiin. Aktiviinien kudostason vaikutukset luustossa tunnetaan kuitenkin edelleen puutteellisesti. Aktiviinien merkityksen selvittäminen näissä sairaustiloissa voisi johtaa uusien, näiden kasvutekijöiden toimintaa rajoittavien lääkeaineiden kehittämiseen. Intraperitoneaalisesti annettu liukoinen tyypin IIB aktiviinireseptori (ActRIIB-Fc) estää reseptorin ligandien toimintaa hiirellä. Tässä työssä tutkimme liukoisen ActRIIB-Fc:n vaikutusta luun muodostukseen ja kehon koostumukseen käyttäen erilaisia hiirimalleja. Ensimmäisessä osatyössä osoitimme, että ActRIIB-Fc lisäsi luun määrää ja tiheyttä sekä lisäsi merkittävästi luurankolihaksen kasvua lihasrappeumahiirimallissa. Toisessa osatyössä tuloksemme osoittivat, että ActRIIB-Fc nopeuttaa hiiren sääriluunmurtuman paranemista lisäämällä luun muodostusta. Viimeisessä osatyössä osoitimme, että ActRIIB-Fc lisää luun muodostusta mutta vähentää rasvan kertymistä elimistöön. Tuloksemme osoittavat, että liukoinen ActRIIB-Fc tarjoaa kiinnostavan hoitovaihtoehdon erilaisiin tuki- ja liikuntaelimistön sekä aineenvaihduntasairauksiin, jotka vaikuttavat luustoon, lihakseen sekä rasvaan

"A" stands for airway - Which factors guide the need for on-scene airway management in facial fracture patients?

Background Numerous guidelines highlight the need for early airway management in facial trauma patients since specific fracture patterns may induce airway obstruction. However, the incidence of these hallmark injuries, including flail mandibles and posterior displacement of the maxilla, is contentious. We aim to evaluate specific trauma-related variables in facial fracture patients, which affect the need for on-scene versus in-hospital airway management. Methods This retrospective cohort study included all patients with any type of facial fracture, who required early airway management on-scene or in-hospital. The primary outcome variable was the site of airway management (on-scene versus hospital) and the main predictor variable was the presence of a traumatic brain injury (TBI). The association of fracture type, mechanism, and method for early airway management are also reported. Altogether 171 patients fulfilled the inclusion criteria. Results Of the 171 patients included in the analysis, 100 (58.5) had combined midfacial fractures or combination fractures of facial thirds. Altogether 118 patients (69.0%) required airway management on-scene and for the remaining 53 patients (31.0%) airway was secured in-hospital. A total of 168 (98.2%) underwent endotracheal intubation, whereas three patients (1.8%) received surgical airway management. TBIs occurred in 138 patients (80.7%), but presence of TBI did not affect the site of airway management. Younger age, Glasgow Coma Scale-score of eight or less, and oro-naso-pharyngeal haemorrhage predicted airway management on-scene, whereas patients who had fallen at ground level and in patients with facial fractures but no associated injuries, the airway was significantly more often managed in-hospital. Conclusions Proper preparedness for airway management in facial fracture patients is crucial both on-scene and in-hospital. Facial fracture patients need proper evaluation of airway management even when TBI is not present.Peer reviewe

Craniofacial Fractures in Equine-Related Injuries : What Should a Maxillofacial Surgeon Expect?

Patients with equine-related injuries (ERI) have high rates of hospitalization and often require surgical treatment. This study aimed to clarify the injury profiles of patients sustaining ERI-related craniofacial fractures and their relationship with other severe head and neck injuries. This retrospective study included all patients with craniofacial fractures admitted to a tertiary trauma center during 2013 to 2018. Out of 3256 patients, a total of 39 patients were included in the study (1.2%). Demographic and clinically relevant variables were reported and statistically evaluated. Males represented only 7.7% of the study population. Isolated facial fractures were over-represented in this study population at 84.6% whereas only 7.7% of patients sustained isolated cranial fractures and 7.7% of patients sustained combined craniofacial fractures, respectively. Surgical intervention for craniofacial fractures was required in 48.7% of patients. In total, 17.9% of patients sustained severe head and neck injuries. Periods of unconsciousness and/or post-traumatic amnesia were seen in 41% of patients. Helmet use could only be confirmed in 17.9% of patients. As trauma mechanisms behind ERI are often multifactorial and patients are at a high risk of sustaining associated injuries, attentive examination, and exclusion of serious life-threatening injuries through a multi-disciplinary approach is imperative for this specific patient population.Peer reviewe

Sports-based distribution of facial fractures - findings from a four-season country

Objective The aim of this study was to elucidate the relationship between injury mechanisms and sports-related facial fractures, and to evaluate the changes in incidence rates of facial fractures sustained in sports-related events in a 30-year period. Material and methods This retrospective cohort study included all patients sports-related facial fractures admitted to a tertiary trauma centre during 2013-2018. Specific fracture types, sports, injury mechanisms as well as patient- and injury related variables are presented. The results underwent evaluated statistically with logistic regression analysis. Results Facial fractures occurred most frequently while playing ice hockey and football. Unilateral zygomatic-maxillary-orbital and isolated mandibular fractures accounted for 74.2% of all fracture types. In total, 99 patients (46.5%) required surgical intervention for their facial injuries. About 12.7% of patients sustained associated injuries in addition to facial fractures. Overall, the number of sports-related facial fractures has increased during the last three decades mostly due to the surging rates of ice hockey- and football-related facial fractures. Conclusions Sport-related facial fractures have markedly increased in different sports disciplines during the past decades. The use of safety gear to protect the facial area should be enforced particularly in ice hockey.Peer reviewe

Are the Elderly With Maxillofacial Injuries at Increased Risk of Associated Injuries?

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Urban drinking and driving:comparison of electric scooter and bicycle related accidents in facial fracture patients

In recent years, electric scooters (e-scooter) have emerged as an alternative mode of urban transport due to their availability and effortless use. However, e-scooter-related trauma and injuries, especially to the head, have received wide media coverage and raised public concern about their safety. We aim to determine and compare clinically relevant variables, incidence, and severity between bicycle and e-scooter-related facial fractures and potential protective measures for injury prevention. This retrospective study comprised all patients admitted to a tertiary trauma center with bicycle or e-scooter-related facial fractures between January 2019 and October 2020. Patient- and injury-related variables, including demographics, injury mechanisms, helmet use, influence of alcohol, types of facial injuries, types of other injuries, given treatment, and hospital stay, were collected, analysed, and compared between bicycle and e-scooter injuries. Altogether 169 patients with facial fractures, 124 bicycle-related injuries (73.4%) and 45 e-scooter-related injuries (26.6%) were included. Alcohol involvement was significantly higher in e-scooter patients (88.9%) than in bicycle patients (31.5%) (p<0.001). Driving under the influence of alcohol was associated with driving without a helmet in both groups (p<0.001). In multivariate analyses, e-scooter accidents were 18 times more likely to occur under the influence of alcohol (OR 17.85, p<0.001) and were more likely to involve collision with a stationary object (OR 3.81, p=0.028). E-scooter patients were significantly younger (OR 0.95, p<0.001) and had significantly more cranial fractures (OR 10.15, p=0.014) than bicycle patients. Compared with patients in bicycle accidents, facial fracture patients injured in e-scooter accidents are younger, are more likely under the influence of alcohol, and sustain more severe craniofacial skeleton fractures. Our results for both groups of patients advocate stricter adherence to helmet and road safety legislation as well as public education for injury prevention

Treatment with Soluble Activin Type IIB Receptor Ameliorates Ovariectomy-Induced Bone Loss and Fat Gain in Mice

Introduction In postmenopausal osteoporosis, hormonal changes lead to increased bone turnover and metabolic alterations including increased fat mass and insulin resistance. Activin type IIB receptors bind several growth factors of the TGF-beta superfamily and have been demonstrated to increase muscle and bone mass. We hypothesized that ActRIIB-Fc treatment could improve bone and muscle mass, inhibit fat accumulation, and restore metabolic alterations in an ovariectomy (OVX) model of postmenopausal osteoporosis. Materials and Methods Female C57Bl/6 N mice were subjected to SHAM or OVX procedures and received intraperitoneal injections of either PBS or ActRIIB-Fc (5 mg/kg) once weekly for 7 weeks. Glucose and insulin tolerance tests (GTT and ITT, respectively) were performed at 7 and 8 weeks, respectively. Bone samples were analyzed with micro-computed tomography imaging, histomorphometry, and quantitative RT-PCR. Results Bone mass decreased in OVX PBS mice compared to the SHAM PBS group but ActRIIB-Fc was able to prevent these changes as shown by mu CT and histological analyses. This was due to decreased osteoclast numbers and function demonstrated by histomorphometric and qRT-PCR analyses. OVX induced adipocyte hypertrophy that was rescued by ActRIIB-Fc, which also decreased systemic adipose tissue accumulation. OVX itself did not affect glucose levels in GTT but ActRIIB-Fc treatment resulted in impaired glucose clearance in both SHAM and OVX groups. OVX induced mild insulin resistance in ITT but ActRIIB-Fc treatment did not affect this. Conclusion Our results reinforce the potency of ActRIIB-Fc as a bone-enhancing agent but also bring new insight into the metabolic effects of ActRIIB-Fc in normal and OVX mice.Peer reviewe

Three-Dimensional Computer-Aided Analysis of 293 Isolated Blowout Fractures - Which Radiological Findings Guide Treatment Decision?

Purpose: Our study purpose was to clarify the extent of isolated unilateral orbital blowout fracture in relation to surgical treatment and other factors behind the treatment decision. The specific aim was to determine which computer-aided measurements based on radiological images associate with treatment choice. Methods: A retrospective cohort study was implemented on patients with an isolated unilateral orbital blowout fracture. Computer-aided measurement of fracture extent was performed. The study variables included treatment as primary outcome (surgical vs nonsurgical), post-traumatic orbital volume difference (mL) compared to contralateral orbit, fracture area (mm(2)), fracture depth (mm) as predictor variables, and age, sex, injury mechanism, side and site of orbital fracture and positions of recti muscles as explanatory variables. Postoperative outcomes were reported. Logistic regression analysis was used to determine the risk factors for surgery. The statistical significance level was set at P < .05. Results: Of 293 patients, 28.0% received surgical and 72.0% nonsurgical treatment. Volume difference, fracture area and fracture depth predicted surgical outcome (P < .001). In adjusted univariate regression analyses, fractures with moderate and severe displacement of recti muscles were more likely to receive surgical treatment than fractures with mild or no displacement (OR 6.15 and 30.75, respectively, P < .001). Isolated medial wall fractures were significantly less often (OR 0.05, P = .006) and patients with older age (OR 0.97, P = .013) slightly less often treated with surgery. Patients with preoperative symptoms had more often persisting postoperative symptoms than patients without preoperative symptoms. Conclusions: Positions of the recti muscles are an independent radiological factor guiding orbital blowout fracture treatment decision. The bony fracture extent is a combination of volume difference, fracture area and fracture depth which are strongly correlated to each other. A computer-aided method significantly facilitates the systematic evaluation of bone fragments, and the extent of orbital fractures. (C) 2021 The Author. Published by Elsevier Inc. on behalf of The American Association of Oral and Maxillofacial Surgeons.Peer reviewe

Associated Injuries Are Common Among Patients With Bicycle-Related Craniofacial Fractures

Purpose: Ample evidence exists on the relationship between bicycle injuries and craniofacial fractures. However, as the mechanism behind these injuries is often multifactorial, the presence of associated injuries (AIs) in this study population requires further examination. We hypothesized that patients with craniofacial fracture injured in bicycle accidents are at high risk of sustaining severe AIs, especially those of the head and neck region. Patients and Methods: The investigators performed a retrospective study on all patients with bicyclerelated craniofacial fracture admitted to a tertiary trauma centre during 2013 to 2018. The predictor variable was defined as any type of craniofacial fracture. The outcome variable was defined as any kind of AI. Other study variables included demographic and injury-related parameters. Variables were analyzed using bivariate and Firth's logistic regression analyses. Results: A total of 407 patients were included in the analysis. Our results revealed that AIs were present in 150 (36.9%) patients; there were multiple AIs in 47 cases. Traumatic brain injuries followed by upper limb injuries were the most frequent AIs. Severe head and neck injuries were present in 20.1% of all patients with craniofacial fracture. AIs were observed in 57.4% of patients with combined midfacial fractures (P < .001). Helmet use had a protective effect against traumatic brain injuries (P < .001). Conclusions: Our results suggest that AIs are relatively common in this specific patient population. Close co-operation in multidisciplinary trauma centers allowing comprehensive evaluation and treatment can be recommended for patients with bicycle-related craniofacial fracture. (C) 2021 American Association of Oral and Maxillofacial Surgeons.Peer reviewe

Soluble activin type IIB receptor improves fracture healing in a closed tibial fracture mouse model

Fractures still present a significant burden to patients due to pain and periods of unproductivity. Numerous growth factors have been identified to regulate bone remodeling. However, to date, only the bone morphogenetic proteins (BMPs) are used to enhance fracture healing in clinical settings. Activins are pleiotropic growth factors belonging to the TGF-beta superfamily. We and others have recently shown that treatment with recombinant fusion proteins of activin receptors greatly increases bone mass in different animal models by trapping activins and other ligands thus inhibiting their signaling pathways. However, their effects on fracture healing are less known. Twelve-week old male C57Bl mice were subjected to a standardized, closed tibial fracture model. Animals were divided into control and treatment groups and were administered either PBS control or a soluble activin type IIB receptor (ActRIIB-Fc) intraperitoneally once a week for a duration of two or four weeks. There were no significant differences between the groups at two weeks but we observed a significant increase in callus mineralization in ActRIIB-Fc-treated animals by microcomputed tomography imaging at four weeks. Bone volume per tissue volume was 60%, trabecular number 55% and bone mineral density 60% higher in the 4-week calluses of the ActRIIB-Fc-treated mice (p<0.05 in all). Biomechanical strength of 4-week calluses was also significantly improved by ActRIIBFc treatment as stiffness increased by 64% and maximum force by 45% (p<0.05) compared to the PBS-injected controls. These results demonstrate that ActRIIB-Fc treatment significantly improves healing of closed long bone fractures. Our findings support the previous reports of activin receptors increasing bone mass but also demonstrate a novel approach for using ActRIIB-Fc to enhance fracture healing.Peer reviewe