ObjectivesIn addition to bone fragility, patients with osteogenesis imperfecta (OI) type III have typical craniofacial abnormalities, such as a triangular face and maxillary micrognathism. However, in the osteogenesis imperfecta mouse (oim), a validated model of OI type III, few descriptions exist of craniofacial phenotype. Treatment of OI mostly consists of bisphosphonate administration. Cathepsin K inhibition has been tested as a promising therapeutic approach for osteoporosis and positive results were observed in long bones of cathepsin K knocked out oim (oim/CatK–/–). This craniometry study aimed to highlight the craniofacial characteristics of oim and Cathepsin K KO mouse.Materials and methodsWe analyzed the craniofacial skeleton of 51 mice distributed in 4 genotype groups: Wt (control), oim, CatK–/–, oim/CatK–/–. The mice were euthanized at 13 weeks and their heads were analyzed using densitometric (pQCT), X-ray cephalometric, and histomorphometric methods.ResultsThe craniofacial skeleton of the oim mouse is frailer than the Wt one, with a reduced thickness and mineral density of the cranial vault and mandibular ramus. Different cephalometric data attest a dysmorphism similar to the one observed in humans with OI type III. Those abnormalities were not improved in the oim/CatK–/– group.ConclusionThese results suggest that oim mouse could serve as a complete model of the human OI type III, including the craniofacial skeleton. They also suggest that invalidation of cathepsin K has no impact on the craniofacial abnormalities of the oim model.

Background: Hypermobile Ehlers-Danlos Syndrome (hEDS) is the most common type of EDS. Apart from joint symptoms, people with hEDS have systemic manifestations as a chronic modification of the breathing pattern (functional respiratory complaints (FRCs)) and mental disorders. However, the prevalence of FRCs, and its relationship with mental disorders, have not yet been estimated for this population. Objectives: To assess the FRCs, central sensitization, disease perception, depression, and anxiety in people with hEDS from Belgium; and to identify the clustering of FRCs and determine any association with the characteristics assessed for this sample. Methods: This cross-sectional study assessed socio-demographic characteristics, Nijmegen questionnaire (NQ), Central Sensitization Inventory (CSI), Brief Illness Perception Questionnaire, and the Hospital Anxiety and Depres-sion Scale (HADS) in people with hEDS from Belgium. A two-step cluster analysis was performed to identify clusters according to NQ, and to understand how the other questionnaires are grouped among these clusters.Results: The Spearman correlation coefficients showed that all the outcomes were significantly and positively correlated with each other (p<0.05). Furthermore, 84.9% of the sample had symptoms suggestive of FRCs, and 54.3% had probable anxiety. Three clusters were grouped (no FRCs, mild FRCs, and severe FRCs), with NQ, HADS-D and CSI-part A being the variables that contributed the most. People from cluster of severe FRCs got the worst scores for all the questionnaires. Conclusion: FRCs, central sensitization, depression, and anxiety are prevalent comorbidities in people with hEDS. Moreover, those people with FRCs had worse results in the investigated parameters, with depression being the variable that contributed the most to the clusters of FRCs. Consequently, investigating mechanisms for these co-occurring symptom profiles may improve our understanding of pathogenesis and indicate new management strategies to alleviate these symptoms and lead to the development of more effective care for persons with hEDS.& COPY; 2023 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Osteogenesis imperfecta (OI), which is most often due to a collagen type 1 gene mutation, is characterized by low bone density and bone fragility. In OI patients, gender-related differences were reported, but data in the literature are not convergent. We previously observed that sclerostin antibody (Scl-Ab), which stimulates osteoblast Wnt pathway via sclerostin inactivation, improved spine and long-bone parameters and biomechanical strength in female oim/oim mice, a validated model of human type 3 OI. Here, we wanted to highlight the effect of Scl-Ab on male oim/oim bones in order to identify a possible distinct therapeutic effect from that observed in females. According to the same protocol as our previous study with female mice, male wild-type (Wt) and oim/oim mice received vehicle or Scl-Ab from 5 to 14 weeks of age. Clinimetric and quantitative bone parameters were studied using X-rays, peripheral quantitative computed tomography, microradiography, and dynamic histomorphometry and compared to those of females. Contrary to Wt mice, male oim/oim had significantly lower weight, snout–sacrum length, and bone mineral content than females at 5 weeks. No significant difference in these clinimetric parameters was observed at 14 weeks, whereas male oim showed significantly more long-bone fractures than females. Scl-Ab improved bone mineral density and bone volume/total volume ratio (BV/TV) of vertebral body in Wt and oim/oim, without significant difference between male and female at 14 weeks. Male vehicle oim/oim had a significantly lower cortical thickness (Ct.Th) and BV/TV of tibial diaphysis than female and showed a higher number of fractures at 14 weeks. Scl-Ab increased midshaft periosteal apposition rate in such a way that tibial Ct.Th of male oim/oim was not significantly different from the female one at 14 weeks. The number of fractures was lower in male than female oim/oim after 14 weeks of Scl-Ab treatment, but this difference was not significant. Nevertheless, Scl-Ab–treated oim/oim male and female mice remained smaller than the Wt ones. In conclusion, our results highlighted differences between male and female oim/oim at 4 and 14 weeks of age, as well as some male-specific response of cortical bone to Scl-Ab. These gender-related particularities of oim/oim should be considered when testing experimental treatments.

Outre une grande fragilité osseuse, les patients atteints de la forme sévère (type III) d'ostéogenèse imparfaite présentent un facies triangulaire, une protubérance fronto-pariétale, un prognathisme relatif et de fréquents os wormiens [1]. La souris oim est un modèle validé des manifestations squelettiques de la maladie humaine, mais peu de données existent à propos des anomalies craniofaciales. Nous rapportons ici des observations densitométriques et céphalométriques chez la souris oim. Après euthanasie à 13 semaines, les têtes de souris oim (n = 13) et Wild type (n = 12) ont subi des analyses densitométrique (pQCT), céphalométrique et histomorphométrique. Chez les souris oim, la densité minérale osseuse et la surface totale de l'os pariétal et du ramus mandibulaire sont significativement inférieures à celles des souris Wild type. À l'analyse histomorphométrique, l'épaisseur de l'os pariétal des souris oim est significativement inférieure à celle des Wild type. Ces résultats attestent la fragilité de ces os et corroborent des observations de fractures du crâne chez des patients atteints de l'ostéogenèse imparfaite de type III. Sur les coupes frontales utilisées pour la densitométrie, la hauteur frontale supérieure, correspondant à la hauteur de la partie antérieure de la cavité crânienne, et la largeur interpariétale sont supérieures chez les souris oim par comparaison avec les Wild type, tandis que la largeur inter-temporale n'est pas modifiée. Ces données céphalométriques reflètent celles rapportées à propos du phénotype craniofacial de patient souffrant de l'ostéogenèse imparfaite de type III. Ces résultats permettent d'envisager la souris oim comme un modèle complet de l'ostéogenèse imparfaite humaine de type III, incluant le squelette craniofacial. Des analyses complémentaires, notamment par microCTscan et reconstruction tridimensionnelle, permettront d'obtenir des données supplémentaires à propos de la base du crâne et de la présence d'os wormiens.

•Spam1-/- mice express a tibial subchondral bone mineral density significantly lower compared to WT mice. The WT mice BMD was from 980 to 1010 mg HAP/cm3 from 10 to 52 weeks of age compared to Spam1-/- mice BMD that was from 940 to 880 mg HAP/cm3 from 10 to 52 weeks of age. These differences became significant from 14 weeks of age.•At 52 weeks of age, the modified Mankin score was significantly lower in Spam1-/- than WT mice. Only in WT mice, the medial subchondral bone appeared somewhat more abundant at 52 weeks. No ectopic calcification or osteophyte formation was visible in the frontal sections of both groups.•As highlighted by qPCR, the chondrocytes of Spam1-/- mice expressed significantly less Hyal2 than WT chondrocytes at 10, 30 and 52 weeks of age. Through all the experiment, the Hyal1 expression of Spam1-/- chondrocytes remained approximatively the same compared to WT mice that express significantly more Hyal1 at 52 weeks than 10 weeks of age. At 52 weeks, WT chondrocytes expressed significantly more Mmp-13 than Spam1-/- chondrocytes and WT chondrocytes at 10 weeks of age. The expression of Adamts-5, type 2 collagen and has2 did not appear different between both groups and did not change from 10 to 52 weeks.

In osteogenesis imperfecta (OI), vertebrae brittleness causes thorax deformations and leads to cardiopulmonary failure. As sclerostin-neutralizing antibodies increase bone mass and strength in animal models of osteoporosis, their administration in two murine models of severe OI enhanced the strength of vertebrae in growing female Crtap−/− mice but not in growing male Col1a1Jrt/+ mice. However, these two studies ignored the impact of antibodies on spine growth, fracture rates, and compressive mechanical properties. Here, we conducted a randomized controlled trial in oim/oim mice, an established model of human severe OI type III due to a mutation in Col1a2. Five-week-old female WT and oim/oim mice received either PBS or sclerostin antibody (Scl-Ab) for 9 weeks. Analyses included radiography, histomorphometry, pQCT, microcomputed tomography, and biomechanical testing. Though it did not modify vertebral axial growth, Scl-Ab treatment markedly reduced the fracture prevalence in the pelvis and caudal vertebrae, enhanced osteoblast activity (L4), increased cervico-sacral spine BMD, and improved the lumbosacral spine bone cross-sectional area. Scl-Ab did not impact vertebral height and body size but enhanced the cortical thickness and trabecular bone volume significantly in the two Scl-Ab groups. At lumbar vertebrae and tibial metaphysis, the absolute increase in cortical and trabecular bone mass was higher in Scl-Ab WT than in Scl-Ab oim/oim. The effects on trabecular bone mass were mainly due to changes in trabecular number at vertebrae and in trabecular thickness at metaphyses. Additionally, Scl-Ab did not restore a standard trabecular network, but improved bone compressive ultimate load with more robust effects at vertebrae than at metaphysis. Overall, Scl-Ab treatment may be beneficial for reducing vertebral fractures and spine deformities in patients with severe OI.

Osteogenesis imperfecta type III (OI) is a serious genetic condition with poor bone quality and a high fracture rate in children. In a previous study, it was shown that a monoclonal antibody neutralizing sclerostin (Scl-Ab) increases strength and vertebral bone mass while reducing the number of axial fractures in oim/oim, a mouse model of OI type III. Here, we analyze the impact of Scl-Ab on long bones in OI mice. After 9 weeks of treatment, Scl-Ab significantly reduced long bone fractures (3.6 ± 0.3 versus 2.1 ± 0.8 per mouse, p < 0.001). In addition, the cortical thickness of the tibial midshaft was increased (+42%, p < 0.001), as well as BMD (+28%, p < 0.001), ultimate load (+86%, p < 0.05), plastic energy (+184%; p < 0.05) and stiffness (+172%; p < 0.01) in OI Scl-Ab mice compared to OI vehicle controls. Similar effects of Scl-Ab were observed in Wild type (Wt) mice. The plastic energy, which reflects the fragility of the tissue, was lower in the OI than in the Wt and significantly improved with the Scl-Ab treatment. At the tissue level by nanoindentation, Scl-Ab slightly increased the elastic modulus in bones of both OI and Wt, while moderately increasing tissue hardness (+13% compared to the vehicle; p < 0.05) in Wt bones, but not in OI bones. Although it did not change the properties of the OI bone matrix material, Scl-Ab reduced the fracture rate of the long bones by improving its bone mass, density, geometry, and biomechanical strength. These results suggest that Scl-Ab can reduce long-bone fractures in patients with OI.

Renal infarction is a relatively infrequent condition, most commonly occurring in the presence of predisposing factors, including atherosclerosis, valvular or ischemic heart disease, atrial fibrillation, endocarditis, hypercoagulability, malignancy, vasculitis, and kidney trauma.1,2 About 30% of renal infarctions, however, occur in the absence of these classic risk factors and are usually called "idiopathic."1 In this noncategorized group, an emerging diagnosis is spontaneous renal artery dissection (SRAD), which may account for several, if not the majority of cases.

As exertional inspiratory dyspnea is a common disabling complaint in hypermobile Ehlers–Danlos syndrome (hEDS) often also known as joint hypermobility syndrome (JHS), we investigated inspiratory muscle (IM) strength in patients with hEDS, and we assessed the effects of IM training (IMT) on IM strength, lung function, and exercise capacity. A prospective evaluation of IM strength followed by a randomized controlled trial of IMT was performed in women with hEDS. Sniff nasal inspiratory pressure (SNIP) was used to routinely measure IM strength and IMT was carried out using a pressure threshold device. IM strength (main outcome), cardiopulmonary function, exercise capacity, and emotional distress of both the treated and control groups were evaluated at the start and at the end of the 6‐week training period. IM strength was reduced (<80% of predicted) in 77% of patients (80/104). Lung function was normal, although 24% of patients had a higher forced expiratory vital capacity (FVC) than normal and 12% of patients had a higher total lung capacity (TLC) than normal. Both the IMT and control groups (n = 20) had similar baseline characteristics. Significant changes were noted only in the IMT group after IMT. At the end of the program, IMT improved SNIP (20%) (before: 41 ± 17 cm H2O [28, 53] vs. after: 49 ± 18 cm H2O [34;65]), six‐minute walking distance (6MWD) (60 m) (455 ± 107 m [379,532] vs. 515 ± 127 m [408, 621]), and forced expiratory volume in one second (FEV1) (285 mL) (94 ± 14% pred [84,104] vs. 103 ± 11% pred [94, 112]). IM strength is significantly reduced in patients with hEDS. IMT improved IM strength, lung function, and exercise capacity. Our findings suggest that IMT should be added to usual care.

We report the history of a 15-year old patient with a hypermobile Ehlers-Danlos syndrome (hEDS) (his mother, his two brothers and his sister have the same phenotype as him). He suffers mainly from a severe mast cell activation syndrome (MCAS) with an overreaction of the skin to any kind of contact (water of the shower, clothes, bed sheets) but he has also fatigue, headaches, and rash. This impressive rash is exacerbated after the shower and he has the urge to rest («shower's sign»). We describe the MCAS and its easy, fast and very effective medication management, without any significant side effects as well as its frequent association with the hEDS. We finally introduce the original term of «MASED» to this MCAS, associated, linked or entangled to hEDS.

OBJECTIVE:To determine if diagnostic signs of adhesive capsulitis (AC) of the shoulder at Magnetic Resonance Imaging (MRI) and arthrography (MRA) are applicable to CT arthrography (CTA). METHODS:22 shoulder CTAs with AC were retrospectively reviewed for features described in MR literature. The control group was composed of 83 shoulder CTA divided into four subgroups 1) normal (N = 20), 2) omarthrosis (N = 19), 3) labral injury (N = 23), and 4) rotator cuff tear (N = 21). Two musculoskeletal radiologists assessed the rotator interval (RI) for obliteration, increased width and thickening of coracohumeral ligament (CHL). The width and capsule thickness of the axillary recess were measured. RESULTS:The width of the axillary recess was significantly decreased in the AC group (4.6 ± 2.6 mm versus 9.9 ± 4.6 mm, p ≤ 0.0001; sensitivity and specificity of 84% and 80%). Thickness of the medial and lateral walls of the axillary capsule was significantly increased in the AC group (5.9 ± 1.3 mm versus 3.7 ± 1.1 mm, p ≤ 0.0001 and 5.7 ± 1 mm versus 3.5 ± 1.3 mm, p ≤ 0.0001, respectively). CHL thickness was significantly increased in the AC group (4.1 ± 1 mm (p ≤ 0.001)) in comparison to others groups. Obliteration of the RI was statistically significantly more frequent in patients with AC (72.7% (16/22) vs. 12% (10/83), p < 0.0001). Width of the RI did not differ significantly between patients and controls (p ≥ 0.428). CONCLUSION:Decreased axillary width, and thickened axillary capsule are MR signs of AC applicable to CTA. Evaluation of rotator interval seems useful and reproducible only for obliteration.

Ehlers-Danlos Syndrome (EDS) represents a cluster of specific genetic connective tissue disorders.It is clinically evoked when skin appears velvety and hyperextensible, in combination with joint laxity and connective tissue fragility.The hypermobile variant (EDSH) is among the most common presentations.It presents as an autosomal dominant pathology.The genetic mutation presently remains undisclosed in most cases.However, ultrastructural alterations are often distinguishable.Ehlers-Danlos Syndrome Hypermobile (EDSH) is mostly observed in women in whom additional signs to joint laxity are present.Hyperextensibility and/or velvety presentation of skin is one of the two major diagnostic signs in EDSH.Atrophic scars and delayed wound healing are commonly present.These features have to be considered in particular by plastic surgeons.The ultrastructural skin changes show various numbers of flower-like collagen fibres as well as other abnormalities in the connective tissue components.

Glucocorticoids (GCs) remain as the cornerstone of therapy in most inflammatory diseases, even if newly developed biological molecules became available. GCs are potent, possess a fast action, and are cheap and relatively easy to prescribe. However, their beneficial therapeutic activity has a nasty counterpart: quite a lot of complications, notably secondary osteoporosis, aseptic bone osteonecrosis, and fractures. The skeleton is continuously remodeling, old bone being resorbed and replaced by new young bone. GCs interfere with the bone turnover and provoke a disequilibrium in favor of bone loss and fragility. The mechanisms of bone fragility consist of a decreased activity and in apoptosis of osteoblasts, as well as an increase in bone resorption. These changes have already been observed histomorphometrically a long time ago in transiliac bone biopsies. Biological parameters of bone turnover, chiefly degradation products of type I collagen, can help to assess atraumatically the bone metabolism. If, in idiopathic osteoporosis, they can have a predictive value of bone loss, they cannot be considered as surrogates for bone mineral density measurements. In GC-OP, the concentrations of the bone turnover markers (BTMs) of bone formation dramatically and rapidly decrease, whereas the BTMs of bone resorption slightly increase. During GC therapy, they cannot be used as predictive tools of bone fragility on an individual basis. Other markers such as RANKL/RANK/osteoprotegerin seem to be promising in this aim, but this still awaits confirmation.