Study Design Retrospective cohort study. Objectives Odontoid fractures are the most common cervical spine fractures in the elderly. The optimal treatment remains controversial. The aim of this... Show moreStudy Design Retrospective cohort study. Objectives Odontoid fractures are the most common cervical spine fractures in the elderly. The optimal treatment remains controversial. The aim of this study was to compare results of a low-threshold-for-surgery strategy (surgery for dislocated fractures in relatively healthy patients) to a primarily-conservative strategy (for all patients). Methods Patient records from 5 medical centers were reviewed for patients who met the selection criteria (e.g. age & GE;55 years, type II/III odontoid fractures). Demographics, fracture types/characteristics, fracture union/stability, clinical outcome and mortality were compared. The influence of age on outcome was studied (& GE;55-80 vs & GE;80 years). Results A total of 173 patients were included: 120 treated with low-threshold-for-surgery (of which 22 primarily operated, and 23 secondarily) vs 53 treated primarily-conservative. No differences in demographics and fracture characteristics between the groups were identified. Fracture union (53% vs 43%) and fracture stability (90% vs 85%) at last follow-up did not differ between groups. The majority of patients (56%) achieved clinical improvement compared to baseline. Analysis of differences in clinical outcome between groups was infeasible due to data limitations. In both strategies, patients & GE;80 years achieved worse union (64% vs 30%), worse stability (97% vs 77%), and - as to be expected - increased mortality <104 weeks (2% vs 22%). Conclusions Union and stability rates did not differ between the treatment strategies. Advanced age (& GE;80 years) negatively influenced both radiological outcome and mortality. No cases of secondary neurological deficits were identified, suggesting that concerns for the consequences of under-treatment may be unjustified. Show less
Given the multi-tissue aspects of osteoarthritis (OA) pathophysiology, translation of OA susceptibility genes towards underlying biological mechanism and eventually drug target discovery requires... Show moreGiven the multi-tissue aspects of osteoarthritis (OA) pathophysiology, translation of OA susceptibility genes towards underlying biological mechanism and eventually drug target discovery requires appropriate human in vitro OA models that incorporate both functional bone and cartilage tissue units. Therefore, a microfluidic chip is developed with an integrated fibrous polycaprolactone matrix in which neo-bone and cartilage are produced, that could serve as a tailored human in vitro disease model of the osteochondral unit of joints. The model enables to evaluate OA-related environmental perturbations to (individual) tissue units by controlling environmental cues, for example by adding biochemical agents. After establishing the co-culture in the system, a layer of cartilaginous matrix is deposited in the chondrogenic compartment, while a bone-like matrix is deposited between the fibers, indicated by both histology and gene expression levels of collagen type 2 and osteopontin, respectively. As proof-of-principle, the bone and cartilaginous tissue are exposed to active thyroid hormone, creating an OA disease model. This results in increased expression levels of hypertrophy markers integrin-binding sialoprotein and alkaline phosphatase in both cartilage and bone, as expected. Altogether, this model could contribute to enhanced translation from OA risk genes towards novel OA therapies. Show less
Context: Follicle-stimulating hormone (FSH) concentrations increase during the perimenopausal transition and remain high after menopause. Loss of bone mineral density (BMD) and gain of bone marrow... Show moreContext: Follicle-stimulating hormone (FSH) concentrations increase during the perimenopausal transition and remain high after menopause. Loss of bone mineral density (BMD) and gain of bone marrow adiposity (BMA) and body fat mass also occur during this time. In mice, blocking the action of FSH increases bone mass and decreases fat mass.Objective: To investigate the associations between endogenous FSH levels and BMD, BMA, and body composition in older adults, independent of estradiol and testosterone levels.Design, Setting, and Participants: Older adults from the AGES-Reykjavik Study, an observational cohort study.Main Outcome Measures: Areal BMD, total body fat, and lean mass were measured with dual-energy x-ray absorptiometry. Lumbar vertebral BMA was measured by H-1-magnetic resonance spectroscopy. Volumetric BMD and visceral and subcutaneous adipose tissue (VAT, SAT) areas were measured with quantitative computed tomography. The least squares means procedure was used to determine sex hormone-adjusted associations between quartiles of serum FSH and BMD, BMA, and body composition.Results: In women (N = 238, mean age 81 years), those in the highest FSH quartile, compared with the lowest quartile, had lower adjusted mean spine integral BMD (-8.6%), lower spine compressive strength index (-34.8%), higher BMA (+8.4%), lower weight (-8.4%), lower VAT (-17.6%), lower lean mass (-6.1%), and lower fat mass (-11.9%) (all P < 0.05). In men, FSH level was not associated with any outcome.Conclusions:Older postmenopausal women with higher FSH levels have higher BMA, but lower BMD and lower fat and lean mass, independent of estradiol and testosterone levels. Longitudinal studies are needed to better understand the underlying mechanisms. Show less
Vinuesa, A.G. de; Sanchez Duffhues, G.; Blaney-Davidson, E.; Caam, A. van; Lodder, K.; Ramos, Y.; ... ; Dijke, P. ten 2021
Chondrocytes in mice developing osteoarthritis (OA) exhibit an aberrant response to the secreted cytokine transforming growth factor (TGF)-beta, consisting in a potentiation of intracellular... Show moreChondrocytes in mice developing osteoarthritis (OA) exhibit an aberrant response to the secreted cytokine transforming growth factor (TGF)-beta, consisting in a potentiation of intracellular signaling downstream of the transmembrane type I receptor kinase activin receptor-like kinase (ALK)1 against canonical TGF-beta receptor ALK5-mediated signaling. Unfortunately, the underlying mechanisms remain elusive. In order to identify novel druggable targets for OA, we aimed to investigate novel molecules regulating the ALK1/ALK5 balance in OA chondrocytes. We performed gene expression analysis of TGF-beta signaling modulators in joints from three different mouse models of OA and found an upregulated expression of the TGF-beta co-receptor Cripto (Tdgf1), which was validated in murine and human cartilage OA samples at the protein level. In vitro and ex vivo, elevated expression of Cripto favors the hypertrophic differentiation of chondrocytes, eventually contributing to tissue calcification. Furthermore, we found that Cripto participates in a TGF-beta-ALK1-Cripto receptor complex in the plasma membrane, thereby inducing catabolic SMAD1/5 signaling in chondrocytes. In conclusion, we demonstrate that Cripto is expressed in OA and plays a functional role promoting chondrocyte hypertrophy, thereby becoming a novel potential therapeutic target in OA, for which there is no efficient cure or validated biomarker. (C) 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. Show less
Lima, M.L.D.; Medeiros, C.A.C.X. de; Guerra, G.C.B.; Santos, R.; Bader, M.; Pirih, F.Q.; ... ; Araujo, A.A. de 2021
Background: The aim of this study was to evaluate the role of AT1 and AT2 receptors in a periodontal inflammation experimental model. Methods: Periodontal inflammation was induced by LPS... Show moreBackground: The aim of this study was to evaluate the role of AT1 and AT2 receptors in a periodontal inflammation experimental model. Methods: Periodontal inflammation was induced by LPS/Porphyromonas gingivalis. Maxillae, femur, and vertebra were scanned using Micro-CT. Maxillae were analyzed histopathologically, immunohistochemically, and by RT-PCR. Results: The vertebra showed decreased BMD in AT1 H compared with WT H (p < 0.05). The femur showed increased Tb.Sp for AT1 H and AT2 H, p < 0.01 and p < 0.05, respectively. The Tb.N was decreased in the vertebra (WT H-AT1 H: p < 0.05; WT H-AT2 H: p < 0.05) and in the femur (WT H-AT1 H: p < 0.01; WT H-AT2 H: p < 0.05). AT1 PD increased linear bone loss (p < 0.05) and decreased osteoblast cells (p < 0.05). RANKL immunostaining was intense for AT1 PD and WT PD (p < 0.001). OPG was intense in the WT H, WT PD, and AT2 PD when compared to AT1 PD (p < 0.001). AT1 PD showed weak immunostaining for osteocalcin compared with WT H, WT PD, and AT2 PD (p < 0.001). AT1 H showed significantly stronger immunostaining for osteonectin in fibroblasts compared to AT2 H (p < 0.01). Conclusion: AT1 receptor knockout changed bone density, the quality and number of bone trabeculae, decreased the number of osteoblast cells, and increased osteonectin in fibroblasts. Show less
Ventura, F.; Williams, E.; Ikeya, M.; Bullock, A.N.; Dijke, P. ten; Goumans, M.J.; Sanchez Duffhues, G. 2021
Fibrodysplasia ossificans progressiva (FOP) is an ultrarare congenital disease that progresses through intermittent episodes of bone formation at ectopic sites. FOP patients carry heterozygous gene... Show moreFibrodysplasia ossificans progressiva (FOP) is an ultrarare congenital disease that progresses through intermittent episodes of bone formation at ectopic sites. FOP patients carry heterozygous gene point mutations in activin A receptor type I ACVR1, encoding the bone morphogenetic protein (BMP) type I serine/threonine kinase receptor ALK2, termed activin receptor-like kinase (ALK)2. The mutant ALK2 displays neofunctional responses to activin, a closely related BMP cytokine that normally inhibits regular bone formation. Moreover, the mutant ALK2 becomes hypersensitive to BMPs. Both these activities contribute to enhanced ALK2 signalling and endochondral bone formation in connective tissue. Being a receptor with an extracellular ligand-binding domain and intrinsic intracellular kinase activity, the mutant ALK2 is a druggable target. Although there is no approved cure for FOP yet, a number of clinical trials have been recently initiated, aiming to identify a safe and effective treatment for FOP. Among other targeted approaches, several repurposed drugs have shown promising results. In this review, we describe the molecular mechanisms underlying ALK2 mutation-induced aberrant signalling and ectopic bone formation. In addition, we recapitulate existing in vitro models to screen for novel compounds with a potential application in FOP. We summarize existing therapeutic alternatives and focus on repositioned drugs in FOP, at preclinical and clinical stages. Show less
Davies, M.; Lalam, R.; Woertler, K.; Bloem, J.L.; Astrom, G. 2020
The diagnosis of tumors and tumorlike lesions of bone is a routine part of both general and specialist radiologic practices. The spectrum of disorders ranges from the small incidental lesion to the... Show moreThe diagnosis of tumors and tumorlike lesions of bone is a routine part of both general and specialist radiologic practices. The spectrum of disorders ranges from the small incidental lesion to the potentially life-limiting malignancies whether primary or secondary. In this review, authored by experts from several European orthopaedic oncology centers, we present a collection of pieces of advice in the form of 10 commandments. Adherence in daily practice to this guidance should help minimize adverse patient experiences and outcomes. Show less
Gomez-Puerto, M.C.; Iyengar, P.V.; Vinuesa, A.G. de; Dijke, P. ten; Sanchez-Duffhues, G. 2019
