Jacinto Monteiro

Upregulation of Inflammatory Genes and Downregulation of Sclerostin Gene Expression Are Key Elements in the Early Phase of Fragility Fracture Healing

Background Fracture healing is orchestrated by a specific set of events that culminates in the repair of bone and reachievement of its biomechanical properties. The aim of our work was to study the sequence of gene expression events involved in inflammation and bone remodeling occurring in the early phases of callus formation in osteoporotic patients. Methodology/Principal Findings Fifty-six patients submitted to hip replacement surgery after a low-energy hip fracture were enrolled in this study. The patients were grouped according to the time interval between fracture and surgery: bone collected within 3 days after fracture (n = 13); between the 4th and 7th day (n = 33); and after one week from the fracture (n = 10). Inflammation- and bone metabolism-related genes were assessed at the fracture site. The expression of pro-inflammatory cytokines was increased in the first days after fracture. The genes responsible for bone formation and resorption were upregulated one week after fracture. The increase in RANKL expression occurred just before that, between the 4th–7th days after fracture. Sclerostin expression diminished during the first days after fracture. Conclusions The expression of inflammation-related genes, especially IL-6, is highest at the very first days after fracture but from day 4 onwards there is a shift towards bone remodeling genes, suggesting that the inflammatory phase triggers bone healing. We propose that an initial inflammatory stimulus and a decrease in sclerostin-related effects are the key components in fracture healing. In osteoporotic patients, cellular machinery seems to adequately react to the inflammatory stimulus, therefore local promotion of these events might constitute a promising medical intervention to accelerate fracture healing.

Rheumatoid Arthritis Bone Fragility Is Associated With Upregulation of IL17 and DKK1 Gene Expression

Our aim was to compare bone gene expression in rheumatoid arthritis (RA) and primary osteoporosis (OP) patients. Secondary aims were to determine the association of gene expression of the Wnt/β-catenin signaling pathway with inflammatory cytokines in the bone microenvironment and to assess the serum levels of Wnt/β-catenin proteins in both groups. RA patients referred for hip replacement surgery were recruited. Primary OP patients were used as controls. Gene expression of Wnt pathway mediators, matrix proteins, and pro-inflammatory cytokines were analyzed in bone samples. Bone turnover markers, inflammatory cytokines, and Wnt mediators were measured in serum. Twenty-two patients were included: 10 with RA and 12 with primary OP. The expressions of Wnt10b (p = 0.034), its co-receptor LRP6 (p = 0.041), and its negative regulator DKK1 (p = 0.008) were upregulated in RA bone. IL17 gene expression in bone was upregulated in RA patients (p = 0.031) and correlated positively with Wnt10b (r = 0.810, p = 0.015), DKK2 (r = 0.800, p = 0.010), and RANKL/OPG ratio (r = 0.762, p = 0.028). DKK2 (p = 0.04) was significantly decreased in RA serum compared with primary OP. In conclusion, bone fragility in RA patients is induced by an unbalanced bone microenvironment and is associated with a specific gene expression pattern, namely, the upregulation of IL17 and DKK1, suggesting that the modulation of these two pathways might prevent RA systemic bone loss.

The Influence of the Pelvic Bone on the Computational Results of the Acetabular Component of a Total Hip Prosthesis

The computational models developed to evaluate the hip joint performance usually neglect the presence of the pelvic bone. However, deformation depends on the stiffness of the underlying bone, and thus, the inclusion of the pelvic bone in the model influences the computed contact pressure and wear. This work discusses the influence of the pelvic bone, and how it depends on the acetabular component stiffness. It was modeled as two different polyethylene acetabular cups, considering or not a metal-backing for both 28 mm and 32 mm diametric cups. Two finite element models are developed, considering either the acetabular component rigidly fixed or attached to the deformable bone. Results present 28% and 42% difference on the contact pressure for a polyethylene cup without metal-backing when the support conditions are changed, for the 28 mm and 32 mm cups, respectively. Linear wear results present 21% and 31% difference for the same type of cups of 28 mm and 32 mm, correspondingly. The numerical results obtained in the present work show that to model the pelvic bone of the patient with a metal-backed cup did not greatly affect contact pressures and linear wear. However, when a total hip replacement is performed with an all-polyethylene acetabular cup, the presence of the pelvic bone in the model has a major influence.

Critical analysis of musculoskeletal modelling complexity in multibody biomechanical models of the upper limb

The inverse dynamics technique applied to musculoskeletal models, and supported by optimisation techniques, is used extensively to estimate muscle and joint reaction forces. However, the solutions of the redundant muscle force sharing problem are sensitive to the detail and modelling assumptions of the models used. This study presents four alternative biomechanical models of the upper limb with different levels of discretisation of muscles by bundles and muscle paths, and their consequences on the estimation of the muscle and joint reaction forces. The muscle force sharing problem is solved for the motions of abduction and anterior flexion, acquired using video imaging, through the minimisation of an objective function describing muscle metabolic energy consumption. While looking for the optimal solution, not only the equations of motion are satisfied but also the stability of the glenohumeral and scapulothoracic joints is preserved. The results show that a lower level of muscle discretisation provides worse estimations regarding the muscle forces. Moreover, the poor discretisation of muscles relevant to the joint in analysis limits the applicability of the biomechanical model. In this study, the biomechanical model of the upper limb describing the infraspinatus by a single bundle could not solve the complete motion of anterior flexion. Despite the small differences in the magnitude of the forces predicted by the biomechanical models with more complex muscular systems, in general, there are no significant variations in the muscular activity of equivalent muscles.

Bone remodelling analysis of the humerus after a shoulder arthroplasty

The shoulder arthroplasty has become an efficient treatment for some pathologies. However there are complications that can compromise its success. Among them, the stress shielding effect on the humerus has been reported as a possible cause of failure. The objective of this work was to investigate the bone remodelling in the humerus after a shoulder arthroplasty. For this purpose, computational models were developed to analyse the stress shielding contribution to the humeral component failure of shoulder arthroplasties, with a cemented and an uncemented prosthesis. A computational remodelling model was used to characterize the bone apparent density at each site of the humerus. The density distribution was obtained by the solution of a problem that takes into account both structural stiffness and the metabolic cost of bone maintenance. Bone was subjected to 6 load cases that include the glenohumeral reaction force and the action of 10 muscles. In the implanted models, different interface conditions were tested for the bone-implant and the cement-implant interfaces. Moreover, a pathological case defined by a poorer quality of bone was considered. In the healthy situation, the models that better model in vivo conditions showed no significant changes in bone mass. However, the results for the pathological case showed some bone resorption which supports the importance given to the quality of bone in the success of the joint replacement. Bearing in mind the conditions addressed, the results lead to conclude that the stress shielding is not a key factor for the humeral component failure of shoulder arthroplasties in a healthy situation though several issues, including muscle function and bone quality, may heighten its effect.

Low osteocalcin/collagen type I bone gene expression ratio is associated with hip fragility fractures

INTRODUCTION Osteocalcin (OC) is the most abundant non-collagenous bone protein and is determinant for bone mineralization. We aimed to compare OC bone expression and serum factors related to its carboxylation in hip fragility fracture and osteoarthritis patients. We also aimed to identify which of these factors were associated with worse mechanical behavior and with the hip fracture event. METHODS In this case-control study, fragility fracture patients submitted to hip replacement surgery were evaluated and compared to a group of osteoarthritis patients submitted to the same procedure. Fasting blood samples were collected to assess apolipoproteinE (apoE) levels, total OC and undercarboxylated osteocalcin (ucOC), vitamin K, LDL cholesterol, triglycerides and bone turnover markers. The frequency of the apoε4 isoform was determined. Femoral epiphyses were collected and trabecular bone cylinders drilled in order to perform compression mechanical tests. Gene expression of bone matrix components was assessed by quantitative RT-PCR analysis. RESULTS 64 patients, 25 submitted to hip replacement surgery due to fragility fracture and 39 due to osteoarthritis, were evaluated. Bone OC/collagen expression (OC/COL1A1) ratio was significantly lower in hip fracture compared to osteoarthritis patients (p<0.017) adjusted for age, gender and body mass index. Moreover, OC/COL1A1 expression ratio was associated with the hip fracture event (OR ~0; p=0.003) independently of the group assigned, or the clinical characteristics. Apoε4 isoform was more frequent in the hip fracture group (p=0.029). ucOC levels were higher in the fracture group although not significantly (p=0.058). No differences were found regarding total OC (p=0.602), apoE (p=0.467) and Vitamin K (p=0.371). In hip fracture patients, multivariate analysis, adjusted for clinical characteristics, serum factors related to OC metabolism and gene expression of bone matrix proteins showed that low OC/COL1A1 expression ratio was significantly associated with worse trabecular strength (β=0.607; p=0.013) and stiffness (β=0.693; p=0.003). No association was found between ucOC and bone mechanics. Moreover, in osteoarthritis patients, the multivariate analysis revealed that serum total OC was negatively associated with strength (β=-0.411; p=0.030) and stiffness (β=-0.487; p=0.009). CONCLUSION We demonstrated that low bone OC/COL1A1 expression ratio was an independent predictor of worse trabecular mechanical behavior and of the hip fracture event. These findings suggest that in hip fracture patients the imbalance of bone OC/COL1A1 expression ratio reflects disturbances in osteoblast activity leading to bone fragility.

Multibody System of the Upper Limb Including a Reverse Shoulder Prosthesis

The reverse shoulder replacement, recommended for the treatment of several shoulder pathologies such as cuff tear arthropathy and fractures in elderly people, changes the biomechanics of the shoulder when compared to the normal anatomy. Although several musculoskeletal models of the upper limb have been presented to study the shoulder joint, only a few of them focus on the biomechanics of the reverse shoulder. This work presents a biomechanical model of the upper limb, including a reverse shoulder prosthesis, to evaluate the impact of the variation of the joint geometry and position on the biomechanical function of the shoulder. The biomechanical model of the reverse shoulder is based on a musculoskeletal model of the upper limb, which is modified to account for the properties of the DELTA® reverse prosthesis. Considering two biomechanical models, which simulate the anatomical and reverse shoulder joints, the changes in muscle lengths, muscle moment arms, and muscle and joint reaction forces are evaluated. The muscle force sharing problem is solved for motions of unloaded abduction in the coronal plane and unloaded anterior flexion in the sagittal plane, acquired using video-imaging, through the minimization of an objective function related to muscle metabolic energy consumption. After the replacement of the shoulder joint, significant changes in the length of the pectoralis major, latissimus dorsi, deltoid, teres major, teres minor, coracobrachialis, and biceps brachii muscles are observed for a reference position considered for the upper limb. The shortening of the teres major and teres minor is the most critical since they become unable to produce active force in this position. Substantial changes of muscle moment arms are also observed, which are consistent with the literature. As expected, there is a significant increase of the deltoid moment arms and more fibers are able to elevate the arm. The solutions to the muscle force sharing problem support the biomechanical advantages attributed to the reverse shoulder design and show an increase in activity from the deltoid, teres minor, and coracobrachialis muscles. The glenohumeral joint reaction forces estimated for the reverse shoulder are up to 15% lower than those in the normal shoulder anatomy. The data presented here complements previous publications, which, all together, allow researchers to build a biomechanical model of the upper limb including a reverse shoulder prosthesis.

Bone remodelling of the scapula after a total shoulder arthroplasty.

According to Wolff’s law, the changes in stress after a prosthesis implantation may modify the shape and internal structure of bone, thus compromising the long-term prosthesis fixation and, consequently, be a significant factor for glenoid loosening. The aim of the present study is to evaluate the changes in the bone adaptation process of the scapula after an anatomical and reverse total shoulder arthroplasty. Five finite element models of the implanted scapula are developed considering the implantation of three anatomical, cemented, all-polyethylene components; an anatomical, cementless, metal-backed component; and a reverse, all-metal component. The methodology followed to simulate the bone adaptation of the scapula was previously validated for the intact model, prior to the prosthesis implantation. Additionally, the influence of the bone quality on the adaptation process is also investigated by considering an osteoporotic condition. The results show that the stress shielding phenomenon is more concerning in cementless, metal-based components than in cemented, all-polyethylene components, regardless of the bone quality. Consequently, as far as the bone adaptation process of the bone is concerned, cemented, all-polyethylene components are better suited for the treatment of the shoulder joint.

Wear analysis in anatomical and reversed shoulder prostheses

This paper describes the development of a computational model to calculate wear rates in total shoulder prostheses, for a 5–150 degrees arm abduction. Anatomical keeled and pegged prosthesis as well as reversed prosthesis were the studied implants. The bone models were built based on computed tomography (CT) images and using a computer aided design-based modelling pipeline. The finite element method was used to solve the contact problem between the surface of the polyethylene (PE) components and the corresponding articular component. The aim of this work was to determine linear and volumetric PE wear, for several radial mismatches, in conditions of pathological (rheumatoid arthritis) and non-pathological bone. Results showed that contact pressures and linear wear developed in anatomical prosthesis were higher than those visualised in reversed prosthesis. However, anatomical prosthesis exhibited a better volumetric wear performance. Moreover, our findings indicated higher values of volumetric wear in higher congruent models and on pathological bone conditions.

A new shoulder model with a biologically inspired glenohumeral joint.

Kinematically unconstrained biomechanical models of the glenohumeral (GH) joint are needed to study the GH joint function, especially the mechanisms of joint stability. The purpose of this study is to develop a large-scale multibody model of the upper limb that simulates the 6 degrees of freedom (DOF) of the GH joint and to propose a novel inverse dynamics procedure that allows the evaluation of not only the muscle and joint reaction forces of the upper limb but also the GH joint translations. The biomechanical model developed is composed of 7 rigid bodies, constrained by 6 anatomical joints, and acted upon by 21 muscles. The GH joint is described as a spherical joint with clearance. Assuming that the GH joint translates according to the muscle load distribution, the redundant muscle load sharing problem is formulated considering as design variables the 3 translational coordinates associated with the GH joint translations, the joint reaction forces associated with the remaining kinematic constraints, and the muscle activations. For the abduction motion in the frontal plane analysed, the muscle and joint reaction forces estimated by the new biomechanical model proposed are similar to those estimated by a model in which the GH joint is modeled as an ideal spherical joint. Even though this result supports the assumption of an ideal GH joint to study the muscle load sharing problem, only a 6 DOF model of the GH joint, as the one proposed here, provides information regarding the joint translations. In this study, the biomechanical model developed predicts an initial upward and posterior migration of the humeral head, followed by an inferior and anterior movement, which is in good agreement with the literature.