PU.1 controls fibroblast polarization and tissue fibrosis

Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs

Cementless femoral components in bicondylar hybrid knee arthroplasty in patients with rheumatoid arthritis: A 10-year survivorship analysis

Background: Total knee arthroplasty (TKA) has been established as a successful surgical treatment in the late stages of rheumatoid joint destruction. The purpose of this study was to review the clinical outcome and survivorship in rheumatoid arthritis (RA) patients undergoing TKA in hybrid technique with a cementless fixation of the femoral component. Methods: We analysed retrospectively 66 RA patients who underwent 72 TKAs (P.F.C. Sigma®). Mean follow-up time was 124 ± 41 months. To evaluate postoperative clinical outcome, knee injury and osteoarthritis outcome score (KOOS) and Oxford knee score (OKS) were assessed. Kaplan–Meier analysis was used to calculate survivorship. The primary outcome was revision for any reason. Results: Thirty-four patients (36 knees) died and two patients (2 knees) were lost to follow-up. Three patients (four knees) did not agree to participate. Twenty-seven patients (30 knees) were available for assessing clinical scores. The average scores were 85 ± 14 for KOOS and 34 ± 10 for OKS. In three patients (three knees), revision was necessary, including restricted range of motion (n = 1), instability (n = 1), and infection (n = 1). There were no cases of loosening in this cohort study. The survival rates were 100% at 5 years, 97.1% at 10 years (95% CI 89.0–99.2%) and 95.6% at 15 years (95% CI 86.9–98.5%). Conclusions: This study confirms that excellent clinical results and a good 10-year survivorship can be obtained with hybrid fixation technique in TKA in the unique population of RA patients

Trefoil Factor 3 (TFF3) Is Involved in Cell Migration for Skeletal Repair

The aim of the study was to explore the possible role of Trefoil Factor Family peptide 3 (TFF3) for skeletal repair. The expression of TFF3 was analyzed in human joint tissues as well as in a murine bone fracture model. Serum levels of TFF3 following a defined skeletal trauma in humans were determined by ELISA. The mRNA expression of TFF3 was analyzed under normoxia and hypoxia. Expression analysis after stimulation of human mesenchymal progenitor cells (MPCs) with TFF3 was performed by RT2 Profiler PCR Array. The effect of recombinant human (rh)TFF3 on MPCs was analysed by different migration and chemotaxis assays. The effect on cell motility was also visualized by fluorescence staining of F-Actin. TFF3 was absent in human articular cartilage, but strongly expressed in the subchondral bone and periosteum of adult joints. Strong TFF3 immunoreactivity was also detected in murine fracture callus. Serum levels of TFF3 were significantly increased after skeletal trauma in humans. Expression analysis demonstrated that rhTFF3 significantly decreased mRNA of ROCK1. Wound healing assays showed increased cell migration of MPCs by rhTFF3. The F-Actin cytoskeleton was markedly influenced by rhTFF3. Cell proliferation was not increased by rhTFF3. The data demonstrate elevated expression of TFF3 after skeletal trauma. The stimulatory effects on cell motility and migration of MPCs suggest a role of TFF3 in skeletal repair

Three-Dimensional Biomechanical Analysis of Rearfoot and Forefoot Running

Background: In the running community, a forefoot strike (FFS) pattern is increasingly preferred compared with a rearfoot strike (RFS) pattern. However, it has not been fully understood which strike pattern may better reduce adverse joint forces within the different joints of the lower extremity. Purpose: To analyze the 3-dimensional (3D) stress pattern in the ankle, knee, and hip joint in runners with either a FFS or RFS pattern. Study Design: Descriptive laboratory study. Methods: In 22 runners (11 habitual rearfoot strikers, 11 habitual forefoot strikers), RFS and FFS patterns were compared at 3.0 m/s (6.7 mph) on a treadmill with integrated force plates and a 3D motion capture analysis system. This combined analysis allowed characterization of the 3D biomechanical forces differentiated for the ankle, knee, and hip joint. The maximum peak force (MPF) and maximum loading rate (LR) were determined in their 3 ordinal components: vertical, anterior-posterior (AP), and medial-lateral (ML). Results: For both strike patterns, the vertical components of the MPF and LR were significantly greater than their AP or ML components. In the vertical axis, FFS was generally associated with a greater MPF but significantly lower LR in all 3 joints. The AP components of MPF and LR were significantly lower for FFS in the knee joint but significantly greater in the ankle and hip joints. The ML components of MPF and LR tended to be greater for FFS but mostly did not reach a level of significance. Conclusion: FFS and RFS were associated with different 3D stress patterns in the ankle, knee, and hip joint, although there was no global advantage of one strike pattern over the other. The multimodal individual assessment for the different anatomic regions demonstrated that FFS seems favorable for patients with unstable knee joints in the AP axis and RFS may be recommended for runners with unstable ankle joints. Clinical Relevance: Different strike patterns show different 3D stress in joints of the lower extremity. Due to either rehabilitation after injuries or training in running sports, rearfoot or forefoot running should be preferred to prevent further damage or injuries caused by inadequate biomechanical load. Runners with a history of knee joint injuries may benefit from FFS whereas RFS may be favorable for runners with a history of ankle joint injuries

Deletion of the oxygen-dependent degradation domain results in impaired transcriptional activity of hypoxia-inducible factors

Hypoxia-inducible factors (HIF1α/HIF2α) are key transcription factors that promote angiogenesis. The overexpression of degradation-resistant HIF mutants is considered a promising pro-angiogenic therapeutic tool. We compared the transcriptional activity of HIF1α/HIF2α mutants that obtained their resistance to oxygen-dependent degradation either by deletion of their entire oxygen-dependent degradation (ODD) domain or by replacement of prolyl residues that are crucial for oxygen-dependent degradation. Although all HIF mutants translocated into the nucleus, HIF1α and HIF2α mutants inclosing the point mutations were significantly more effective in trans-activating the target gene VEGF and in inducing tube formation of endothelial cells than mutants lacking the complete ODD domain

Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis

STAT3 is a transcription factor that is activated in fibrotic diseases such as systemic sclerosis. Here the authors show that STAT3 is the converging point for multiple pro-fibrotic signalling pathways, and that its genetic ablation or inhibition ameliorate skin fibrosis in mouse models

Production and Secretion of Gelsolin by Both Human Macrophage- and Fibroblast-like Synoviocytes and GSN Modulation in the Synovial Fluid of Patients with Various Forms of Arthritis

Gelsolin (GSN) is an actin-binding protein involved in cell formation, metabolism and wound closure processes. Since this protein is known to play a role in arthritis, here we investigate how the synovial membrane with its specific synoviocytes contributes to the expression of GSN and how the amount of GSN expressed is modulated by different types of arthritis. Synovial membranes from adult healthy subjects and patients with rheumatoid arthritis (RA) and osteoarthritis (OA) are analyzed by immunofluorescence, Western blot and ELISA. Macrophage-like synoviocytes (MLS) and fibroblast-like synoviocytes (FLS) were isolated, cultured and analyzed for their potential to produce and secrete GSN. In addition, the GSN concentrations in the synovial fluid of various forms of arthritis are determined by ELISA. GSN is produced by the healthy and arthritic synovial membranes. Both forms of synoviocytes (MLS and FLS) release GSN. The results show that there is a significant reduction in GSN in the synovial fluid in adult patients with OA. This reduction is also detectable in adult patients with RA but is not as evident. In juvenile arthritis, there is a slight increase in GSN concentration in the synovial fluid. This study shows that primary MLS and FLS express GSN and that these cells, in addition to articular chondrocytes, contribute to GSN levels in synovial fluid. Furthermore, GSN concentrations are modulated in different types of arthritis. Further studies are needed to fully understand how GSN is involved in joint homeostasis