Sex Differences in Pain Sensitivity in a Dutch Cohort: Cross-Sectional and Web-Based Multidimensional Study.

Background: Sex is an important factor influencing the development and treatment of chronic pain, but the extent of its influence is still unclear. Other demographic factors as well as nonpharmacological interventions might influence pain sensitivity differently in men and women.

Objective: In this study, we aimed to investigate the influence of sex and other demographic, lifestyle, behavioral, clinical, and environmental factors on pain sensitivity in the Dutch population.

Sclerostin antibody enhances implant osseointegration in bone with Col1a1 mutation.

We evaluated the potential of sclerostin antibody (SclAb) therapy to enhance osseointegration of dental and orthopaedic implants in a mouse model (Brtl/+) mimicking moderate to severe Osteogenesis Imperfecta (OI). To address the challenges in achieving stable implant integration in compromised bone conditions, our aim was to determine the effectiveness of sclerostin antibody (SclAb) at improving bone-to-implant contact and implant fixation strength. Utilizing a combination of micro-computed tomography, mechanical push-in testing, immunohistochemistry, and Western blot analysis, we observed that SclAb treatment significantly enhances bone volume fraction (BV/TV) and bone-implant contact (BIC) in Brtl/+ mice, suggesting a normalization of bone structure toward WT levels.

Growth factors that drive aggrecan synthesis in healthy articular cartilage. Role for transforming growth factor-β?

Introduction: Articular cartilage makes smooth movement possible and destruction of this tissue leads to loss of joint function. An important biomolecule that determines this function is the large aggregating proteoglycan of cartilage, aggrecan. Aggrecan has a relatively short half-life in cartilage and therefore continuous production of this molecule is essential.

Profiling of plasma extracellular vesicles identifies proteins that strongly associate with patient's global assessment of disease activity in rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial inflammation and cartilage/bone damage. Intercellular messengers such as IL-1 and TNF play a crucial role in the pathophysiology of RA but have limited diagnostic and prognostic values. Therefore, we assessed whether the protein content of the recently discovered extracellular vesicles (EVs), which have gained attention in the pathogenesis of RA, correlates with disease activity parameters in RA patients.

Separating friend from foe: Inhibition of TGF-β-induced detrimental SMAD1/5/9 phosphorylation while maintaining protective SMAD2/3 signaling in OA chondrocytes.

Objective: Transforming growth factor-β (TGF-β) signaling via SMAD2/3 is crucial to control cartilage homeostasis. However, TGF-β can also have detrimental effects by signaling via SMAD1/5/9 and thereby contribute to diseases like osteoarthritis (OA). In this study, we aimed to block TGF-β-induced SMAD1/5/9 signaling in primary human OA chondrocytes, while maintaining functional SMAD2/3 signaling.

Innate Immunity and Sex: Distinct Inflammatory Profiles Associated with Murine Pain in Acute Synovitis.

Joint pain severity in arthritic diseases differs between sexes and is often more pronounced in women. This disparity is thought to stem from biological mechanisms, particularly innate immunity, yet the understanding of sex-specific differences in arthritic pain remains incomplete. This study aims to investigate these disparities using an innate immunity-driven inflammation model induced by intra-articular injections of Streptococcus Cell Wall fragments to mimic both acute and pre-sensitized joint conditions.

Early pain in females is linked to late pathological features in murine experimental osteoarthritis.

Background: Osteoarthritis (OA) is a progressive joint disease and a major cause of chronic pain in adults. The prevalence of OA is higher in female patients, who tend to have worse OA outcomes, partially due to pain. The association between joint pain and OA pathology is often inconclusive.

Gas6/Axl Axis Activation Dampens the Inflammatory Response in Osteoarthritic Fibroblast-like Synoviocytes and Synovial Explants.

Osteoarthritis (OA) is the most prevalent joint disease, and it is characterized by cartilage degeneration, synovitis, and bone sclerosis, resulting in swelling, stiffness, and joint pain. TAM receptors (Tyro3, Axl, and Mer) play an important role in regulating immune responses, clearing apoptotic cells, and promoting tissue repair. Here, we investigated the anti-inflammatory effects of a TAM receptor ligand, i.

Analysis of CCN4/WISP1 Effects on Joint Tissues Using Gain- and Loss-of-Function Approaches.

The matricellular protein Wnt-induced secreted protein 1 (WISP1) is the fourth member of the CCN family of proteins, which has been shown to affect tissues of the musculoskeletal system. In the context of the musculoskeletal disorder osteoarthritis, our lab studied the function of CCN4/WISP1 in joint tissues, including synovium and cartilage, using both gain- and loss-of-function approaches. In mice, this was done by genetic engineering and recombination to generate mice deficient in CCN4/WISP1 protein.

Innate Immunity at the Core of Sex Differences in Osteoarthritic Pain?

Osteoarthritis (OA) is a progressive whole-joint disease; no disease-modifying drugs are currently available to stop or slow its process. Symptoms alleviation is the only treatment option. OA is the major cause of chronic pain in adults, with pain being the main symptom driving patients to seek medical help.

Identification of Transcription Factors Responsible for a Transforming Growth Factor-β-Driven Hypertrophy-like Phenotype in Human Osteoarthritic Chondrocytes.

During osteoarthritis (OA), hypertrophy-like chondrocytes contribute to the disease process. TGF-β's signaling pathways can contribute to a hypertrophy(-like) phenotype in chondrocytes, especially at high doses of TGF-β. In this study, we examine which transcription factors (TFs) are activated and involved in TGF-β-dependent induction of a hypertrophy-like phenotype in human OA chondrocytes.

Pain descriptors and determinants of pain sensitivity in knee osteoarthritis: a community-based cross-sectional study.

Objectives: The aim was to explore pain characteristics in individuals with knee OA (KOA), to compare pain sensitivity across individuals with KOA, individuals with chronic back pain (CBP) and pain-free individuals (NP) and to examine the relationship between clinical characteristics and pain sensitivity and between pain characteristics and pain sensitivity in KOA.

Methods: We carried out a cross-sectional, community-based online survey. Two data sets were combined, consisting of Dutch individuals ≥40 years of age, who were experiencing chronic knee pain (KOA,  = 445), chronic back pain (CBP,  = 504) or no pain (NP,  = 256).

The alarmins S100A8 and S100A9 mediate acute pain in experimental synovitis.

Background: Synovitis-associated pain is mediated by inflammatory factors that may include S100A8/9, which is able to stimulate nociceptive neurons via Toll-like receptor 4. In this study, we investigated the role of S100A9 in pain response during acute synovitis.

Methods: Acute synovitis was induced by streptococcal cell wall (SCW) injection in the knee joint of C57Bl/6 (WT) and S100A9 mice.

A roadmap to target interleukin-6 in osteoarthritis.

Joint inflammation is present in the majority of OA patients and pro-inflammatory mediators, such as IL-6, are actively involved in disease progression. Increased levels of IL-6 in serum or synovial fluid from OA patients correlate with disease incidence and severity, with IL-6 playing a pivotal role in the development of cartilage pathology, e.g.

The level of synovial AXL expression determines the outcome of inflammatory arthritis, possibly depending on the upstream role of TGF-β1.

Objective: To investigate the role of AXL, a member of the anti-inflammatory TYRO3, AXL MER (TAM) receptor family, in arthritis.

Methods: KRN serum transfer arthritis was induced in Axl-/- and wild-type mice. Knee and ankle joints were scored macro- and microscopically.

Identification of TGFβ-related genes regulated in murine osteoarthritis and chondrocyte hypertrophy by comparison of multiple microarray datasets.

Objective: Osteoarthritis (OA) is a joint disease characterized by progressive degeneration of articular cartilage. Some features of OA, including chondrocyte hypertrophy and focal calcification of articular cartilage, resemble the endochondral ossification processes. Alterations in transforming growth factor β (TGFβ) signaling have been associated with OA as well as with chondrocyte hypertrophy.

Treatment of collagenase-induced osteoarthritis with a viral vector encoding TSG-6 results in ectopic bone formation.

Objective: Tumor necrosis factor-inducible gene 6 (TSG-6) has anti-inflammatory and chondroprotective effects in mouse models of inflammatory arthritis. Because cartilage damage and inflammation are also observed in osteoarthritis (OA), we determined the effect of viral overexpression of TSG-6 in experimental osteoarthritis.

Methods: Bone marrow-derived cells were differentiated to multinucleated osteoclasts in the presence of recombinant TSG-6 or after transduction with a lentiviral TSG-6 expression vector.

Interleukin 1 β-induced SMAD2/3 linker modifications are TAK1 dependent and delay TGFβ signaling in primary human mesenchymal stem cells.

Background: Chondrogenic differentiation of mesenchymal stem cells (MSC) requires transforming growth factor beta (TGFβ) signaling. TGFβ binds to the type I receptor activin-like kinase (ALK)5 and results in C-terminal SMAD2/3 phosphorylation (pSMAD2/3C). In turn pSMAD2/3C translocates to the nucleus and regulates target gene expression.

Activin and Nodal Are Not Suitable Alternatives to TGFβ for Chondrogenic Differentiation of Mesenchymal Stem Cells.

Objective Previously, we demonstrated the importance of transforming growth factor-β (TGFβ)-activated SMAD2/3 signaling in chondrogenesis of bone marrow-derived mesenchymal stem cells (BMSCs). However, TGFβ also signals via the SMAD1/5/9 pathway, which is known to induce terminal differentiation of BMSCs. In this study, we investigated whether other SMAD2/3-activating ligands, Activin and Nodal, can induce chondrogenic differentiation of BMSCs without inducing terminal differentiation.

SMAD3 and SMAD4 have a more dominant role than SMAD2 in TGFβ-induced chondrogenic differentiation of bone marrow-derived mesenchymal stem cells.

To improve cartilage formation by bone marrow-derived mesenchymal stem cells (BMSCs), the signaling mechanism governing chondrogenic differentiation requires better understanding. We previously showed that the transforming growth factor-β (TGFβ) receptor ALK5 is crucial for chondrogenesis induced by TGFβ. ALK5 phosphorylates SMAD2 and SMAD3 proteins, which then form complexes with SMAD4 to regulate gene transcription.

IL37 dampens the IL1β-induced catabolic status of human OA chondrocytes.

Objective: A crucial feature of OA is cartilage degradation. This process is mediated by pro-inflammatory cytokines, among other factors, via induction of matrix-degrading enzymes. Interleukin 37 (IL37) is an anti-inflammatory cytokine and is efficient in blocking the production of pro-inflammatory cytokines during innate immune responses.

Milk extracellular vesicles accelerate osteoblastogenesis but impair bone matrix formation.

The claimed beneficial effect of milk on bone is still a matter for debate. Recently extracellular vesicles (EVs) that contain proteins and RNA were discovered in milk, but their effect on bone formation has not yet been determined. We demonstrated previously that bovine milk-derived EVs (BMEVs) have immunoregulatory properties.

Activin Receptor-Like Kinase Receptors ALK5 and ALK1 Are Both Required for TGFβ-Induced Chondrogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells.

Introduction: Bone marrow-derived mesenchymal stem cells (BMSCs) are promising for cartilage regeneration because BMSCs can differentiate into cartilage tissue-producing chondrocytes. Transforming Growth Factor β (TGFβ) is crucial for inducing chondrogenic differentiation of BMSCs and is known to signal via Activin receptor-Like Kinase (ALK) receptors ALK5 and ALK1. Since the specific role of these two TGFβ receptors in chondrogenesis is unknown, we investigated whether ALK5 and ALK1 are expressed in BMSCs and whether both receptors are required for chondrogenic differentiation of BMSCs.

Cross-talk between bone morphogenetic proteins and inflammatory pathways.

Pro-inflammatory cytokines and bone morphogenetic proteins are generally studied separately and considered to be elements of different worlds, immunology and developmental biology. Varas and colleagues report that these factors show cross-talk in rheumatoid arthritis synoviocytes. They show that pro-inflammatory cytokines not only stimulate the production of bone morphogenetic proteins but that these endogenously produced bone morphogenetic proteins interfere with the effects of pro-inflammatory cytokines on synoviocytes.

Unravelling osteoarthritis-related synovial fibrosis: a step closer to solving joint stiffness.

Synovial fibrosis is often found in OA, contributing heavily to joint pain and joint stiffness, the main symptoms of OA. At this moment the underlying mechanism of OA-related synovial fibrosis is not known and there is no cure available. In this review we discuss factors that have been reported to be involved in synovial fibrosis.