Acute joint inflammation induces a sharp increase in the number of synovial fluid EVs and modifies their phospholipid profile

Inflammation is the hallmark of most joint disorders. However, the precise regulation of induction, perpetuation, and resolution of joint inflammation is not entirely understood. Since extracellular vesicles (EVs) are critical for intercellular communication, we aim to unveil their role in these processes. Here, we investigated the EVs' dynamics and phospholipidome profile from synovial fluid (SF) of healthy equine joints and from horses with lipopolysaccharide (LPS)-induced synovitis. LPS injection triggered a sharp increase of SF-EVs at 5-8 h post-injection, which started to decline at 24 h post-injection. Importantly, we identified significant changes in the lipid profile of SF-EVs after synovitis induction. Compared to healthy joint-derived SF-EVs (0 h), SF-EVs collected at 5, 24, and 48 h post-LPS injection were strongly increased in hexosylceramides. At the same time, phosphatidylserine, phosphatidylcholine, and sphingomyelin were decreased in SF-EVs at 5 h and 24 h post-LPS injection. Based on the lipid changes during acute inflammation, we composed specific lipid profiles associated with healthy and inflammatory state-derived SF-EVs. The sharp increase in SF-EVs during acute synovitis and the correlation of specific lipids with either healthy or inflamed states-derived SF-EVs are findings of potential interest for unveiling the role of SF-EVs in joint inflammation, as well as for the identification of EV-biomarkers of joint inflammation

Extracellular vesicles in joint disease and therapy

The use of extracellular vesicles (EVs) as a potential therapy is currently explored for different disease areas. When it comes to the treatment of joint diseases this approach is still in its infancy. As in joint diseases both inflammation and the associated articular tissue destruction are important factors, both the immune-suppressive and the regenerative properties of EVs are potentially advantageous characteristics for future therapy. There is, however, only limited knowledge on the basic features, such as numerical profile and function, of EVs in joint articular tissues in general and their linking medium, the synovial fluid, in particular. Further insight is urgently needed in order to appreciate the full potential of EVs and to exploit these in EV-mediated therapies. Physiologic joint homeostasis is a prerequisite for proper functioning of joints and we postulate that EVs play a key role in the regulation of joint homeostasis and hence can have an important function in re-establishing disturbed joint homeostasis, and, in parallel, in the regeneration of articular tissues. In this mini-review EVs in the joint are explained from a historical perspective in both health and disease, including the potential niche for EVs in articular tissue regeneration. Furthermore, the translational potential of equine models for human joint biology is discussed. Finally, the use of MSC-derived EVs that is recently gaining ground is highlighted and recommendations are given for further EV research in this field

Extracellular vesicles : New tool for joint repair and regeneration

Cell-derived extracellular vesicles (EVs), present in synovial fluid and cartilage extracellular matrix (ECM), are involved in joint development and in the regulation of joint homeostasis. Although the exact function of EVs in these processes remains incompletely defined, the knowledge already acquired in this field suggests a role for these EVs as biomarkers of joint disease, and as a new tool to restore joint homeostasis and enhance articular tissue regeneration. In addition to direct injection of therapeutic EVs into the target site, surface coating of scaffolds and embedding of EVs in hydrogels might also lead to novel therapeutic possibilities. Based on the existing literature of EVs in synovial fluid and articular tissues, and investigation of the molecular factors (including microRNAs) active in joint homeostasis (or during its disturbance), we postulate novel perspectives for the implementation of EVs as a regenerative medicine approach in joint repair

Extracellular Vesicles in Joint Disease and Therapy

The use of extracellular vesicles (EVs) as a potential therapy is currently explored for different disease areas. When it comes to the treatment of joint diseases this approach is still in its infancy. As in joint diseases both inflammation and the associated articular tissue destruction are important factors, both the immune-suppressive and the regenerative properties of EVs are potentially advantageous characteristics for future therapy. There is, however, only limited knowledge on the basic features, such as numerical profile and function, of EVs in joint articular tissues in general and their linking medium, the synovial fluid, in particular. Further insight is urgently needed in order to appreciate the full potential of EVs and to exploit these in EV-mediated therapies. Physiologic joint homeostasis is a prerequisite for proper functioning of joints and we postulate that EVs play a key role in the regulation of joint homeostasis and hence can have an important function in re-establishing disturbed joint homeostasis, and, in parallel, in the regeneration of articular tissues. In this mini-review EVs in the joint are explained from a historical perspective in both health and disease, including the potential niche for EVs in articular tissue regeneration. Furthermore, the translational potential of equine models for human joint biology is discussed. Finally, the use of MSC-derived EVs that is recently gaining ground is highlighted and recommendations are given for further EV research in this field

Extracellular Vesicles in Joint Disease and Therapy

The use of extracellular vesicles (EVs) as a potential therapy is currently explored for different disease areas. When it comes to the treatment of joint diseases this approach is still in its infancy. As in joint diseases both inflammation and the associated articular tissue destruction are important factors, both the immune-suppressive and the regenerative properties of EVs are potentially advantageous characteristics for future therapy. There is, however, only limited knowledge on the basic features, such as numerical profile and function, of EVs in joint articular tissues in general and their linking medium, the synovial fluid, in particular. Further insight is urgently needed in order to appreciate the full potential of EVs and to exploit these in EV-mediated therapies. Physiologic joint homeostasis is a prerequisite for proper functioning of joints and we postulate that EVs play a key role in the regulation of joint homeostasis and hence can have an important function in re-establishing disturbed joint homeostasis, and, in parallel, in the regeneration of articular tissues. In this mini-review EVs in the joint are explained from a historical perspective in both health and disease, including the potential niche for EVs in articular tissue regeneration. Furthermore, the translational potential of equine models for human joint biology is discussed. Finally, the use of MSC-derived EVs that is recently gaining ground is highlighted and recommendations are given for further EV research in this field

Differential BDNF Responses of Triple Versus Dual Reuptake Inhibition in Neuronal and Astrocytoma Cells as well as in Rat Hippocampus and Prefrontal Cortex

Monoamine reuptake inhibitors increase brain-derived neurotrophic factor (BDNF) activity, and this growth factor is regarded as an interesting target for developing new antidepressant drugs. The aims of this study were to evaluate whether monoaminergic reuptake inhibition increases BDNF in vivo and in vitro as predicted by the neurotrophic hypothesis of depression, and whether triple reuptake inhibition has a superior BDNF response compared to dual reuptake inhibition. Twenty-one days of oral treatment (30 mg/kg) with the dual serotonin/noradrenaline reuptake inhibitor duloxetine or the triple serotonin/noradrenaline/dopamine reuptake inhibitor DOV 216,303 restored BDNF protein levels in the rat hippocampus, which were initially decreased due to injection stress. The prefrontal cortex contained increased BDNF levels only after DOV 216,303 treatment. In vitro, neither duloxetine nor DOV 216,303 altered intracellular BDNF levels in murine HT22 neuronal cells. In contrast, BDNF release was more effectively decreased following treatment with DOV 216,303 in these cells. In rat C62B astrocytomas, both antidepressants increased intracellular BDNF levels at their highest nontoxic concentration. C62B astrocytomas did not release BDNF, even after antidepressant treatment. Increased BDNF levels support the neurotrophic hypothesis of depression, but our findings do not clearly evidence that the BDNF response after triple reuptake inhibitors is more effective than after dual reuptake inhibitors. Moreover, the data suggest that the role of BDNF in neurons and astrocytes is complex and likely depends on factors including specificity of cell types in different brain regions, cell–cell interactions, and different mechanisms of action of antidepressants used

Effects of autologous conditioned plasma® (ACP on the healing of surgically induced core lesions in equine superficial digital flexor tendon

Tendon pathologies are among the most common musculoskeletal disorders in horses. After damage the tendon repairs by forming disorganized scar tissue that is of inferior functional quality than normal tendon, leading to high re-injury rates. Many of the currently available treatment modalities cannot significantly reduce this high recurrence rate. Autologous Conditioned Plasma (ACP, Arthrex Inc., USA) has been described in the literature as a leukocyte-reduced platelet concentrate. This blood product has been used in equine and human medicine for the treatment of tendon and ligament injuries. However, the effect of this therapeutical approach on tendon healing is unknown. Core lesions were surgically induced in the Superficial Digital Flexor Tendons (SDFT) of both fore- and hind limbs in eight healthy horses. At days 7 and 15 after lesion induction one randomly assigned fore- and hindlimb was treated with ACP and the contralateral one with saline. This study used data from the forelimbs SDFTs only. Gray-scale and color Doppler ultrasonographic parameters monitored throughout the study did not differ significantly at any time point. 22 weeks after the last treatment, the ACP treated tendons presented a significantly lower concentration of sulphated glycosaminoglycans (GAGs) (p≤0.05) when compared to saline. Other compositional, biomechanical and histological parameters presented no significant differences. Our study indicates that 2 intra-tendinous ACP treatments (without anticoagulant) during the proliferative phase of healing in surgically induced tendon core lesions have a limited effect on tendon healing when comparing ultrasonographic, biochemical, biomechanical and histological parameters with the control treatment. Long-term placebo controlled clinical trials with more horses are warranted to determine if this effect is clinically significant

Effects of autologous conditioned plasma® (ACP on the healing of surgically induced core lesions in equine superficial digital flexor tendon

Tendon pathologies are among the most common musculoskeletal disorders in horses. After damage the tendon repairs by forming disorganized scar tissue that is of inferior functional quality than normal tendon, leading to high re-injury rates. Many of the currently available treatment modalities cannot significantly reduce this high recurrence rate. Autologous Conditioned Plasma (ACP, Arthrex Inc., USA) has been described in the literature as a leukocyte-reduced platelet concentrate. This blood product has been used in equine and human medicine for the treatment of tendon and ligament injuries. However, the effect of this therapeutical approach on tendon healing is unknown. Core lesions were surgically induced in the Superficial Digital Flexor Tendons (SDFT) of both fore- and hind limbs in eight healthy horses. At days 7 and 15 after lesion induction one randomly assigned fore- and hindlimb was treated with ACP and the contralateral one with saline. This study used data from the forelimbs SDFTs only. Gray-scale and color Doppler ultrasonographic parameters monitored throughout the study did not differ significantly at any time point. 22 weeks after the last treatment, the ACP treated tendons presented a significantly lower concentration of sulphated glycosaminoglycans (GAGs) (p≤0.05) when compared to saline. Other compositional, biomechanical and histological parameters presented no significant differences. Our study indicates that 2 intra-tendinous ACP treatments (without anticoagulant) during the proliferative phase of healing in surgically induced tendon core lesions have a limited effect on tendon healing when comparing ultrasonographic, biochemical, biomechanical and histological parameters with the control treatment. Long-term placebo controlled clinical trials with more horses are warranted to determine if this effect is clinically significant

TrkB in the hippocampus and nucleus accumbens differentially modulates depression-like behavior in mice

Brain-derived neurotrophic factor (BDNF) exerts antidepressant-like effects in the hippocampus and pro-depressant effects in the nucleus accumbens (NAc). It is thought that downstream signaling of the BDNF receptor TrkB mediates the effects of BDNF in these brain structures. Here, we evaluate how TrkB regulates affective behavior in the hippocampus and NAc. We overexpressed TrkB by electroporating a non-viral plasmid in the NAc or hippocampus in mice. Depression- and anxiety-like behaviors were evaluated in the sucrose test (anhedonia), the forced swim test (despair) and the elevated zero maze (anxiety). Targeted brain tissue was biochemically analyzed to identify molecular mechanisms responsible for the observed behavior. Overexpressing TrkB in the NAc increased the number of young neuronal cells and decreased despair and basal corticosterone levels. TrkB overexpression in the hippocampus increased astrocyte production and activation of the transcription factor CREB, yet without altering affective behavior. Our data suggest antidepressant effects of BDNF-TrkB in the NAc, which could not be explained by activation of the transcription factors CREB or β-catenin. The effects TrkB has on depression-related behavior in different brain regions appear to critically depend on the targeted cell type