Semaglutide alleviates knee osteoarthritis pain in persons with obesity
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Modulating neuroplasticity for chronic pain relief: noninvasive neuromodulation as a promising approach
Chronic neuropathic pain is a debilitating neuroplastic disorder that notably impacts the quality of life of millions of people worldwide. This complex condition, encompassing various manifestations, such as sciatica, diabetic neuropathy and postherpetic neuralgia, arises from nerve damage or malfunctions in pain processing pathways and involves various biological, physiological and psychological processes. Maladaptive neuroplasticity, known as central sensitization, plays a critical role in the persistence of chronic neuropathic pain. Current treatments for neuropathic pain include pharmacological interventions (for example, antidepressants and anticonvulsants), invasive procedures (for example, deep brain stimulation) and physical therapies. However, these approaches often have limitations and potential side effects. In light of these challenges, interest in noninvasive neuromodulation techniques as alternatives or complementary treatments for neuropathic pain is increasing. These methods aim to induce analgesia while reversing maladaptive plastic changes, offering potential advantages over conventional pharmacological practices and invasive methods. Recent technological advancements have spurred the exploration of noninvasive neuromodulation therapies, such as repetitive transcranial magnetic stimulation, transcranial direct current stimulation and transcranial ultrasound stimulation, as well as innovative transformations of invasive techniques into noninvasive methods at both the preclinical and clinical levels. Here this review aims to critically examine the mechanisms of maladaptive neuroplasticity in chronic neuropathic pain and evaluate the efficacy of noninvasive neuromodulation techniques in pain relief. By focusing on optimizing these techniques, we can better assess their short-term and long-term effects, refine treatment variables and ultimately improve the quality of neuropathic pain management.
Neuronal guidance factor Sema3A inhibits neurite ingrowth and prevents chondrocyte hypertrophy in the degeneration of knee cartilage in mice, monkeys and humans
Osteoarthritis (OA) is a degenerative joint disease accompanied with the loss of cartilage and consequent nociceptive symptoms. Normal articular cartilage maintains at aneural state. Neuron guidance factor Semaphorin 3A (Sema3A) is a membrane-associated secreted protein with chemorepulsive properties for axons. However, the role of Sema3A in articular cartilage is still not clear. In the present studies, we investigated the functions of Sema3A in OA development in mice, non-human primates, and patients with OA. Sema3A has a protective effect on cartilage degradation, validated by the organoid culture in vitro and confirmed in chondrocyte-specific Sema3A conditional knockout mice. We demonstrated that Sema3A is a key molecule in maintaining cartilage homeostasis from chondrocyte hypertrophy via activating the PI3K pathway. The potential usage of Sema3A for OA treatment was validated in mouse and Rhesus macaque OA models through intra-articular injection of Sema3A, and also in patients by administering Sema3A containing platelet-rich plasma into the knee joints. Our studies demonstrated that Sema3A exerts a critical role in inhibiting neurite ingrowth and preventing chondrocyte hypertrophy in cartilage, and could be potentially used for OA treatment.
CCN2 mediates fibroblast-macrophage interaction in knee arthrofibrosis based on single-cell RNA-seq analysis
Knee arthrofibrosis, characterized by excessive matrix protein production and deposition, substantially impairs basic daily functions, causing considerable distress and financial burden. However, the underlying pathomechanisms remain unclear. Here, we characterized the heterogeneous cell populations and cellular pathways by combination of flow cytometry and single-cell RNA-seq analysis of synovial tissues from six patients with or without knee arthrofibrosis. Increased macrophages and fibroblasts were observed with decreased numbers of fibroblast-like synoviocytes, endothelial cells, vascular smooth muscle cells, and T cells in the arthrofibrosis group compared with negative controls. Notably, fibroblasts were discovered to interact with macrophages, and lead to fibrosis through TGF-β pathway induced CCN2 expression in fibroblasts. CCN2 was demonstrated to be required for fibroblast pro-fibrotic functions (activation, proliferation, and migration) through TGFBR/SMAD pathway. The expression of CCN2 was positively correlated with the collagen volume and TGF-β expression and negatively associated with patient-reported outcome measures in another cohort of patients with knee arthrofibrosis. Our study reveals the role of CCN2 in the fibroblast-macrophage interaction through TGF-β pathway which might help to shed light on CCN2 as a potential biomarker.
Effect of regional crosstalk between sympathetic nerves and sensory nerves on temporomandibular joint osteoarthritic pain
Temporomandibular joint osteoarthritis (TMJ-OA) is a common disease often accompanied by pain, seriously affecting physical and mental health of patients. Abnormal innervation at the osteochondral junction has been considered as a predominant origin of arthralgia, while the specific mechanism mediating pain remains unclear. To investigate the underlying mechanism of TMJ-OA pain, an abnormal joint loading model was used to induce TMJ-OA pain. We found that during the development of TMJ-OA, the increased innervation of sympathetic nerve of subchondral bone precedes that of sensory nerves. Furthermore, these two types of nerves are spatially closely associated. Additionally, it was discovered that activation of sympathetic neural signals promotes osteoarthritic pain in mice, whereas blocking these signals effectively alleviates pain. In vitro experiments also confirmed that norepinephrine released by sympathetic neurons promotes the activation and axonal growth of sensory neurons. Moreover, we also discovered that through releasing norepinephrine, regional sympathetic nerves of subchondral bone were found to regulate growth and activation of local sensory nerves synergistically with other pain regulators. This study identified the role of regional sympathetic nerves in mediating pain in TMJ-OA. It sheds light on a new mechanism of abnormal innervation at the osteochondral junction and the regional crosstalk between peripheral nerves, providing a potential target for treating TMJ-OA pain.
Cellular and molecular mechanisms underlying obesity in degenerative spine and joint diseases
Degenerative spine and joint diseases, including intervertebral disc degeneration (IDD), ossification of the spinal ligaments (OSL), and osteoarthritis (OA), are common musculoskeletal diseases that cause pain or disability to the patients. However, the pathogenesis of these musculoskeletal disorders is complex and has not been elucidated clearly to date. As a matter of fact, the spine and joints are not independent of other organs and tissues. Recently, accumulating evidence demonstrates the association between obesity and degenerative musculoskeletal diseases. Obesity is a common metabolic disease characterized by excessive adipose tissue or abnormal adipose distribution in the body. Excessive mechanical stress is regarded as a critical risk factor for obesity-related pathology. Additionally, obesity-related factors, mainly including lipid metabolism disorder, dysregulated pro-inflammatory adipokines and cytokines, are reported as plausible links between obesity and various human diseases. Importantly, these obesity-related factors are deeply involved in the regulation of cell phenotypes and cell fates, extracellular matrix (ECM) metabolism, and inflammation in the pathophysiological processes of degenerative spine and joint diseases. In this study, we systematically discuss the potential cellular and molecular mechanisms underlying obesity in these degenerative musculoskeletal diseases, and hope to provide novel insights for developing targeted therapeutic strategies.
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