Effects of Testosterone in Mediating the Relationship Between Daytime Napping and Osteoporosis in European Populations: A Mendelian Randomization Study.

We aimed to explore the causal effect of daytime napping on the risk of osteoporosis and the mediation role of testosterone in explaining this relationship. Summary data for Mendelian randomization (MR) analysis were obtained from the IEU OpenGWAS database. Univariable MR(UVMR) analysis and multiple sensitivity analyses were applied to explore the casual relationship between daytime napping and bone mineral density (BMD)/osteoporosis. We also conducted multivariable Mendelian randomization (MVMR) analysis to evaluate the correlation between testosterone-associated single-nucleotide variations and BMD/osteoporosis. Then, mediation analysis was performed to explore whether the association between daytime napping and BMD/osteoporosis was mediated via testosterone. Genetically predicted daytime napping was significantly associated with femoral neck BMD (ß [95% CI]: 0.2573 [0.0487, 0.4660]; P = 0.0156), lumbar spine BMD (ß [95% CI]: 0.2526 [0.0211, 0.4840]; P = 0.0324), and osteoporosis (OR [95% CI]: 0.5063 [0.2578, 0.9942]; P = 0.0481). ß and 95%CIs indicate the standard deviation (SD) unit of BMD increase per category increase in daytime napping. OR and 95%CIs represent the change in the odds ratio of osteoporosis per category increase in daytime napping. We observed a potentially causal effect of more frequent daytime napping on higher BMD and a lower risk of osteoporosis. Daytime napping was causally associated with a higher level of bioavailable testosterone (ß [95% CI]: 0.1397 [0.0619, 0.2175]; P = 0.0004). ß and 95%CIs represent the change in the SD of testosterone per category increase in daytime napping. Furthermore, the causal effects of daytime napping on BMD/osteoporosis were partly mediated by bioavailable testosterone. Daytime napping can efficiently increase BMD and reduce the risk of osteoporosis, and testosterone plays a key mediating role in this process.

Cell Reprogramming Strategies for Treating Osteoarthritis and Intervertebral Disc Degeneration.

Osteoarthritis (OA) and intervertebral disc degeneration (IVDD) are the most common degenerative bone and joint diseases, posing a major threat to patients' physical and mental health due to the occurrence of chronic pain and disability. Within this context, the absence of efficacious therapies has led to a growing interest in regenerative medicine. In particular, as a method that can erase the memory of differentiation and re-endow cells with pluripotency, cell reprogramming technologies have ushered in a new era of personalized therapy, which not only show great potential for the treatment of degenerative osteoarthropathies but also promise to achieve tissue regenerative and repair. However, compared to other areas of research, reprogramming technologies to treat OA and IVDD are still in the preliminary stages and require further investigation. This paper briefly introduces the characteristics of cell reprogramming; summarizes the pathological mechanisms of reprogramming to improves energy metabolism, aging, inflammation, oxidative stress, and immune imbalance in OA and IVDD under the background of microenvironment and immunity; highlights the significant advantages of reprogramming-derived cells compared to embryonic stem cells and mesenchymal stem cells, based on these advances, providing important strategies for its development and clinical application in OA and IVDD.

Multiple Natural Polymers in Drug and Gene Delivery Systems.

BACKGROUND: Natural polymers are organic compounds produced by living organisms. In nature, they exist in three main forms, including proteins, polysaccharides and nucleic acids. In recent years, with the continuous research on drug and gene delivery systems, scholars have found that natural polymers have promising applications in drug and gene delivery systems due to their excellent properties such as biocompatibility, biodegradability, low immunogenicity and easy modification. However, since the structure, physicochemical properties, pharmacological properties and biological characteristics of biopolymer molecules have not yet been entirely understood, further studies are required before large-scale clinical application. METHODS: This review focuses on recent advances in the representative natural polymers such as proteins (albumin, collagen, elastin), polysaccharides (chitosan, alginate, cellulose) and nucleic acids. RESULTS: We introduce the characteristics of various types of natural polymers, and further outline the characterization methods and delivery forms of these natural polymers. CONCLUSION: Finally, we discuss possible challenges for natural polymers in subsequent experimental studies and clinical applications. It provides an important strategy for the clinical application of natural polymers in drug and gene delivery systems.

New Progress in Basic Research of Macrophages in the Pathogenesis and Treatment of Low Back Pain.

Low back pain (LBP) is quite common in clinical practice, which can lead to long-term bed rest or even disability. It is a worldwide health problem remains to be solved. LBP can be induced or exacerbated by abnormal structure and function of spinal tissue such as intervertebral disc (IVD), dorsal root ganglion (DRG) and muscle; IVD degeneration (IVDD) is considered as the most important among all the pathogenic factors. Inflammation, immune response, mechanical load, and hypoxia etc., can induce LBP by affecting the spinal tissue, among which inflammation and immune response are the key link. Inflammation and immune response play a double-edged sword role in LBP. As the main phagocytic cells in the body, macrophages are closely related to body homeostasis and various diseases. Recent studies have shown that macrophages are the only inflammatory cells that can penetrate the closed nucleus pulposus, expressed in various structures of the IVD, and the number is positively correlated with the degree of IVDD. Moreover, macrophages play a phagocytosis role or regulate the metabolism of DRG and muscle tissues through neuro-immune mechanism, while the imbalance of macrophages polarization will lead to more inflammatory factors to chemotaxis and aggregation, forming an "inflammatory waterfall" effect similar to "positive feedback," which greatly aggravates LBP. Regulation of macrophages migration and polarization, inhibition of inflammation and continuous activation of immune response by molecular biological technology can markedly improve the inflammatory microenvironment, and thus effectively prevent and treat LBP. Studies on macrophages and LBP were mainly focused in the last 3-5 years, attracting more and more scholars' attention. This paper summarizes the new research progress of macrophages in the pathogenesis and treatment of LBP, aiming to provide an important clinical prevention and treatment strategy for LBP.

Inflammatory Stimulation Mediates Nucleus Pulposus Cell Necroptosis Through Mitochondrial Function Disfunction and Oxidative Stress Pathway.

BACKGROUND: The mutual activation between nucleus pulposus (NP) cells death and inflammation is an important pathogenic factor of intervertebral disc degeneration. Whether inflammation mediates NP cells necroptosis, and its relationship with mitochondrial dysfunction and oxidative stress remains unclear. METHODS: In this study, 50 ng/mL of TNF-α and 20 ng/mL of IL-1ß were used to co-treatment with rat NP cells for 0, 24, 48, 72 hours, then Western blot and RT-PCR techniques were utilized to evaluate the expression level of necroptosis-associated target molecules, such as RIPK1, RIPK3 and MLKL. The results established that with prolongation of TNF-α and IL-1ß treatment time, the expression level of necroptosis-associated molecules gradually increased. The 48 hours of TNF-α and IL-1ß treatment was selected throughout the following experiments. The RIPK1 specific inhibitor necrostatin-1 (Nec-1), RIPK3 inhibitor GSK872, MLKL inhibitor necrosulfonamide (NSA) and small interfering RNA (siRNA) technology were employed. RESULTS: Under the treatment of TNF-α or IL-1ß, administration of Nec-1, GSK872 or NSA notably reduced NP cells death and up-regulated NP cells viability. Consistently, SiRNA-mediated knockdown of RIPK3 (SiRIPK3) or MLKL (SiMLKL) promoted the survival of NP cells. However, SiRIPK1 aggravated NP cells death. Furthermore, after 48 hours of TNF-α and IL-1ß treatment, the mitochondrial membrane potential decreased, opening of mitochondrial permeability transition pore enhanced, and oxidative stress level notably elevated. The Nec-1, GSK872 or NSA treatment largely restored the normal mitochondrial function and down-regulated oxidative stress. CONCLUSIONS: In summary, RIPK1/RIPK3/MLKL-mediated necroptosis play an important role in NP cells death during inflammatory irritation, which might be closely related to mitochondrial dysfunction and up-regulation of oxidative stress.

A patient with Turner syndrome received the percutaneous vertebroplasty seven times: a case report and literature review.

BACKGROUND: Turner syndrome (TS) is characterized as the complete or partial absence of one X chromosome and is an extremely rare disease affecting approximately 1:2500 live female births. Though the prevalence of osteoporosis among women with TS is estimated to be around 55-64% and they suffer more frequently from fractures than normal, few reports concerning TS patients with osteoporosis are able to be seen due to tiny number of patients. CASE PRESENTATION: Here, we report a rare case of TS with osteoporosis, who has undergone percutaneous vertebroplasty (PVP) seven times because of several vertebral compression fractures (VCFs). G-banded karyotype analysis was performed and the result was 45,X[43]/47,XXX[17], indicating that the patient was a mosaicism of TS karyotype and Trisomy X syndrome karyotype. TS is the underlying cause of low level of estrogen for this patient. The interaction of aging, estrogen deficiency and intestinal dysbacteriosis leads to her severe osteoporosis and multi-segmental VCFs. The aim of this report is to provide recommendations regarding the management of TS patients with osteoporosis by reviewing the clinical presentation of TS, the influence of estrogen deficiency in osteoporosis, etc. CONCLUSIONS: Early diagnosis and hormone replacement treatment are essential for TS patients to prevent osteoporosis and reduce the risk of fractures. This is a rare case report describing TS patient with severe osteoporosis and VCFs.

Sprifermin: Effects on Cartilage Homeostasis and Therapeutic Prospects in Cartilage-Related Diseases.

When suffering from osteoarthritis (OA), articular cartilage homeostasis is out of balance and the living quality declines. The treatment of knee OA has always been an unsolved problem in the world. At present, symptomatic treatment is mainly adopted for OA. Drug therapy is mainly used to relieve pain symptoms, but often accompanied with adverse reactions; surgical treatment involves the problem of poor integration between the repaired or transplanted tissues and the natural cartilage, leading to the failure of repair. Biotherapy which aims to promote cartilage in situ regeneration and to restore endochondral homeostasis is expected to be an effective method for the prevention and treatment of OA. Disease-modifying osteoarthritis drugs (DMOADs) are intended for targeted treatment of OA. The DMOADs prevent excessive destruction of articular cartilage through anti-catabolism and stimulate tissue regeneration via excitoanabolic effects. Sprifermin (recombinant human FGF18, rhFGF18) is an effective DMOAD, which can not only promote the proliferation of articular chondrocyte and the synthesis of extracellular matrix, increase the thickness of cartilage in a dose-dependent manner, but also inhibit the activity of proteolytic enzymes and remarkedly slow down the degeneration of cartilage. This paper reviews the unique advantages of Sprifermin in repairing cartilage injury and improving cartilage homeostasis, aiming to provide an important strategy for the effective prevention and treatment of cartilage injury-related diseases.

Resveratrol-enhanced SIRT1-mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors.

Low back pain (LBP) is a major clinical problem that lacks effective treatments. The sensory innervation in porous vertebral endplates and anxiety contributes to spinal hyperalgesia. We hypothesized that SIRT1 activator resveratrol alleviates LBP and anxiety via promotion of osteogenesis in the porous endplates. The hyperalgesia and anxiety-related behaviors; sensory innervation, inflammation and porosity of endplates; and osteogenic/osteoclastic factors expression were measured following resveratrol treatment after lumbar spine instability (LSI) surgery. To explore whether resveratrol promotes endplates osteogenesis and thus alleviates LBP through activation of SIRT1 in the osteoprogenitor cells of endplates, SIRT1OSX-/- mice were employed. Additionally, the levels of inflammation markers, phosphorylation of cAMP response element-binding protein (pCREB), and brain-derived neurotrophic factor (BDNF) in hippocampus were evaluated. After 4 or 8 weeks LSI surgery, the mice suffered from hyperalgesia and anxiety, which were efficiently attenuated by resveratrol at 8 weeks. Resveratrol treatment-enhanced osteogenesis and decreased endplates porosities accompanied with the reduction of TNFα, IL-1ß, and COX2 levels and CGRP+ nerve fibers innervation in porous endplates. Resveratrol-mediated endplates osteogenesis, decreased endplates porosities, and analgesic and antianxiety effects were abrogated in SIRT1OSX-/- mice. Furthermore, resveratrol relieved inflammation and increased pCREB and BDNF expression in the hippocampus after 8 weeks, which alleviate anxiety-related behaviors. This study provides that resveratrol-mediated porous endplates osteogenesis via the activation of SIRT1 markedly blocked sensory innervation and inflammation in endplates, therefore, alleviating LSI surgery-induced LBP and hippocampus-related anxiety.

Curcumin Modulates the Crosstalk Between Macrophages and Bone Mesenchymal Stem Cells to Ameliorate Osteogenesis.

Bone healing is thought to be influenced by the cross-talk between bone forming and immune cells. In particular, macrophages play a crucial role in the regulation of osteogenesis. Curcumin, the major bioactive polyphenolic ingredient of turmeric, has been shown to regulate inflammatory response and osteogenic activities. However, whether curcumin could regulate macrophage polarization and subsequently influence osteogenesis remain to be elucidated. In this study, the potential immunomodulatory capability of curcumin on inflammatory response and phenotype switch of macrophages and the subsequent impact on osteogenic differentiation of MSCs are investigated. We demonstrated that curcumin exhibited significant anti-inflammatory effect by polarizing the macrophages toward anti-inflammatory phenotype, with increased expression of IL-4, IL-10, and CD206, and decreased expression of IL-1ß, TNF-α, CCR7, and iNOS. In addition, curcumin could improve the osteo-immune microenvironment via promoting osteogenesis-related regenerative cytokine BMP-2 and TGF-ß production. Moreover, the co-cultured test of macrophages and BMSCs showed that curcumin-modulated macrophages conditioned medium could promote osteogenic differentiation of BMSCs with increased gene (ALP, Runx-2, OCN, and OPN) and protein (Runx-2 and OCN) expression levels, enhanced ALP activity, and obvious formation of mineralized nodules. Taken together, with the interaction between curcumin-conditioned macrophage and curcumin-stimulated BMSCs, curcumin could remarkably enhance the osteogenic differentiation of BMSCs in LPS-activated inflammatory macrophage-BMSCs coculture system.

Daphnetin ameliorates glucocorticoid-induced osteoporosis via activation of Wnt/GSK-3ß/ß-catenin signaling.

Glucocorticoids have been widely used in multiple inflammatory and autoimmune diseases. However, long-term glucocorticoid therapy may result in osteoporosis. The present study aimed to evaluate the potential therapeutic effects and investigate the underlying mechanisms of Daphnetin (Daph) on glucocorticoid-induced osteoporosis (GIOP). In vivo, male Sprague Dawley rats were intramuscularly injected with dexamethasone (DEX) to induce GIOP and Daph was given intraperitoneally. Bone histological changes, mineral content, microstructure parameters and bone turnover markers were detected. Gut microbiota composition and intestinal barrier function were further assessed. In vitro, MC3T3-E1 pre-osteoblasts were treated with DEX and the abilities of Daph on osteoblast proliferation, differentiation and mineralization were assessed. A Wnt signaling inhibitor, XAV939, was added additionally to evaluate the effect of Daph on Wnt signaling. The results showed that in vivo, Daph increased the DEX-induced reduction in body weight gain, bone mineral content and microstructure parameters and restored the levels of bone turnover markers in GIOP rats. In vitro, Daph promoted osteoblast proliferation, differentiation and mineralization in DEX-treated MC3T3-E1 pre-osteoblasts. Moreover, Daph activated the Wnt/GSK-3ß/ß-catenin signaling pathway. XAV939 successfully abolished the beneficial effects of Daph on GIOP in vitro. Besides, Daph showed improvement on gut microbiota disorder and intestinal barrier dysfunction post GIOP. Collectively, these data demonstrated that Daph effectively ameliorates GIOP and the possible mechanism may be that Daph activated Wnt/GSK-3ß/ß-catenin signaling.