Reversible dougong structured receptor-ligand recognition for building dynamic extracellular matrix mimics.

Dynamic biomaterials excel at recapitulating the reversible interlocking and remoldable structure of the extracellular matrix (ECM), particularly in manipulating cell behaviors and adapting to tissue morphogenesis. While strategies based on dynamic chemistries have been extensively studied for ECM-mimicking dynamic biomaterials, biocompatible molecular means with biogenicity are still rare. Here, we report a nature-derived strategy for fabrication of dynamic biointerface as well as a three-dimensional (3D) hydrogel structure based on reversible receptor-ligand interaction between the glycopeptide antibiotic vancomycin and dipeptide d-Ala-d-Ala. We demonstrate the reversible regulation of multiple cell types with the dynamic biointerface and successfully implement the dynamic hydrogel as a functional antibacterial 3D scaffold to treat tissue repair. In view of the biogenicity and high applicability, this nature-derived reversible molecular strategy will bring opportunities for malleable biomaterial design with great potential in biomedicine.

NOX4 blockade suppresses titanium nanoparticle-induced bone destruction via activation of the Nrf2 signaling pathway.

Periprosthetic osteolysis (PPO) triggered by wear particles is the most severe complication of total joint replacement (TJR) surgeries, representing the major cause of implant failure, which is public health concern worldwide. Previous studies have confirmed the specialized role of osteoclast-induced progressive bone destruction in the progression of PPO. Additionally, the reactive oxygen species (ROS) induced by wear particles can promote excessive osteoclastogenesis and bone resorption. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), a cellular enzyme, is considered to be responsible for the production of ROS and the formation of mature osteoclasts. However, NOX4 involvement in PPO has not yet been elucidated. Therefore, we investigated the mechanism by which NOX4 regulates osteoclast differentiation and the therapeutic effects on titanium nanoparticle-induced bone destruction. We found that NOX4 blockade suppressed osteoclastogenesis and enhanced the scavenging of intracellular ROS. Our rescue experiment revealed that nuclear factor-erythroid 2-related factor 2 (Nrf2) silencing reversed the effects of NOX4 blockade on ROS production and osteoclast differentiation. In addition, we found increased expression levels of NOX4 in PPO tissues, while NOX4 inhibition in vivo exerted protective effects on titanium nanoparticle-induced osteolysis through antiosteoclastic and antioxidant effects. Collectively, these findings suggested that NOX4 blockade suppresses titanium nanoparticle-induced bone destruction via activation of the Nrf2 signaling pathway and that NOX4 blockade may be an attractive therapeutic approach for preventing PPO.

Urolithin A suppresses RANKL-induced osteoclastogenesis and postmenopausal osteoporosis by, suppresses inflammation and downstream NF-κB activated pyroptosis pathways.

Osteoporosis (OP) is characterized by decreased trabecular bone volume and microarchitectural deterioration in the medullary cavity. Urolithin A (UA) is a biologically active metabolite generated by the gut microbiota. UA is the measurable product considered the most relevant urolithin as the final metabolic product of polyphenolic compounds. Considering that catabolic effects mediated by the intestinal microbiota are highly involved in pathological bone disorders, exploring the biological influence and molecular mechanisms by which UA alleviates OP is crucial. Our study aimed to investigate the effect of UA administration on OP progression in the context of estrogen deficiency-induced bone loss. The in vivo results indicated that UA effectively reduced ovariectomy-induced systemic bone loss. In vitro, UA suppressed Receptor Activator for Nuclear Factor-κB Ligand (RANKL)-triggered osteoclastogenesis in a concentration-dependent manner. Signal transduction studies and sequencing analysis showed that UA significantly decreased the expression of inflammatory cytokines (e.g., IL-6 and TNF-α) in osteoclasts. Additionally, attenuation of inflammatory signaling cascades inhibited the NF-κB-activated NOD-like receptor signaling pathway, which eventually led to decreased cytoplasmic secretion of IL-1ß and IL-18 and reduced expression of pyroptosis markers (NLRP3, GSDMD, and caspase-1). Consistent with this finding, an NLRP3 inflammasome inhibitor (MCC950) was employed to treat OP, and modulation of pyroptosis was found to ameliorate osteoclastogenesis and bone loss in ovariectomized (OVX) mice, suggesting that UA suppressed osteoclast formation by regulating the inflammatory signal-dependent pyroptosis pathway. Conceivably, UA administration may be a safe and promising therapeutic strategy for osteoclast-related bone diseases such as OP.

Exosomes derived from miR-155-5p-overexpressing synovial mesenchymal stem cells prevent osteoarthritis via enhancing proliferation and migration, attenuating apoptosis, and modulating extracellular matrix secretion in chondrocytes.

Synovial mesenchymal stem cells (SMSCs) have the potential to attenuate osteoarthritis (OA)-induced injury. The role and mechanism of SMSC-derived exosomes (SMSC-Exos), pivotal paracrine factors of stem cells, in OA-associated injury remain unclear. We aimed to confirm the effect of SMSC-Exos with specific modifications on OA-induced damage and to investigate the potential molecular mechanisms. Exosomes derived from miR-155-5p-overexpressing SMSCs (SMSC-155-5p-Exos) and SMSCs (SMSC-Exos) were isolated and characterized. CCK-8, Transwell, and Western blot analyses were used to detect proliferation, migration, extracellular matrix (ECM) secretion, and apoptosis of osteoarthritic chondrocytes. The therapeutic effect of exosomes in a mouse model of OA was examined using immunohistochemical staining and OARSI scores. SPSS 17.0 and GraphPad software were used for all statistical analyses in this study. The SMSC-Exos enhanced the proliferation and migration and inhibited the apoptosis of osteoarthritic chondrocytes but had no effect on ECM secretion. The miR-155-5p-overexpressing exosomes showed common characteristics of exosomes in vitro and further promoted ECM secretion by targeting Runx2. Thus, the SMSC-155-5p-Exos promoted proliferation and migration, suppressed apoptosis and enhanced ECM secretion of osteoarthritic chondrocytes, and effectively prevented OA in a mouse model. In addition, overexpression of Runx2 partially reversed the effect of the SMSC-155-5p-Exos on osteoarthritic chondrocytes. Given the insufficient effect of the SMSC-Exos on the ECM secretion of osteoarthritic chondrocytes, we modified the SMSM-Exos and demonstrated that the SMSC-155-5p-Exos could prevent OA. Exosomes derived from modified SMSCs may be a new treatment strategy to prevent OA. Graphical abstract.

Human bone mesenchymal stem cells-derived exosomal miRNA-361-5p alleviates osteoarthritis by downregulating DDX20 and inactivating the NF-κB signaling pathway.

Osteoarthritis (OA) is a chronic disease featured by joint hyperplasia, deterioration of articular cartilage, and progressive degeneration. Abnormal expression of microRNAs (miRNAs) has been found to be implicated in the pathological process of OA. In this study, the role of miR-361-5p transferred by exosomes derived from human bone mesenchymal stem cells (hBMSCs) in OA was investigated. The expression of Asp-Glu-Ala-Asp-box polypeptide 20 (DDX20) and miR-361-5p in interleukin-1ß (IL-1ß)-treated chondrocytes was determined by reverse transcription quantitative polymerase chain reaction. DDX20 was knocked down by transfection of short hairpin RNA targeting DDX20, and the effects of DDX20 downregulation on IL-1ß-induced damage of chondrocytes were detected. The interaction between DDX20 and miR-361-5p was tested by luciferase report assay. hBMSCs-derived exosomes loaded with miR-361-5p were co-incubated with chondrocytes followed by detection of cell viability, proliferation and inflammatory response. An OA rat model was established to further explore the role of miR-361-5p in vivo. Western blot, luciferase reporter and immunofluorescence staining assays were used to evaluate the activation of the nuclear factor kappa-B (NF-κB) signaling pathway. We found that DDX20 was upregulated, while miR-361-5p was underexpressed in IL-1ß-treated chondrocytes. Downregulation of DDX20 inhibits levels of matrix metalloproteinases (MMPs) and suppresses inflammation induced by IL-1ß. Mechanistically, miR-361-5p was verified to directly target DDX20. In addition, hBMSC-derived exosomes-transferred miR-361-5p alleviates chondrocyte damage and inhibits the NF-κB signaling pathway via targeting DDX20. Inhibition of NF-κB signaling reverses the effect of overexpressed DDX20 on IL-1ß-induced chondrocyte damage. Moreover, exosomal miR-361-5p alleviates OA damage in vivo. Overall, hBMSC-derived exosomal miR-361-5p alleviates OA damage by targeting DDX20 and inactivating the NF-κB signaling pathway.

MiR-106b inhibition suppresses inflammatory bone destruction of wear debris-induced periprosthetic osteolysis in rats.

Aseptic loosening caused by periprosthetic osteolysis (PPO) is the main reason for the primary artificial joint replacement. Inhibition of inflammatory osteolysis has become the main target of drug therapy for prosthesis loosening. MiR-106b is a newly discovered miRNA that plays an important role in tumour biology, inflammation and the regulation of bone mass. In this study, we analysed the in vivo effect of miR-106b on wear debris-induced PPO. A rat implant loosening model was established. The rats were then administrated a lentivirus-mediated miR-106b inhibitor, miR-106b mimics or an equivalent volume of PBS by tail vein injection. The expression levels of miR-106b were analysed by real-time PCR. Morphological changes in the distal femurs were assessed via micro-CT and histopathological analysis, and cytokine expression levels were examined via immunohistochemical staining and ELISA. The results showed that treatment with the miR-106b inhibitor markedly suppressed the expression of miR-106b in distal femur and alleviated titanium particle-induced osteolysis and bone loss. Moreover, the miR-106b inhibitor decreased TRAP-positive cell numbers and suppressed osteoclast formation, in addition to promoting the activity of osteoblasts and increasing bone formation. MiR-106b inhibition also significantly regulated macrophage polarization and decreased the inflammatory response as compared to the control group. Furthermore, miR-106b inhibition blocked the activation of the PTEN/PI3K/AKT and NF-κB signalling pathways. Our findings indicated that miR-106b inhibition suppresses wear particles-induced osteolysis and bone destruction and thus may serve as a potential therapy for PPO and aseptic loosening.

Puerarin inhibits titanium particle-induced osteolysis and RANKL-induced osteoclastogenesis via suppression of the NF-κB signaling pathway.

Osteolysis around the prosthesis and subsequent aseptic loosening are the main causes of prosthesis failure. Inflammation due to wear particles and osteoclast activation are the key factors in osteolysis and are also potential targets for the treatment of osteolysis. However, it is not clear whether puerarin can inhibit chronic inflammation and alleviate osteolysis. In this study, we investigated the effect of puerarin on Ti particle-induced inflammatory osteolysis in vivo in rat femoral models and in vitro in receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast activation models. Our in vivo results showed that puerarin significantly inhibited Ti particle-induced osteolysis and the expression of matrix metallopeptidase 9 (MMP-9), nuclear factor of activated T cells 1 (NFATc1), tumour necrosis factor (TNF)-α and interleukin (IL)-6. In vitro, puerarin prevented RANKL-induced osteoclast differentiation, bone resorption and F-actin ring formation in a concentration-dependent manner. Furthermore, puerarin decreased the phosphorylation of p65 and prevented p65 moving from the cytoplasm to the nucleus. Puerarin also reduced the expression of osteoclast-specific factors and inhibited the inflammatory response. In conclusion, our study proves that puerarin can block the NF-κB signalling pathway to inhibit osteoclast activation and inflammatory processes, which provides a new direction for the treatment of osteolysis-related diseases.

Aspirin inhibits osteoclast formation and wear-debris-induced bone destruction by suppressing mitogen-activated protein kinases.

Excessive osteoclast recruitment and activation is the chief cause of periprosthetic osteolysis and subsequent aseptic loosening, so blocking osteolysis may be useful for protecting against osteoclastic bone resorption. We studied the effect of aspirin on titanium (Ti)-particle-induced osteolysis in vivo and in vitro using male C57BL/6J mice randomized to sham (sham surgery), Ti (Ti particles), low-dose aspirin (Ti/5 mg·kg-1 ·d-1 aspirin), and high-dose aspirin (Ti/30 mg·kg-1 ·d-1 aspirin). After 2 weeks, a three-dimensional reconstruction evaluation using micro-computed tomography and histomorphology assessment were performed on murine calvariae. Murine hematopoietic macrophages and RAW264.7 lineage cells were studied to investigate osteoclast formation and function. Aspirin attenuated Ti-particle-induced bone erosion and reduced osteoclasts. In vitro, aspirin suppressed osteoclast formation, osteoclastic-related gene expression, and osteoclastic bone erosion in a dose-dependent manner. Mechanically, aspirin reduced osteoclast formation by suppressing receptor activator of nuclear factor kappa-B ligand-induced activation of extracellular signal-related kinase, p-38 mitogen-activated protein kinase, and c-Jun N-terminal kinase. Thus, aspirin may be a promising option for preventing and curing osteoclastic bone destruction, including peri-implant osteolysis.

KLF2 regulates osteoblast differentiation by targeting of Runx2.

Osteoblast differentiation plays a critical role in bone formation and maintaining balance in bone remodeling. Runt-related transcription factor 2 (Runx2) is a central transcription factor regulating osteoblast differentiation and promoting bone mineralization. Until now, the molecular regulatory basis and especially the gene regulatory network of osteogenic differentiation have been unclear. Krüppel-like factor 2 (KLF2) is a zinc finger structure and DNA-binding transcription factor. The current study aimed to investigate the physiological function of KLF2 in osteoblast differentiation. Our results indicate that KLF2 is expressed in pre-osteoblast MC3T3-E1 cells and primary osteoblasts. Interestingly, KLF2 expression is increased in osteoblasts during the osteoblastic differentiation process. Overexpression of KLF2 in MC3T3-E1 cells promoted the expression of the osteoblastic differentiation marker genes Alp, Osx, and Ocn, and stimulated mineralization by increasing Runx2 expression at both the mRNA and protein levels. In contrast, knockdown of KLF2 produced the opposite effects. Importantly, we found that KLF2 could physically interact with Runx2. KLF2 promoted osteoblast differentiation by regulating Runx2 and physically interacting with Runx2. Taken together, the findings of this study identify KLF2 as a novel regulator of osteoblast differentiation. Our findings suggest that KLF2 might be a new therapeutic target for bone disease.

Exenatide ameliorates inflammatory response in human rheumatoid arthritis fibroblast-like synoviocytes.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of unknown etiology characterized by degradation of cartilage and bone, accompanied by unimpeded proliferation of synoviocytes of altered phenotype. In the present study, we investigated the involvement of the glucagon-like peptide 1 (GLP-1) receptor on human fibroblast-like synoviocytes (FLS) in the pathogenesis of RA using the selective GLP-1 agonist exenatide, a licensed drug used for the treatment of type 2 diabetes. Our results indicate that exenatide may play a role in regulating tumor necrosis factor-α-induced mitochondrial dysfunction by increasing mitochondrial membrane potential, oxidative stress by reducing the production of reactive oxygen species, the expression of NADPH oxidase 4, expression of matrix metalloproteinase (MMP)-3 and MMP-13, release of proinflammatory cytokines including interleukin-1ß (IL-1ß), IL-6, monocyte chemoattractant protein-1, and high-mobility group protein 1, as well as activation of the p38/nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α/nuclear factor κB signaling pathway in primary human RA FLS. These positive results indicate that exenatide may have potential as a therapeutic agent for the treatment and prevention of RA. © 2019 IUBMB Life, 9999(9999):1-9, 2019.

Relaxin inhibits patellar tendon healing in rats: a histological and biochemical evaluation.

BACKGROUND: Female patients are more likely to have tendon injuries than males, especially those who has a higher concentration of relaxin. Previous studies have demonstrated that relaxin attenuates extracellular matrix (ECM) formation. However, the mechanism of relaxin on tendon repair remains unclear. We hypothesize that relaxin inhibits tendon healing by disrupting collagen synthesis. METHODS: A patellar tendon window defect model was established using Sprague-Dawley rats. The center of the patellar tendon was removed from the patella distal apex and inserted to the tibia tuberosity in width of 1 mm. Then, the rats were injected with saline (0.2 µg/kg/day) or relaxin (0.2 µg/kg/day) for two and four weeks, which was followed by biomechanical analysis and histological and histochemical examination. RESULTS: Mechanical results indicated that relaxin induces a significant decrease in tear resistance, stiffness, and Young's modulus compared to those rats without relaxin treatment. In addition, it was shown that relaxin activates relaxin family peptide receptor 1(RXFP1), disturbs the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteases (TIMPs), and reduces the deposition of collagen in injury areas. CONCLUSIONS: Relaxin impairs tendon healing in rats. Also, relaxin might lead to tendon injury more commonly for females than males.

The obesity challenge in joint replacement: a multifaceted analysis of self-reported health status and exercise capacity using NHANES data: a population-based study.

BACKGROUND: Joint replacement is successful for end-stage oeteoarthritis, with obesity linked to elevated risk. But the impact of obesity on self-reported health and exercise capacity among joint replacement patients remains complex and requires investigation. METHODS: This study utilizes data from the National Health and Nutrition Examination Survey (NHANES) to examine the relationship between obesity severity, demographic factors, medical comorbidities, and self-reported health status. The relationship between general health status and BMI was analyzed using multivariable regression, and further illustrated using a restricted cubic spline. Additionally, a bibliometric analysis and systematic review was done to frame the research within the broader context of existing knowledge and demographic specifics. RESULTS: Analysis of NHANES data involving 327 joint replacement patients yielded intriguing insights. The difference in self-reported health between BMI groups did not achieve conventional statistical significance ( P =0.06), and multivariable analysis showed that even severely obese patients did not exhibit significantly elevated risk of poor/fair self-reported health compared to normal weight subjects. Among severely obese individuals (BMI>40), 40.63% still rated their health positively. However, stratified analyses indicated that obesity correlated with negative health reports across sex, age, and education strata. Notably, physical functioning emerged as a robust predictor of self-reported health, with those reporting no walking difficulties having significantly lower odds of poor/fair health (Odds ratio=0.37, P =0.01). CONCLUSION: The study highlights the need for healthcare providers to consider individual physical abilities and comorbidities alongside obesity severity when discussing treatment options with joint replacement patients. It supports tailored interventions and informed shared decision-making. Future research could explore effective weight management strategies for obese individuals undergoing joint replacement.

Nitrite reductase-mimicking catalysis temporally regulating nitric oxide concentration gradient adaptive for antibacterial therapy.

The unique bacterial infection microenvironment (IME) usually requires complicated design of nanomaterials to adapt to IME for enhancing antibacterial therapy. Here, an alternative IME adaptative nitrite reductase-mimicking nanozyme is constructed by in situ growth of ultrasmall copper sulfide clusters on the surface of a nanofibrillar lysozyme assembly (NFLA/CuS NHs), which can temporally regulate nitric oxide (NO) gradient concentration to kill bacteria initially and promote tissue regeneration subsequently. Benefiting from a copper nitrite reductase (CuNIR)-inspired structure with CuS cluster as active center and NFLA as skeleton, NFLA/CuS NHs efficiently boost the catalytic reduction of nitrite to NO. The inherent supramolecular fibrillar networks displays excellent bacterial capture capability, facilitating initial high-concentration NO attacks on the bacteria. The subsequent catalytic release of low-concentration NO by NFLA/CuS NHs-mediated nitrite reduction remarkably promotes cell migration and angiogenesis. This work paves the way for dynamically eliminating MDR bacterial infection and promoting tissue regeneration in a simple and smart way through CuNIR-mimicking catalysis.

Crosstalk Between the Neuroendocrine System and Bone Homeostasis.

The homeostasis of bone microenvironment is the foundation of bone health and comprises 2 concerted events: bone formation by osteoblasts and bone resorption by osteoclasts. In the early 21st century, leptin, an adipocytes-derived hormone, was found to affect bone homeostasis through hypothalamic relay and the sympathetic nervous system, involving neurotransmitters like serotonin and norepinephrine. This discovery has provided a new perspective regarding the synergistic effects of endocrine and nervous systems on skeletal homeostasis. Since then, more studies have been conducted, gradually uncovering the complex neuroendocrine regulation underlying bone homeostasis. Intriguingly, bone is also considered as an endocrine organ that can produce regulatory factors that in turn exert effects on neuroendocrine activities. After decades of exploration into bone regulation mechanisms, separate bioactive factors have been extensively investigated, whereas few studies have systematically shown a global view of bone homeostasis regulation. Therefore, we summarized the previously studied regulatory patterns from the nervous system and endocrine system to bone. This review will provide readers with a panoramic view of the intimate relationship between the neuroendocrine system and bone, compensating for the current understanding of the regulation patterns of bone homeostasis, and probably developing new therapeutic strategies for its related disorders.

Exosomes based strategies for cardiovascular diseases: Opportunities and challenges.

Exosomes, as nanoscale extracellular vesicles (EVs), are secreted by all types of cells to facilitate intercellular communication in living organisms. After being taken up by neighboring or distant cells, exosomes can alter the expression levels of target genes in recipient cells and thereby affect their pathophysiological outcomes depending on payloads encapsulated therein. The functions and mechanisms of exosomes in cardiovascular diseases have attracted much attention in recent years and are thought to have cardioprotective and regenerative potential. This review summarizes the biogenesis and molecular contents of exosomes and details the roles played by exosomes released from various cells in the progression and recovery of cardiovascular disease. The review also discusses the current status of traditional exosomes in cardiovascular tissue engineering and regenerative medicine, pointing out several limitations in their application. It emphasizes that some of the existing emerging industrial or bioengineering technologies are promising to compensate for these shortcomings, and the combined application of exosomes and biomaterials provides an opportunity for mutual enhancement of their performance. The integration of exosome-based cell-free diagnostic and therapeutic options will contribute to the further development of cardiovascular regenerative medicine.

Mussel-Derived and Bioclickable Peptide Mimic for Enhanced Interfacial Osseointegration via Synergistic Immunomodulation and Vascularized Bone Regeneration.

Inadequate osseointegration at the interface is a key factor in orthopedic implant failure. Mechanistically, traditional orthopedic implant interfaces fail to precisely match natural bone regeneration processes in vivo. In this study, a novel biomimetic coating on titanium substrates (DPA-Co/GFO) through a mussel adhesion-mediated ion coordination and molecular clicking strategy is engineered. In vivo and in vitro results confirm that the coating exhibits excellent biocompatibility and effectively promotes angiogenesis and osteogenesis. Crucially, the biomimetic coating targets the integrin α2ß1 receptor to promote M2 macrophage polarization and achieves a synergistic effect between immunomodulation and vascularized bone regeneration, thereby maximizing osseointegration at the interface. Mechanical push-out tests reveal that the pull-out strength in the DPA-Co/GFO group is markedly greater than that in the control group (79.04 ± 3.20 N vs 31.47 ± 1.87 N, P < 0.01) and even surpasses that in the sham group (79.04 ± 3.20 N vs 63.09 ± 8.52 N, P < 0.01). In summary, the novel biomimetic coating developed in this study precisely matches the natural process of bone regeneration in vivo, enhancing interface-related osseointegration and showing considerable potential for clinical translation and applications.

Regulation of bone homeostasis: signaling pathways and therapeutic targets.

As a highly dynamic tissue, bone is continuously rebuilt throughout life. Both bone formation by osteoblasts and bone resorption by osteoclasts constitute bone reconstruction homeostasis. The equilibrium of bone homeostasis is governed by many complicated signaling pathways that weave together to form an intricate network. These pathways coordinate the meticulous processes of bone formation and resorption, ensuring the structural integrity and dynamic vitality of the skeletal system. Dysregulation of the bone homeostatic regulatory signaling network contributes to the development and progression of many skeletal diseases. Significantly, imbalanced bone homeostasis further disrupts the signaling network and triggers a cascade reaction that exacerbates disease progression and engenders a deleterious cycle. Here, we summarize the influence of signaling pathways on bone homeostasis, elucidating the interplay and crosstalk among them. Additionally, we review the mechanisms underpinning bone homeostatic imbalances across diverse disease landscapes, highlighting current and prospective therapeutic targets and clinical drugs. We hope that this review will contribute to a holistic understanding of the signaling pathways and molecular mechanisms sustaining bone homeostasis, which are promising to contribute to further research on bone homeostasis and shed light on the development of targeted drugs.

Crosstalk between Lipid Metabolism and Bone Homeostasis: Exploring Intricate Signaling Relationships.

Bone is a dynamic tissue reshaped by constant bone formation and bone resorption to maintain its function. The skeletal system accounts for approximately 70% of the total volume of the body, and continuous bone remodeling requires quantities of energy and material consumption. Adipose tissue is the main energy storehouse of the body and has a strong adaptive capacity to participate in the regulation of various physiological processes. Considering that obesity and metabolic syndrome have become major public health challenges, while osteoporosis and osteoporotic fractures have become other major health problems in the aging population, it would be interesting to explore these 2 diseases together. Currently, an increasing number of researchers are focusing on the interactions between multiple tissue systems, i.e., multiple organs and tissues that are functionally coordinated together and pathologically pathologically interact with each other in the body. However, there is lack of detailed reviews summarizing the effects of lipid metabolism on bone homeostasis and the interactions between adipose tissue and bone tissue. This review provides a detailed summary of recent advances in understanding how lipid molecules and adipose-derived hormones affect bone homeostasis, how bone tissue, as a metabolic organ, affects lipid metabolism, and how lipid metabolism is regulated by bone-derived cytokines.

Arachidonic acid in aging: New roles for old players.

BACKGROUND: Arachidonic acid (AA), one of the most ubiquitous polyunsaturated fatty acids (PUFAs), provides fluidity to mammalian cell membranes. It is derived from linoleic acid (LA) and can be transformed into various bioactive metabolites, including prostaglandins (PGs), thromboxanes (TXs), lipoxins (LXs), hydroxy-eicosatetraenoic acids (HETEs), leukotrienes (LTs), and epoxyeicosatrienoic acids (EETs), by different pathways. All these processes are involved in AA metabolism. Currently, in the context of an increasingly visible aging world population, several scholars have revealed the essential role of AA metabolism in osteoporosis, chronic obstructive pulmonary disease, and many other aging diseases. AIM OF REVIEW: Although there are some reviews describing the role of AA in some specific diseases, there seems to be no or little information on the role of AA metabolism in aging tissues or organs. This review scrutinizes and highlights the role of AA metabolism in aging and provides a new idea for strategies for treating aging-related diseases. KEY SCIENTIFIC CONCEPTS OF REVIEW: As a member of lipid metabolism, AA metabolism regulates the important lipids that interfere with the aging in several ways. We present a comprehensivereviewofthe role ofAA metabolism in aging, with the aim of relieving the extreme suffering of families and the heavy economic burden on society caused by age-related diseases. We also collected and summarized data on anti-aging therapies associated with AA metabolism, with the expectation of identifying a novel and efficient way to protect against aging.

PP2Ac Regulates Autophagy via Mediating mTORC1 and ULK1 During Osteoclastogenesis in the Subchondral Bone of Osteoarthritis.

The molecular mechanism underlying abnormal osteoclastogenesis triggering subchondral bone remodeling in osteoarthritis (OA) is still unclear. Here, single-cell and bulk transcriptomics sequencing analyses are performed on GEO datasets to identify key molecules and validate them using knee joint tissues from OA patients and rat OA models. It is found that the catalytic subunit of protein phosphatase 2A (PP2Ac) is highly expressed during osteoclastogenesis in the early stage of OA and is correlated with autophagy. Knockdown or inhibition of PP2Ac weakened autophagy during osteoclastogenesis. Furthermore, the ULK1 expression of the downstream genes is significantly increased when PP2Ac is knocked down. PP2Ac-mediated autophagy is dependent on ULK1 phosphorylation activity during osteoclastogenesis, which is associated with enhanced dephosphorylation of ULK1 Ser637 residue regulating at the post-translational level. Additionally, mTORC1 inhibition facilitated the expression level of PP2Ac during osteoclastogenesis. In animal OA models, decreasing the expression of PP2Ac ameliorated early OA progression. The findings suggest that PP2Ac is also a promising therapeutic target in early OA.