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Mechanotransduction is a fundamental ability that allows living organisms to receive and respond to physical signals from both the external and internal environments. The mechanotransduction process requires a range of special proteins termed mechanotransducers to convert mechanical forces into biochemical signals in cells. The Piezo proteins are mechanically activated nonselective cation channels and the largest plasma membrane ion channels reported thus far. The regulation of two family members, Piezo1 and Piezo2, has been reported to have essential functions in mechanosensation and transduction in different organs and tissues. Recently, the predominant contributions of the Piezo family were reported to occur in the skeletal system, especially in bone development and mechano-stimulated bone homeostasis. Here we review current studies focused on the tissue-specific functions of Piezo1 and Piezo2 in various backgrounds with special highlights on their importance in regulating skeletal cell mechanotransduction. In this review, we emphasize the diverse functions of Piezo1 and Piezo2 and related signaling pathways in osteoblast lineage cells and chondrocytes. We also summarize our current understanding of Piezo channel structures and the key findings about PIEZO gene mutations in human diseases.

Osteoarthritis (OA) is a chronic degenerative joint disorder that leads to disability and affects more than 500 million population worldwide. OA was believed to be caused by the wearing and tearing of articular cartilage, but it is now more commonly referred to as a chronic whole-joint disorder that is initiated with biochemical and cellular alterations in the synovial joint tissues, which leads to the histological and structural changes of the joint and ends up with the whole tissue dysfunction. Currently, there is no cure for OA, partly due to a lack of comprehensive understanding of the pathological mechanism of the initiation and progression of the disease. Therefore, a better understanding of pathological signaling pathways and key molecules involved in OA pathogenesis is crucial for therapeutic target design and drug development. In this review, we first summarize the epidemiology of OA, including its prevalence, incidence and burdens, and OA risk factors. We then focus on the roles and regulation of the pathological signaling pathways, such as Wnt/β-catenin, NF-κB, focal adhesion, HIFs, TGFβ/ΒΜP and FGF signaling pathways, and key regulators AMPK, mTOR, and RUNX2 in the onset and development of OA. In addition, the roles of factors associated with OA, including MMPs, ADAMTS/ADAMs, and PRG4, are discussed in detail. Finally, we provide updates on the current clinical therapies and clinical trials of biological treatments and drugs for OA. Research advances in basic knowledge of articular cartilage biology and OA pathogenesis will have a significant impact and translational value in developing OA therapeutic strategies.

Mesenchymal stem cells (MSCs) have emerged as a highly promising strategy in regenerative medicine due to their self-renewal, pluripotency and immunomodulatory properties. MSCs are nonhematopoietic, multipotent stem cells that can differentiate into various mesodermal lineages and modulate the immune system. The therapeutic potential of MSCs from different tissues has been widely explored in preclinical models and clinical trials for human diseases, ranging from autoimmune diseases and inflammatory disorders to neurodegenerative diseases and orthopedic injuries. The therapeutic effects of MSCs can be mediated through the release of bioactive molecules, including growth factors, cytokines, and extracellular vesicles, which play crucial roles in modulating the local cellular environment, promoting tissue repair, angiogenesis, and cell survival, and exerting anti-inflammatory effects. MSCs can also interact with various immune cells, such as T cells, B cells, dendritic cells, and macrophages, modulating the immune response through both direct cell‒cell interactions and the release of immunoregulatory molecules. This review delves into the molecular mechanisms, signaling pathways, and regulatory factors that underpin the therapeutic effects of MSCs. This review also highlights the clinical applications and challenges associated with the use of MSC-based drugs to promote the safety and efficacy of MSC-based therapies. Overall, this comprehensive review provides valuable insights into the current state of MSC research and its potential for transforming the field of regenerative medicine as well as immune-mediated inflammatory diseases.

Bone has long been acknowledged as a fundamental structural entity that provides support and protection to the body's organs. However, emerging research indicates that bone plays a crucial role in the regulation of systemic metabolism. This is achieved through the secretion of a variety of hormones, cytokines, metal ions, extracellular vesicles, and other proteins/peptides, collectively referred to as bone-derived factors (BDFs). BDFs act as a medium through which bones can exert targeted regulatory functions upon various organs, thereby underscoring the profound and concrete implications of bone in human physiology. Nevertheless, there remains a pressing need for further investigations to elucidate the underlying mechanisms that inform the effects of bone on other body systems. This review aims to summarize the current findings related to the roles of these significant modulators across different organs and metabolic contexts by regulating critical genes and signaling pathways in vivo. It also addresses their involvement in the pathogenesis of various diseases affecting the musculoskeletal system, circulatory system, glucose and lipid metabolism, central nervous system, urinary system, and reproductive system. The insights gained from this review may contribute to the development of innovative therapeutic strategies through a focused approach to bone secretomes. Continued research into BDFs is expected to enhance our understanding of bone as a multifunctional organ with diverse regulatory roles in human health.

Protein-encoding genes only constitute less than 2% of total human genomic sequences, and 98% of genetic information was previously referred to as “junk DNA”. Meanwhile, non-coding RNAs (ncRNAs) consist of approximately 60% of the transcriptional output of human cells. Thousands of ncRNAs have been identified in recent decades, and their essential roles in the regulation of gene expression in diverse cellular pathways associated with fundamental cell processes, including proliferation, differentiation, apoptosis, and metabolism, have been extensively investigated. Furthermore, the gene regulation networks they form modulate gene expression in normal development and under pathological conditions. In this review, we integrate current information about the classification, biogenesis, and function of ncRNAs and how these ncRNAs support skeletal development through their regulation of critical genes and signaling pathways in vivo. We also summarize the updated knowledge of ncRNAs involved in common skeletal diseases and disorders, including but not limited to osteoporosis, osteoarthritis, rheumatoid arthritis, scoliosis, and intervertebral disc degeneration, by highlighting their roles established from in vivo, in vitro, and ex vivo studies.

The features of the asynchronous correlation between accident indices and the factors that influence accidents can provide an effective reference for warnings of coal mining accidents. However, what are the features of this correlation? To answer this question, data from the China coal price index and the number of deaths from coal mining accidents were selected as the sample data. The fluctuation modes of the asynchronous correlation between the two data sets were defined according to the asynchronous correlation coefficients, symbolization, and sliding windows. We then built several directed and weighted network models, within which the fluctuation modes and the transformations between modes were represented by nodes and edges. Then, the features of the asynchronous correlation between these two variables could be studied from a perspective of network topology. We found that the correlation between the price index and the accidental deaths was asynchronous and fluctuating. Certain aspects, such as the key fluctuation modes, the subgroups characteristics, the transmission medium, the periodicity and transmission path length in the network, were analyzed by using complex network theory, analytical methods and spectral analysis method. These results provide a scientific reference for generating warnings for coal mining accidents based on economic indices.

The mechanosensitive Piezo1 channel protein plays a pivotal role in promoting bone formation and repair; however, its underlying molecular mechanism(s) are poorly defined. Here this study shows that Sirt1 positively regulates Piezo1 expression and activity to promote osteogenesis and bone repair in mice. This study finds that Piezo1 is up‐regulated in the cartilage callus during bone repair. Deleting Piezo1 in chondrocytes largely impairs endochondral ossification and mechanically induced osteogenesis and delays fracture healing in mice, while Yoda1 activation of Piezo1 exerts opposite effects. Sirt1 overexpression or activation dramatically increases Piezo1 protein expression in a dose‐dependent manner. Sirt1 binds to Piezo1 protein and deacetylates and activates Piezo1 and Ca2+ influx in chondrocytes. Piezo1 loss in chondrocytes abolishes the ability of Sirt1 activator SRT2104 to accelerate bone repair. Resveratrol (RSV), a natural Sirt1 activator, also potently activates Piezo1 and enhances bone repair. A yeast microcapsule‐based oral formulation of RSV (YC‐RSV) is developed to improve drug bioavailability and therapeutic efficacy, which highly and selectively targets to the inflammatory fracture site. Thus, it demonstrates that Sirt1 is a novel and potent activator of Piezo1 to promote bone formation and repair, supporting the potential clinical application of Sirt1 activators in promoting bone formation and repair. Piezo1 upregulates in cartilage callus during bone repair, where its deletion impairs ossification and healing in mice, while activation enhances these processes. Sirt1 positively regulates Piezo1 expression and activity to promote osteogenesis and bone repair in mice. Resveratrol potently activates Piezo1, and a novel yeast microcapsule formulation targets fractures, advancing Sirt1 activators for clinical bone repair.

BackgroundMesenchymal stromal/stem cells (MSCs) are multipotent cells that can differentiate into multiple cell types. MSCs display various beneficial properties against infectious and immune diseases and disorders, driven by their paracrine effects through trophic factors; however, their mechanism(s) remain incompletely defined. Focal adhesions (FAs) are a vital mechanical linkage that connects the extracellular matrix and cytoskeleton, allowing for crucial cell-environment communication. Recent studies have highlighted the essential roles of FA proteins in inflammatory-related illnesses. Hence, this study aims to elucidate the potential roles of Pinch, one of FA proteins, in the bone marrow stromal cells (BMSCs).MethodsWe generated Pinch1/2 double knockout transgenic mice and collected their bone marrow cells for single-cell RNA-sequencing combined with 4D proteomics analysis. The results were validated through various in vitro and in vivo experiments. Additionally, we conducted two mouse disease models to enhance the translational significance.ResultsBMSCs lacking Pinch1/2 display a dramatically reduced ability to suppress lipopolysaccharide (LPS)-induced acute lung injury and dextran sulfate sodium (DSS)-induced inflammatory bowel disease in mice (IDDF2024-ABS-0142 Figure 1). Prx1-Cre; Pinch1f/f; Pinch2−/− transgenic mice severely reduced chondrocyte proliferation, leading to dwarfism and severe osteopenia (IDDF2024-ABS-0142 Figure 2). Moreover, they have severe defects in both immune and hematopoietic functions, resulting in premature death (IDDF2024-ABS-0142 Figure 3), which can be restored by intravenous injection of wild-type BMSCs (IDDF2024-ABS-0142 Figure 4). Single-cell sequencing analyses reveal dramatic alterations in subpopulations of the BMSCs in Pinch mutant mice (IDDF2024-ABS-0142 Figure 2). We find that Pinch is critical for the expression of Cxcl12 in BMSCs; reduced production of Cxcl12 protein from Pinch-deficient BMSCs reduces expression of the Mbl2 complement in hepatocytes, thus impairing the innate immunity and thereby contributing to infection and death (IDDF2024-ABS-0142 Figure 5). Administration of recombinant Mbl2 protein restores the lethality induced by Pinch loss in mice (IDDF2024-ABS-0142 Figure 5).Abstract IDDF2024-ABS-0142 Figure 1Abstract IDDF2024-ABS-0142 Figure 2Abstract IDDF2024-ABS-0142 Figure 3Abstract IDDF2024-ABS-0142 Figure 4Abstract IDDF2024-ABS-0142 Figure 5ConclusionsWe demonstrate that the novel Pinch-Cxcl12-Mbl2 signaling pathway promotes the interactions between bone and liver to modulate immunity and hematopoiesis. It provides valuable insights for the improved utilization of BMSCs to mitigate the occurrence of infectious and immune-mediated disorders.

Degenerative disc disease (DDD) represents a significant global health challenge, yet its underlying molecular mechanisms remain elusive. This study aimed to investigate the role of type 1 phosphatidylinositol 4‐phosphate 5‐kinase (Pip5k1) in intervertebral disc (IVD) homeostasis and disease. All three Pip5k1 isoforms, namely Pip5k1α, Pip5k1β, and Pip5k1γ, were detectable in mouse and human IVD tissues, with Pip5k1γ displaying a highest expression in nucleus pulposus (NP) cells. The expression of Pip5k1γ was significantly down‐regulated in the NP cells of aged mice and patients with severe DDD. To determine whether Pip5k1γ expression is required for disc homeostasis, we generated a Pip5k1γfl/fl; AggrecanCreERT2 mouse model for the conditional knockout of the Pip5k1γ gene in aggrecan‐expressing IVD cells. Our findings revealed that the conditional deletion of Pip5k1γ did not affect the disc structure or cellular composition in 5‐month‐old adult mice. However, in aged (15‐month‐old) mice, this deletion led to several severe degenerative disc defects, including decreased NP cellularity, spontaneous fibrosis and cleft formation, and a loss of the boundary between NP and annulus fibrosus. At the molecular level, the absence of Pip5k1γ reduced the anabolism of NP cells without markedly affecting their catabolic or anti‐catabolic activities. Moreover, the loss of Pip5k1γ significantly dampened the activation of the protective Ampk pathway in NP cells, thereby accelerating NP cell senescence. Notably, Pip5k1γ deficiency blunted the effectiveness of metformin, a potent Ampk activator, in activating the Ampk pathway and mitigating lumbar spine instability (LSI)‐induced disc lesions in mice. Overall, our study unveils a novel role for Pip5k1γ in promoting anabolism and maintaining disc homeostasis, suggesting it as a potential therapeutic target for DDD. This study identifies the lipid kinase Pip5k1γ as a crucial factor for maintaining intervertebral disc homeostasis, revealing its significant down‐regulation in aged and severely degenerated discs. Conditional deletion of Pip5k1γ in mice leads to advanced disc degeneration, underscoring its importance in extracellular matrix anabolism and the activation of the Ampk pathway. These findings suggest Pip5k1γ as a potential therapeutic target for degenerative disc disease.

Mesenchymal stromal cells (MSCs) are used to treat infectious and immune diseases and disorders; however, its mechanism(s) remain incompletely defined. Here we find that bone marrow stromal cells (BMSCs) lacking Pinch1/2 proteins display dramatically reduced ability to suppress lipopolysaccharide (LPS)-induced acute lung injury and dextran sulfate sodium (DSS)-induced inflammatory bowel disease in mice. Prx1-Cre; Pinch1 f/f ; Pinch2 −/− transgenic mice have severe defects in both immune and hematopoietic functions, resulting in premature death, which can be restored by intravenous injection of wild-type BMSCs. Single cell sequencing analyses reveal dramatic alterations in subpopulations of the BMSCs in Pinch mutant mice. Pinch loss in Prx1 + cells blocks differentiation and maturation of hematopoietic cells in the bone marrow and increases production of pro-inflammatory cytokines TNF-α and IL-1β in monocytes. We find that Pinch is critical for expression of Cxcl12 in BMSCs; reduced production of Cxcl12 protein from Pinch-deficient BMSCs reduces expression of the Mbl2 complement in hepatocytes, thus impairing the innate immunity and thereby contributing to infection and death. Administration of recombinant Mbl2 protein restores the lethality induced by Pinch loss in mice. Collectively, we demonstrate that the novel Pinch-Cxcl12-Mbl2 signaling pathway promotes the interactions between bone and liver to modulate immunity and hematopoiesis and may provide a useful therapeutic target for immune and infectious diseases.