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This study identifies senescent osteocytes in the femur and tibia of young rodents and explores their role in bone remodeling. The proximity of osteoclasts to senescent osteocytes was observed, which is a new finding. Cultured osteocytes, sorted using a podoplanin antibody in FACS, exhibited osteocytic characteristics and increased senescence‐related genes. Senescent osteocytes secreted cytokines associated with senescence, remodeling, and inflammation. Notably, IGF1 and MMP2 were elevated in podoplanin‐positive (pdpn+) osteocytes. Migration assays demonstrated significant osteoclast precursor migration towards senescent osteocytes, further confirmed by co‐culture experiments leading to osteoclast differentiation. These findings suggest that senescent osteocytes have a pivotal role in initiating bone resorption, with recruitment of osteoclast precursors during early bone remodeling stages. In conclusion, our research enhances our understanding of complicated bone remodeling mechanisms and bone homeostasis. [ABSTRACT FROM AUTHOR]

We fabricated a microfluidic chip (osteoblast [OB]–osteoclast [OC] chip) that could regulate the mixture amounts of OB and OC supernatants to investigate the effect of different supernatant distributions on osteogenesis or osteoclastogenesis. Computer-aided design was used to produce an OB–OC chip from polydimethylsiloxane. A pressure controller was assembled and different blends of OB and OC supernatants were correctly determined. OB and OC supernatants were placed on the upper panels of the OB–OC chip after differentiation for an in vitro evaluation. We then tested the changes in osteogenesis using MC3T3-E1 cells in the middle chambers. We observed that a 75:25 distribution of OB and OC supernatants was the most potent in osteogenesis. We then primed the osteogenic differentiation of MC3T3-E1 cells using an OB–OC mixed supernatant or an OB supernatant alone (supernatant ratios of 75:25 or 100:0, respectively). These cells were placed on the calvarial defect sites of rats. Microcomputed tomography and histological analyses determined a significantly higher bone formation in the group exposed to the OB–OC supernatant at a ratio of 75:25. In this study, we demonstrate the applicability of an OB–OC chip to evaluate the effect of different supernatant distributions of OB and OC. We observed that the highest bone-forming potential was in MC3T3-E1 cells treated with conditioned media, specifically the OB–OC supernatant at a ratio of 75:25. [ABSTRACT FROM AUTHOR]

The nuclear receptor subfamily 4 group A member 1 (NR4A1) gene plays a crucial role in both osteoporosis and adipogenesis. The present study investigated the mechanisms by which NR4A1 influences osteoblastogenesis and adipogenesis in human bone marrow-derived mesenchymal stem cells (BMD-MSCs). NR4A1 was overexpressed or knocked down in mouse MC3T3-E1 osteoblast cells and 3T3-L1 adipocyte cells, as well as in PCS-500-012, a BMD-MSC line. The alkaline phosphatase (ALP) assay and Alizarin Red S staining were performed using MC3T3-E1 and BMD-MSCs to assess ALP activity and mineralization, while Oil Red O staining was used to assess the lipid content in 3T3-L1 cells and BMD-MSCs. Total RNA was isolated from control, NR4A1-overexpressing and NR4A1 small interfering RNA (siRNA; siNR4A1)-treated BMD-MSCs. RNA sequencing (RNA-seq) was performed to identify differentially expressed genes, followed by ingenuity pathway analysis (IPA) to determine the role of NR4A1 in osteoblastogenesis and adipogenesis. NR4A1 or Nr4a1 knockdown tended to increase ALP activity and significantly increased calcification in BMD-MSCs (P<0.005) and MC3T3-E1 cells (P<0.005), respectively. By contrast, NR4A1 or Nr4a1 overexpression significantly decreased ALP activity and calcification. NR4A1 or Nr4a1 knockdown and overexpression significantly decreased and increased adipogenesis, respectively, in BMD-MSCs (P<0.005 and <0.05, respectively) and 3T3-L1 cells (P<0.005 in both). Treatments of BMD-MSCs with an NR4A1 antagonist, 1,1-bis(3′-indolyl)-1-(p-hydroxyphenyl) methane and siNR4A1 showed similar results. RNA-seq and IPA in control, NR4A1 knockdown and NR4A1 overexpressing cells indicated that Notch signaling mediated the effects of NR4A1 in osteoblastogenesis and adipogenesis. Expression of mastermind-like transcriptional coactivator 3 was reduced in the Notch signaling pathway in cells treated with siNR4A1. In conclusion, NR4A1 suppressed osteoblastogenesis and promotes adipogenesis in human BMD-MSCs. The present study also suggested that NR4A1 plays a role in the progression of osteoporosis and adipogenesis by modulating the Notch signaling cascade. [ABSTRACT FROM AUTHOR]

A critically tapered active accretionary wedge was simulated using a numerical analysis of plastic slip-line theory to understand the mechanics of morphologic evolution. The concept of critical state soil mechanics was applied to describe the entire wedge area overlying a basal décollement fault. Presuming a condition of two-dimensional plane strain along the compressional direction, we obtained the numerical solution of conjugate plastic slip lines at a critical state of stress defined by the Coulomb yield criterion. The velocity vectors were obtained by applying the associate flow rule with the boundary conditions at the upper surface of the wedge. Finally, the detachment was determined from the effective stress condition inside the wedge and the sliding friction coefficient along the fault. Our numerical simulations demonstrate that the morphology of a critically tapered wedge is dependent on the frictional strengths of both the wedge materials and the basal fault. The critical taper angle decreases with increasing internal friction angle and decreasing basal friction coefficient. The results also revealed that the pore pressure controls the morphology of the accretionary wedge for cohesive sediments but not for non-cohesive materials. The effect of pore pressure on the morphology of a critically tapered accretionary wedge becomes more significant as the cohesion increases. Assuming that the cohesion is very low, we could infer the ranges of strengths that most observed wedge geometry data have 0.3–0.6 for the basal friction coefficient and ~35–45° for the internal friction angle of the wedge materials. [ABSTRACT FROM AUTHOR]