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Elevated bone resorption and diminished bone formation have been recognized as the primary features of glucocorticoid-associated skeletal disorders. However, the direct effects of excess glucocorticoids on bone turnover remain unclear. Here, we explored the outcomes of exogenous glucocorticoid treatment on bone loss and delayed fracture healing in mice and found that reduced bone turnover was a dominant feature, resulting in a net loss of bone mass. The primary effect of glucocorticoids on osteogenic differentiation was not inhibitory; instead, they cooperated with macrophages to facilitate osteogenesis. Impaired local nutrient status--notably, obstructed fatty acid transportation--was a key factor contributing to glucocorticoid-induced impairment of bone turnover in vivo. Furthermore, fatty acid oxidation in macrophages fueled the ability of glucocorticoid-liganded receptors to enter the nucleus and then promoted the expression of BMP2, a key cytokine that facilitates osteogenesis. Metabolic reprogramming by localized fatty acid delivery partly rescued glucocorticoid-induced pathology by restoring a healthier immune-metabolic milieu. These data provide insights into the multifactorial metabolic mechanisms by which glucocorticoids generate skeletal disorders, thus suggesting possible therapeutic avenues., Introduction Synthetic glucocorticoids (GCs), acting as antiinflammatory and immunomodulatory agents, are the mainstays in the treatment of immune-related disorders (e.g., rheumatoid arthritis and Graves' disease). GCs are also prescribed to [...]

Bioceramics provide promising tactics for wound healing, yet the on‐shelf products are still unmet, especially for skin appendages regeneration. Herein, the inorganic magnesium silicate sprays (MSS) as mineral factors to overcome the existing challenges is proposed. Results indicate MSS can be synthesized by a green method without organic solvents, templates, calcination, and harmful by‐products. With amorphous phase, nanoscale, and high specific surface area, MSS reveal an improved pH‐responsive degradability and excellent bioactivity for cell proliferation and migration. In rats, MSS display a dose‐dependent effect on accelerating burn‐wound repair via regulating the expressions of iNOS and IL‐10 to attenuate inflammation, elevating the expressions of CD31 and α‐SMA to improve vascularization, and boosting collagen deposition without ectopic calcification. The released Mg and Si ions synergistically potentiate the expressions of Gap43, Tubb3, and K19, suggesting the regeneration of peripheral nerves and hair follicles. These superior features are further verified by comparisons with commercial products, Dermlin® and 45S5 bioglass®, in both rats and minipigs. Motivated by these findings, three MSS‐based formulations of band‐aid patch, adhesive hydrogel, and antibacterial sprays are devised for specific scenarios. Taken together, this proof‐of concept study provides a promising bioactive mineral for future clinical skin wound repair and functional appendages regeneration. [ABSTRACT FROM AUTHOR]

The knowledge of osteoarthritis (OA) has nowadays been extended from a focalized cartilage disorder to a multifactorial disease. Although recent investigations have reported that infrapatellar fat pad (IPFP) can trigger inflammation in the knee joint, the mechanisms behind the role of IPFP on knee OA progression remain to be defined. Here, dysregulated osteopontin (OPN) and integrin β3 signaling are found in the OA specimens of both human and mice. It is further demonstrated that IPFP‐derived OPN participates in OA progression, including activated matrix metallopeptidase 9 in chondrocyte hypertrophy and integrin β3 in IPFP fibrosis. Motivated by these findings, an injectable nanogel is fabricated to provide sustained release of siRNA Cd61 (RGD−Nanogel/siRNA Cd61) that targets integrins. The RGD−Nanogel possesses excellent biocompatibility and desired targeting abilities both in vitro and in vivo. Local injection of RGD−Nanogel/siRNA Cd61 robustly alleviates the cartilage degeneration, suppresses the advancement of tidemark, and reduces the subchondral trabecular bone mass in OA mice. Taken together, this study provides an avenue for developing RGD−Nanogel/siRNA Cd61 therapy to mitigate OA progression via blocking OPN‐integrin β3 signaling in IPFP. [ABSTRACT FROM AUTHOR]

Objectives: Wnt16 is implicated in bone fracture and bone mass accrual both in animals and humans. However, its functional roles and molecular mechanism in chondrocyte differentiation and osteoarthritis (OA) pathophysiology remain largely undefined. In this study, we analysed its mechanistic association and functional relationship in OA progression in chondrocyte lineage.Methods: The role of Wnt16 during skeletal development was examined by Col2a1-Wnt16 transgenic mice and Wnt16fl/fl;Col2a1-Cre (Wnt16-cKO) mice. OA progression was assessed by micro-CT analysis and Osteoarthritis Research Society International score after anterior cruciate ligament transection (ACLT) surgery with Wnt16 manipulation by adenovirus intra-articular injection. The molecular mechanism was investigated in vitro using 3D chondrocyte pellet culture and biochemical analyses. Histological analysis was performed in mouse joints and human cartilage specimens.Results: Wnt16 overexpression in chondrocytes in mice significantly inhibited chondrocyte hypertrophy during skeletal development. Wnt16 deficiency exaggerated OA progression, whereas intra-articular injection of Ad-Wnt16 markedly attenuated ACLT-induced OA. Cellular and molecular analyses showed that, instead of β-catenin and calcium pathways, Wnt16 activated the planar cell polarity (PCP) and JNK pathway by interacting mainly with AP2b1, and to a lesser extend Ror2 and CD146, and subsequently induced PTHrP expression through phosphor-Raptor mTORC1 pathway.Conclusions: Our findings indicate that Wnt16 activates PCP/JNK and crosstalks with mTORC1-PTHrP pathway to inhibit chondrocyte hypertrophy. Our preclinical study suggests that Wnt16 may be a potential therapeutic target for OA treatment. [ABSTRACT FROM AUTHOR]

The momentum variables of streamfunction and velocity potential are used as control variables in a number of operational variational data assimilation systems. However, in this study it is shown that, for limited-area high-resolution data assimilation, the momentum control variables ψ and χ ( ψχ) pose potential difficulties in background error modeling and, hence, may result in degraded analysis and forecast when compared with the direct use of x and y components of wind ( UV). In this study, the characteristics of the modeled background error statistics, derived from an ensemble generated from Weather Research and Forecasting (WRF) Model real-time forecasts of two summer months, are first compared between the two control variable options. Assimilation and forecast experiments are then conducted with both options for seven convective events in a domain that encompasses the Rocky Mountain Front Range using the three-dimensional variational data assimilation (3DVar) system of the WRF Model. The impacts of the two control variable options are compared in terms of their skills in short-term qualitative precipitation forecasts. Further analysis is performed for one case to examine the impacts when radar observations are included in the 3DVar assimilation. The main findings are as follows: 1) the background error modeling used in WRF 3DVar with the control variables ψχ increases the length scale and decreases the variance for u and υ, which causes negative impact on the analysis of the velocity field and on precipitation prediction; 2) the UV-based 3DVar allows closer fits to radar wind observations; and 3) the use of UV control variables improves the 0-12-h precipitation prediction. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a highly prevalent and debilitating joint disorder characterized by the degeneration of articular cartilage. However, no effective medical therapy has been found yet for such condition. In this study, we directly confirmed the existence of articular cartilage stem cells (ACSCs) in vivo and in situ for the first time both in normal and OA articular cartilage, and explored their chondrogenesis in Interleukin-1β (IL-1β) induced inflammation environment and disclose whether the inhibition of NF-κB signaling can induce ACSCs activation thus improve the progression of experimental OA. We found an interesting phenomenon that ACSCs were activated and exhibited a transient proliferative response in early OA as an initial attempt for self-repair. During the in vitro mechanism study, we discovered IL-1β can efficiently activate the NF-κB pathway and potently impair the responsiveness of ACSCs, whereas the NF-κB pathway inhibitor rescued the ACSCs chondrogenesis. The final in vivo experiments further confirmed ACSCs' activation were maintained by NF-κB pathway inhibitor, which induced cartilage regeneration, and protected articular cartilage from injury in an OA animal model. Our results provided in vivo evidence of the presence of ACSCs, and disclosed their action in the early OA stage and gradual quiet as OA process, presented a potential mechanism for both cartilage intrinsic repair and its final degradation, and demonstrated the feasibility of inducing endogenous adult tissue-specific mesenchymal stem cells for articular cartilage repair and OA therapy. S tem C ells 2015;33:3125-3137 [ABSTRACT FROM AUTHOR]

The healing of bone defects after debridement in medication-related osteonecrosis of the jaw (MRONJ) is a challenging medical condition with impaired angiogenesis, susceptible infection, and pro-inflammatory responses. Magnesium (Mg) nanocomposite hydrogel is developed to specifically tackle multiple factors involved in MRONJ. Mg-oxide nanoparticles tune the gelation kinetics in the reaction between N-hydroxysuccinimide-functionalized hyperbranched poly (ethylene glycol) and proteins. This reaction allows an enhanced mechanical property after instant solidification and, more importantly, also stable gelation in challenging environments such as wet and hemorrhagic conditions. The synthesized hydrogel guides mandible regeneration in MRONJ rats by triggering the formation of type H vessels, activating Osterix+ osteoprogenitor cells, and generating anti-inflammatory microenvironments. Additionally, this approach demonstrates its ability to suppress infection by inhibiting specific pathogens while strengthening stress tolerance in the affected alveolar bone. Furthermore, the enhanced osteogenic properties and feasibility of implantation of the hydrogel are validated in mandible defect and iliac crest defect created in minipigs, respectively. Collectively, this study offers an injectable and innovative bone substitute to enhance mandible defect healing by tackling multiple detrimental pathologies., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

Osteosarcoma (OS) is the most commonly occurring primary bone malignant tumor. The clinical postsurgical OS treatment faces big challenges for the staged therapeutic requirements of early anti-tumor, anti-bacterial, and long-lasting osteogenesis. Herein, multi-functional bioactive scaffolds with time-sequential functions of preventing tumor recurrence, inhibiting bacterial infection, and promoting bone defect repair are designed as a novel strategy. Nanocomposite scaffold magnesium peroxide (MgO 2 )/poly (lactide-co-glycolide) is prepared by low-temperature 3D printing for controllable releasing magnesium ions (Mg 2+ ) and reactive oxygen species in a time-sequential manner. The scaffold with 20 wt% MgO 2 (20MP) is verified with desired mechanical properties, as well as exhibits staged release behavior of bioactive elements with hydrogen peroxide (H 2 O 2 ) release for the first 3 weeks, and long-lasting Mg 2+ release for 12 weeks. The released H 2 O 2 initiates chemodynamic therapy to induce apoptosis and ferroptosis in tumor cells, along with activating the anticancer immune microenvironment by M1 polarization of macrophages. The released Mg 2+ subsequently enhances bone repair by activating the Wnt3a/GSK-3β/β-catenin signaling pathway to promote osteogenic differentiation of bone marrow mesenchymal stem cells and create osteopromotive immune microenvironment by M2 polarization of macrophages. In conclusion, the multi-functional 20MP scaffold demonstrates time-sequential therapeutic properties as an innovative strategy for OS-associated bone defect treatment., (© 2023 Wiley‐VCH GmbH.)