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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]

With mechanical strength close to cortical bone, biodegradable and osteopromotive properties, magnesium (Mg)-based implants are promising biomaterials for orthopedic applications. However, during the degradation of such implants, there are still concerns on the potential adverse effects such as formation of cavities, osteolytic phenomena and chronic inflammation. Therefore, to transform Mg-based implants into clinical practice, the present study evaluated the local effects of high-purity Mg screws (HP-Mg, 99.99 wt%) by comparing with clinically approved polylactic acid (PLA) screws in epiphyseal trabecular bone of rabbits. After implantation of screws at the rabbit distal femur, bone microstructural, histomorphometric and biomechanical properties were measured at various time points (weeks 4, 8 and 16) using micro-CT, histology and histomorphometry, micro-indentation and scanning electron microscope. HP-Mg screws promoted peri-implant bone ingrowth with higher bone mass (BV/TV at week 4: 0.189 ± 0.022 in PLA group versus 0.313 ± 0.053 in Mg group), higher biomechanical properties (hardness at week 4: 35.045 ± 1.000 HV in PLA group versus 51.975 ± 2.565 HV in Mg group), more mature osteocyte LCN architecture, accelerated bone remodeling process and alleviated immunoreactive score (IRS of Ram11 at week 4: 5.8 ± 0.712 in PLA group versus 3.75 ± 0.866 in Mg group) as compared to PLA screws. Furthermore, we conducted finite element analysis to validate the superiority of HP-Mg screws as orthopedic implants by demonstrating reduced stress concentration and uniform stress distribution around the bone tunnel, which led to lower risks of trabecular microfractures. In conclusion, HP-Mg screws demonstrated greater osteogenic bioactivity and limited inflammatory response compared to PLA screws in the epiphyseal trabecular bone of rabbits. Our findings have paved a promising way for the clinical application of Mg-based implants. [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]

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.)