standardized-instability-induced-animal-models-for-preclinical

Standardized Instability-induced Animal Models for Preclinical Studies of Osteoarthritis

As the most prevalent joint disorder worldwide, knee osteoarthritis (OA) represents a significant global health burden, prompting extensive research into ...

Zhejiang University School of Medicine

Orthopedics Research Institute of Zhejiang University

Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province

Clinical Research Center of Motor System Disease of Zhejiang Province

Lignin, the most abundant natural and sustainable phenolic compound in biomass, has exhibited medicinal values due to its biological activities decided by physicochemical properties. Recently, the lignin and its derivatives (such as lignosulfonates and lignosulfonate) have been proven efficient in regulating cellular process and the extracellular microenvironment, which has been regarded as the key factor in disease progression. In orthopaedic diseases, especially the degenerative diseases represented by osteoarthritis and osteoporosis, excessive activated inflammation has been proven as a key stage in the pathological process. Due to the excellent biocompatibility, antibacterial and antioxidative activities of lignin and its derivatives, they have been applied to stimulate cells and restore the uncoupling bone remodeling in the degenerative orthopaedic diseases. However, there is a lack of a systemic review to state the current research actuality of lignin and lignin-derived compounds in treating degenerative orthopaedic diseases. Herein, we summarized the current application of lignin and lignin-derived compounds in orthopaedic diseases and proposed their possible therapeutic mechanism in treating degenerative orthopaedic diseases. It is hoped this work could guide the future preparation of lignin/lignin-derived drugs and implants as available therapeutic strategies for clinically degenerative orthopaedic diseases.

Sustainable lignin and lignin-derived compounds as potential therapeutic agents for degenerative orthopaedic diseases: A systemic review.

Invasion and metastasis are the leading causes of death of patients with CRC. 5-Fluorouracil is widely used in clinic practice as the basic chemotherapy drug for CRC. However, it is inefficient in inhibiting tumor metastasis. MicroRNA-10b is uninvolved in regulating the growth of primary tumors; however, it could induce early tumor metastases and is a key regulator of chemotherapeutic resistance to 5-FU. A multifunctional nanovehicle that can carry small molecule drugs not only through the hydrophobic pockets of conjugated β-cyclodextrin but also through electrostatic interaction between the conjugated peptides and siRNA to target functional genes is previously developed. In this study, a nanovehicle, named GCD, with epithelium growth factor receptor (EGFR)-targeted characteristics to simultaneously deliver chemotherapeutic and nucleotide drugs to distinct targets in CRC, is employed. These data show that co-delivery of 5-FU and anti-miR-10b can be effectively applied to targeted therapy of EGFR-overexpressed CRC, particularly inhibiting the metastasis of CRC. Furthermore, the therapeutic effect of this combination on tumor xenograft models derived from patients with CRC is evaluated. Taken together, this study may provide insights into the inhibition of tumor growth and metastasis simultaneously.

Enhancing the Management of Metastatic Tumors by Robust Co-Delivery of 5-Fluorouracil/MicroRNA-10b Inhibitor Using EGFR-Targeted Nanovehicles.

The emerging therapeutic strategies for osteoarthritis (OA) are shifting toward comprehensive approaches that target periarticular tissues, involving both cartilage and subchondral bone. This shift drives the development of single-component therapeutics capable of acting on multiple tissues and cells. Magnesium, an element essential for maintaining skeletal health, shows promise in treating OA. However, the precise effects of magnesium on cartilage and subchondral bone are not yet clear. Here, we investigated the therapeutic effect of Mg on OA, unveiling its protective effects on both cartilage and bone at the cellular and animal levels. The beneficial effect on the cartilage-bone interaction is primarily mediated by the PI3K/AKT pathway. In addition, we developed poly(lactic--glycolic acid) (PLGA) microspheres loaded with nano-magnesium oxide modified with stearic acid (SA), MgO&SA@PLGA, for intra-articular injection. These microspheres demonstrated remarkable efficacy in alleviating OA in rat models, highlighting their translational potential in clinical applications.

Engineered MgO nanoparticles for cartilage-bone synergistic therapy.

Cellulose, hemicellulose, and lignin are the major bio-components in lignocellulosic biomass (BC-LB), which possess excellent biomechanical properties and biocompatibility to satisfy the demands of orthopedic applications. To understand the basis and trends in the development of major bio-components in BC-LB in orthopedics, the bibliometric technology was applied to get unique insights based on the published papers (741) in the Web of Science (WOS) database from January 1st, 2001, to February 14th, 2023. The analysis includes the annual distributions of publications, keywords co-linearity, research hotspots exploration, author collaboration networks, published journals, and clustering of co-cited literature. The results reveal a steady growth in publications focusing on the application of BC-LB in orthopedics, with China and the United States leading in research output. The "International Journal of Biological Macromolecules" was identified as the most cited journal for BC-LB research in orthopedics. The research hotspots encompassed bone tissue engineering, cartilage tissue engineering, and drug delivery systems, indicating the fundamental research and potential development in these areas. This study also highlights the challenges associated with the clinical application of BC-LB in orthopedics and provides valuable insights for future advancements in the field.

Research trends of bio-application of major components in lignocellulosic biomass (cellulose, hemicellulose and lignin) in orthopedics fields based on the bibliometric analysis: A review.

The process of skeletal regeneration initiated by stem cells following injury, especially in fractures, is significantly impaired by aging and adverse factors. Nicotinamide mononucleotide (NMN), a critical endogenous precursor of nicotinamide adenine dinucleotide (NAD), has garnered extensive attention for its multifaceted regulatory functions in living organisms and its wide-ranging therapeutic potential. However, whether NMN contributes to trauma-induced skeletal regeneration remains unclear. : The transverse femoral shaft fracture model was employed to evaluate the potential advantages of NMN administration for overall repair during the initial fracture stages in male mice through micro-CT analysis, histochemistry, and biomechanical testing. The pro-proliferative function of NMN on skeletal stem cells (SSCs) was investigated through flow cytometry, qRT-PCR, NAD content measurement, and cell proliferation assay. : In this study, we observed that the administration of NMN during the initial phase of fracture in mice led to a larger callus and corresponding improvement in micro-CT parameters. NMN enhances the cartilaginous component of the callus by elevating the NAD content, consequently accelerating subsequent endochondral ossification and the fracture healing process. Subsequent analyses elucidated that NMN was beneficial in promoting the expansion of diverse stem cells  and  potentially via modulation of the Notch signaling pathway. Moreover, the depletion of macrophages profoundly obstructs the proliferation of SSCs. : Our discoveries provide a potential strategy for enhancing fracture healing through stimulation of callus SSC proliferation at an early stage, shedding light on the translational value of NMN as an enhancer for skeletal regeneration and highlighting the pivotal role of macrophage-stem cell interactions in governing the regenerative influence of NMN on stem cells.

Nicotinamide mononucleotide enhances fracture healing by promoting skeletal stem cell proliferation.

The rotator cuff tear (RCT) repairing of tendon-to-bone junction (enthese) after surgery in osteoporotic patients is mainly hindered by poor bone formation at the damaged humeral tuberosity region. We found that long-term oral supplementation of Magnesium ions (Mg) can significantly promote humeral tuberosity bone formation and enthese regeneration after RCT surgery in ovariectomized (OVX) rats, attributing to the promotive effect of Mg on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and its inhibition of new bone mineralization. Meanwhile, the in vitro replicative senescent markers of BMSCs are significantly relieved by Mg. The BMSCs' RNA-seq data analysis and cell energy metabolism results indicate that Mg significantly increase senescent BMSCs' mitochondrial transmembrane potential and intracellular ATP content, and reduce reactive oxygen species production.

Article	Year
Sustainable lignin and lignin-derived compounds as potential therapeutic agents for degenerative orthopaedic diseases: A systemic review. International journal of biological macromolecules\| PubMed ID: 35643155	2022
Enhancing the Management of Metastatic Tumors by Robust Co-Delivery of 5-Fluorouracil/MicroRNA-10b Inhibitor Using EGFR-Targeted Nanovehicles. Advanced healthcare materials\| PubMed ID: 36740892	2023
Engineered MgO nanoparticles for cartilage-bone synergistic therapy. Science advances\| PubMed ID: 38457498	2024
Research trends of bio-application of major components in lignocellulosic biomass (cellulose, hemicellulose and lignin) in orthopedics fields based on the bibliometric analysis: A review. International journal of biological macromolecules\| PubMed ID: 38631574	2024
Nicotinamide mononucleotide enhances fracture healing by promoting skeletal stem cell proliferation. Theranostics\| PubMed ID: 39346542	2024
Magnesium promoting OVX rats' rotator cuff tear repair with relieving stem cell senescence effect. Experimental cell research\| PubMed ID: 40348155	2025

Liming Zheng

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