香豆素在肌肉骨骼健康中的作用：一项系统评价。

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【Abstract】 Musculoskeletal diseases encompass a spectrum of pathologies such as osteoporosis, rheumatoid arthritis, osteoarthritis, and osteosarcoma, characterized by degenerative alterations and aberrant hyperplasia in bone mass, synovial tissue, and cartilage. Recently, botanical compounds have demonstrated promising potential in ameliorating skeletal and muscular aging. Coumarins, as naturally occurring phytochemicals, exhibit diverse pharmacological properties including anti-inflammatory, antiviral, antioxidant, antitumor, and immunomodulatory activities. This comprehensive review systematically elucidates how coumarins and their derivatives confer protection against Musculoskeletal Diseases primarily through modulation of inflammatory and oxidative mediators. These compounds target pivotal signaling pathways, such as NF-κB, MAPKs, Wnt/β-catenin, Sirt1, and PI3K/AKT, to enhance bone mineral density, mitigate cartilage degradation, suppress synovial pannus formation, and impede sarcoma cell migration. Despite their therapeutic promise, clinical translation of coumarins requires further investigation. Their dual capabilities in regulating bone metabolic homeostasis and immune responses, coupled with epigenetic interactions in musculoskeletal pathophysiology, provide valuable perspectives for retarding disease progression and advancing novel therapeutic interventions. 【Introduction】 Musculoskeletal diseases (MSDs) represent a class of systemic conditions that impair human morphology, skeletal movement, and muscular function, resulting from systemic degenerative processes and the progression of chronic inflammation (). The musculoskeletal system comprises joints, tendons, ligaments, and synovium, among other components (). Aging and traumatic injury are significant contributors to decreased bone mass, cartilage damage, degenerative changes in joint tissues, reduced muscle strength, and delayed fracture healing (). Although often overlooked by patients due to their chronic nature—such as in osteoporosis (OP), rheumatoid arthritis (RA), osteoarthritis (OA), and osteosarcoma (OS)—these disorders progressively accumulate, leading to permanent functional impairment and significantly diminished quality of life (). With the accelerating global aging population, the incidence of MSDs is rising, particularly among women aged 55–60, currently affecting approximately 1.7 billion people worldwide (, ). These conditions not only cause joint stiffness, swelling, and mobility limitations but also elevate the risk of other chronic diseases, including cardiovascular disorders, endocrine dysfunctions, and psychological burdens, making MSDs the third leading cause of non-communicable diseases (NCDs) globally (). Beyond individual health impacts, MSDs exert substantial pressure on healthcare costs and social productivity (). Conventional treatments for MSDs—such as exercise therapy, non-steroidal anti-inflammatory drugs (NSAIDs), hormone supplements, and laser therapy—have made incremental progress in pain relief, while surgical intervention remains necessary for severe cases (). However, long-term use of these approaches carries risks of hepatorenal toxicity and gastrointestinal ulcers, and surgeries may lead to varying degrees of post-operative tissue damage (). Therefore, the development of safer and more effective therapeutic strategies for MSDs warrants further exploration. For millennia, natural herbs have served as an indispensable source of bioactive plant compounds and have played a significant role in the management of various degenerative diseases, including neurological, immune, and endocrine disorders (, ). Advances in scientific technology have further enabled the development of innovative herbal formulations and the extraction of high-value metabolites from these plants (). A distinctive advantage of plant-derived metabolites—whether used as alternatives to synthetic drugs or as complementary therapies—lies in their favorable safety profile, characterized by lower toxicity and fewer side effects. They exert multifaceted functions, including anti-inflammatory, antioxidant, and anti-aging effects, as well as the regulation of metabolic homeostasis, thereby improving patient compliance and biocompatibility (, ). Coumarins, a class of secondary metabolites derived from the phenylpropanoid pathway, are found in over 30 plant families, such as Fabaceae, Asteraceae, Apiaceae, Rutaceae, Moraceae, and Lamiaceae (). Coumarins exhibit a broad spectrum of pharmacological activities—such as anti-inflammatory, analgesic, antimicrobial, antioxidant, immunomodulatory, antitumor, antidiabetic, anticoagulant, and cardioprotective effects—and are widely distributed in polyphenol-rich plants including angelica (Angelica archangelica), soybeans, chamomile (Matricaria chamomilla), fennel (Foeniculum vulgare), and citrus fruits (Citrus spp.) (). Owing to their extensive pharmacological potential, natural coumarins now demonstrate promising applications in drug discovery, healthcare, and wellness industries (). Consequently, growing research attention is being directed toward exploring their medicinal value. 【Methods】 This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline and checklist (). 【Search strategy】 Systematic searches were conducted in Web of Science, PubMed, and Embase databases for in vivo and in vitro studies published between January 1, 2000, and September 30, 2025, focusing on coumarins in the treatment of osteoporosis (OP), rheumatoid arthritis (RA), osteoarthritis (OA), and osteosarcoma (OS). The detailed search strategy is presented in . A literature search was performed using a combination of keywords and Medical Subject Headings (MeSH) terms, connected by the Boolean operators “AND” or “OR.” The main search terms were: “linear furan coumarins OR angular furan coumarins OR linear pyranocoumarins OR angular pyranocoumarins OR coumarin OR osthenol OR fraxetin OR demethylsuberosin OR scopoletin OR esculetin OR umbelliferone OR Psoralen OR bergaptol OR Seselin OR xanthyletin” AND “osteoporosis OR bone loss OR decreased bone density OR osteoarthritis OR cartilage injury OR rheumatoid arthritis OR osteosarcoma.” All published articles were retrieved, and the titles and abstracts were screened. 【Selection criteria】 The studies included in this report were original or interventional, focusing on the effects of coumarins on musculoskeletal health, and reported outcomes related to OP, RA, OA, and OS. The PICO framework (Population, Intervention/Exposure, Comparison, Outcome) was used to screen relevant literature for this systematic review. Inclusion criteria: studies investigating exposure to coumarins or coumarin-like compounds; studies involving musculoskeletal diseases including OP, RA, OA, and OS; studies with a controlled experimental design, i.e., including both control and experimental groups; experimental groups receiving different doses of coumarins or coumarin-like compounds, while control groups could receive blank control; comparisons involving in vivo or in vitro studies; original studies providing experimental data with clear experimental methods, appropriate interventions, defined comparators, and reliable outcomes. Detailed inclusion criteria are presented in . Exclusion criteria: studies not related to coumarin-like compounds; studies not involving musculoskeletal diseases (OP, RA, OA, and OS); non-original or non-interventional studies, such as review articles, meta-analyses, and case reports; studies involving combinations of coumarins with other compounds but not related to MSDs outcomes; studies written in languages other than English. 【Data extraction】 All records retrieved from the databases were imported into Zotero software as a library. Duplicate records were manually removed using the software tool and subsequently reconfirmed. Based on their titles and abstracts, two reviewers independently performed study eligibility screening and data extraction. Full-text review was then conducted, and quantitative data were organized into tables. Data were extracted from the full text of the included articles and entered into the corresponding columns. The information screened included compound source, exposure components, intervention model, route of administration, applied dose, therapeutic effects, biological targets, drug toxicity, and study limitations/future directions. Any discrepancies were resolved through discussion or by consultation with a third reviewer. 【Risk of bias assessment】 Two reviewers independently assessed study quality using a modified version of the OHAT Risk of Bias Tool for animal studies and the OHAT Risk of Bias Tool for in vitro studies (). Any disagreements between the authors were resolved through discussion or by a third reviewer. Different domains of each included study were evaluated, with one question per domain. Full compliance with a domain and direct evidence of low risk of bias were recorded as “definitely low risk of bias (++).” Minor deviations or indirect evidence of low risk were marked as “probably low risk of bias (+).” Unclear information regarding the relevant risk of bias or indirect evidence of high risk was recorded as “probably high risk (−).” “Definitely high risk (−−)” was used for direct evidence of high-risk bias practices. The overall study assessment adopted a three-tier quality grading system (, ). Under this grading system, Tier I studies were considered high-quality articles, with >50% of criteria rated as definitely or probably low risk; Tier II studies were of moderate quality; and Tier III articles were of low quality, with >50% of criteria rated as definitely and/or probably high risk. 【Results】 【Selection of studies】 2,160 articles were identified from three databases (Web of Science, PubMed, and Embase). A total of 1,740 articles were removed due to duplication, being reviews, case reports, or focusing on other research topics. The remaining 420 articles were screened by title and for eligibility, and 156 articles were excluded. The full-text manuscripts of the remaining 264 articles were obtained for assessment. Of these, 140 full-text manuscripts were excluded due to incomplete text content. Finally, 124 articles were deemed eligible and included in the final analysis (). Flow diagram illustrating inclusion and exclusion criteria for literature on coumarin treatment for skeletal muscle disorders. 124 articles ultimately met the analysis criteria. 【Risk of bias assessment】 The included studies were assessed using the OHAT Risk of Bias Tool. Most in vitro studies exhibited a low risk of bias in terms of selection bias, performance bias, attrition/exclusion bias, detection bias, and reporting bias. None of the included studies clearly described blinding or allocation concealment. In most studies, the purity of coumarins was not disclosed in the assessment of exposure characteristics; information on coumarin treatment duration and tested concentrations or treatment concentrations for cell models was also lacking. More than half of the included studies showed inconsistencies in treatment conditions or failed to disclose some or all parameter information (). All included studies were rated as Tier I [except for the study by Takashima et al. ()], based on more than 50% of the domains being classified as definitely and/or probably low risk of bias. The study by Takashima et al. () had unclear experimental conditions and study outcomes. In animal studies, most studies exhibited a low risk of bias in terms of performance bias, attrition/exclusion bias, detection bias, and reporting bias. No studies reported allocation concealment or blinding assessment. Incomplete reporting was observed regarding randomization, coumarin purity in exposure characteristics, and information on controlled diet/dietary coumarin intake (). No studies were rated as Tier III (low-quality articles with >50% of criteria rated as definitely and/or probably high risk). 【Clinical application of coumarins in the musculoskeletal system】 Natural coumarin was first isolated in 1820 from the leguminous plant (Dipteryx odorata Wild) and is found in a wide variety of natural species, possessing a characteristic aromatic odor (). To date, over 1,300 coumarin species have been discovered. In addition to being found in the roots, leaves, fruits, and flowers of plants, coumarins have also been identified in bacteria, fungi, and marine products (). Based on their structural characteristics, coumarins are mainly classified into simple coumarins and complex coumarins. Complex coumarins are primarily divided into furanocoumarins (linear and angular), pyranocoumarins (linear, angular, and condensed types), substituted coumarins, and other types of coumarins (such as 4-phenylcoumarins and isocoumarins) (). Under glycosylation, coumarins exert potent antioxidant capacity by scavenging oxygen free radicals (). The chemical structures of ten major coumarins are shown in . Chemical structures of 10 major coumarins. Based on pyrone ring structures, the top six structures are simple coumarins, and the latter four are complex coumarins. Given their anti-inflammatory and anti-aging pharmacological effects, coumarins may represent promising agents against age-related musculoskeletal decline. Various coumarin compounds have been employed to advance research on muscle–bone–immune interactions, such as Urolithin A. Urolithin A (UA), also known as phenylcoumarin or dibenzopyrone, ameliorates age-related mitochondrial dysfunction accumulation and muscle function decline (). Whitfield et al. demonstrated that daily administration of 1,000 mg of Urolithin A improved mitochondrial function in the skeletal muscle of clinical subjects, downregulated CRP inflammatory responses, alleviated muscle damage, and enhanced aerobic exercise capacity (). Zhao et al. found that after an 8-week observation period, all participants receiving 1 g/day of UA exhibited good safety and tolerability within one month following the intervention and after the completion of the study, along with reduced levels of 3-MH, a marker of skeletal muscle protein breakdown (). Singh et al. also found that the daily 500 mg UA group significantly downregulated plasma levels of acylcarnitines in participants, improved fatty acid oxidation, and promoted the levels of the glycogen debranching enzyme AGL and myophosphorylase PYGM, thereby influencing muscle aging and metabolism (). Liu et al. reported that although participants taking UA showed no significant improvements in the 6-min walk distance or maximal ATP production in hand muscles, long-term daily administration of 1,000 mg UA significantly enhanced skeletal muscle-specific endurance in older adults and improved metabolic markers of mitochondrial function (). Coumarins not only focus on degeneration and tissue repair in muscle/tendon–aerobic metabolism but also regulate osteoclast differentiation and skeletal degeneration induced by immune system cell lineages (monocytes/macrophages) (). One study found that coumarins alleviated impaired bone turnover and remodeling in diabetic osteoblasts and osteoclasts by disrupting hyperglycemia-mediated AGE-RAGE interactions (). These findings progressively reveal the future prospects of coumarin research and application in musculoskeletal degeneration. Although coumarins have been demonstrated to possess various nutritional and pharmacological properties, the demand for their synthetic organic chemical extraction and derivatives continues to increase (). Most commercial applications of coumarins are achieved through synthesis, primarily in food processing, fragrance production, and the rubber industry (). In the medical field, coumarins and their derivatives have been used in in vitro experiments, animal models, and human studies to realize their pharmacophysiological potential in treating various diseases, such as targeted kinase intervention in degenerative diseases, screening of coumarin nuclear substituents for anticancer significance, and regulation of Th17/Treg immune cell activity (). In 1954, the United States Food and Drug Administration (FDA) banned the use of coumarin in food due to the hepatotoxicity of coumarin extracted from cinnamon (, ). Owing to the multiple metabolic benefits of cinnamon coumarin, Europe adjusted the tolerable daily intake (TDI) of coumarin to 0.1 mg/kg/day to prevent hepatotoxicity and ensure clinical safety (). However, fundamental studies on acute oral toxicity have found that esculetin and the citrus-derived auraptene did not cause death or clinical toxicity at LD50 doses of 125–2000 mg/kg/day, even when validated in animals (). In clinical studies, alternative coumarins may mitigate their toxic effects and, in some cases, may have positive effects in humans (). Due to differences in species origin, synthetic coumarins or those used in combination with other drugs are safe and well-tolerated in most patients, with only a small proportion showing signs of mild liver injury (, ). Another existing assessment of hepatotoxicity risk found that even when cinnamon bark coumarin intake exceeded the TDI, the incidence of coumarin-induced abnormal liver function changes was low, allowing for safe use in clinical practice (). Therefore, as a dietary nutritional supplement, coumarin remains an important candidate for promoting health benefits within a reasonable applied dose. 【Effects of coumarin in musculoskeletal diseases】 Musculoskeletal diseases, such as osteoporosis (OP), rheumatoid arthritis (RA), osteoarthritis (OA), and osteosarcoma (OS), pose major challenges to global healthcare systems. As research into the mechanisms of coumarin in managing these diseases continues to expand, it holds promise for bridging the gap between emerging fields and established therapeutic strategies (). This review Systematically summarized current studies and mechanisms of coumarin across various musculoskeletal diseases, highlighting significant findings to support further pharmacological investigation and clinical exploration. Mechanisms of coumarin in alleviating musculoskeletal diseases. Coumarin, extracted from various natural plants, targets cytokines and signaling pathways involved in osteoporosis, rheumatoid arthritis, osteoarthritis, and osteosarcoma. ↑, promotion; ↓, inhibition. 【Mechanisms of coumarin in osteoporosis】 【Overview of coumarin】 Osteoporosis (OP) is a progressively degenerative skeletal metabolic disorder characterized by reduced bone strength, decreased bone mineral density, and increased bone fragility, with advanced stages frequently leading to fractures (). Major risk factors include declining estrogen levels, genetic predisposition, inadequate intake of nutrients such as calcium, and long-term medication-induced bone loss (). The core pathological mechanism involves an imbalance between osteoclast-mediated bone resorption and osteoblast-driven bone formation (). Disruption of bone metabolic homeostasis activates the OPG/RANKL/RANK signaling cascade, promoting osteoclast activity while impairing osteoblast-mediated bone regeneration, ultimately leading to bone loss and aberrant remodeling (). The condition