2.1 Literature retrieval and screening

Data collection for this study was completed on February 12, 2025, and all data came from publicly available sources prior to that date. The dataset was retrieved from the Web of Science Core Collection (WOSCC) database. In this bibliometric study, we employed the TS (Topic Search) field within the Web of Science Core Collection database to comprehensively capture publications related to growth factors and osteoarthritis mechanisms. The TS field searches across multiple sections of a publication, including titles, abstracts, author keywords, and Keywords Plus (algorithmically generated index terms). This approach was prioritized over narrower fields like TI (Title), AB (Abstract), or AK (Author Keywords) due to the interdisciplinary and evolving nature of the research domain. The advanced search methods are TS=(Growth Factor OR GF) and TS=(Osteoarthritis OR Osteoarthrosis OR Osteoarthritis OR Osteoarthroses OR OA OR Arthritis Degenerative OR Arthritis Degenerative OR Degenerative Arthritis). The search was conducted from January 1, 2005 to January 31, 2025, with the document type limited to “Article” and the language set to English. The detailed parameters of the search policy are shown in Fig. 1.

Close

Fig. 1 Document search flow chart for GFs and OA based on wos database.

Export to PPT

2.2 Data analysis and visualization

This study uses three standardized bibliometric tools: VOSviewer 1.6.20 (web building), CiteSpace 6.4.1 (trend forecasting), and Biblioshiny (based on the R 4.4.2 platform). VOSviewer visual analysis reveals the topology of the cooperative network of countries, institutions and keywords. CiteSpace breakout detection identifies research frontiers. The descriptive statistical analysis was completed through Microsoft Excel 2021, covering the annual number of publications and contributions of countries, institutions and authors. The multi-dimensional analysis method verifies the research hypothesis and ensures the reliability of the conclusion.

3.1 The trend of published literature in recent 20 years

The trend of publication is the core observation index to measure the development trend of academic field. Based on bibliometric data from 2005 to 2024, this study systematically analyzed the dynamics of research output in the field of GFs and OA. Fig. 2 shows an overall upward trend in the number of annual publications in this field, with an compound annual growth rate (CAGR) of 5.35%. Specifically, the number of publications continued to grow from 110 in 2005 to 372 in 2022 (CAGR = 7.43%), with a slight correction to the 300 range in 2023-2024. In the same period, the cited frequency increased more significantly, reaching a peak in 2022. Data analysis shows that the cyclical fluctuation of research popularity is highly correlated with the stage of technological innovation, and the growing academic influence confirms the potential of theoretical value transformation in this field.

Close

Fig. 2 Global trends in annual publications and frequency of citations related to GFs and OA.

Export to PPT

3.2 Distribution of publications by country

The distribution of national scientific research output is the key index to evaluate the development trend of the field. As shown in Table 1, the United States (1378 articles) and China (1297 articles) dominated the field, contributing 28.80% and 27.11% of the global total, respectively. The analysis of time trends (Fig. 3A) shows that research activity continues to rise, particularly in the last five years. Fig. 3B further confirms that the United States and China account for 55.91% of the total number of published documents, forming a dual-core driving pattern.

Close

Fig. 3 A. The trends in the number of publications from the top 10 countries.B. The 10 most productive countries accounted for the percentage of published paper related to growth factor and OA. C. Top 10 countries/regions in the H-Index for growth factor and OA related publications. D. Top 10 countries for average citations per publication related to GFs and OA.E. The cooperation network visualizations map of countries. F. The network map of collaboration between countries/regions was analyzed by VOSviewer.

Export to PPT

Research impact analysis shows that the United States leads the world with H-index 188 (Fig. 3C) and total citations 66,024 (average 47.91). China was cited 29,335 times (22.62 times on average), ranking second, and its H-index (70) surpassed traditional scientific research powers such as Japan, Germany and the United Kingdom. It is worth noting that although the Netherlands only ranked ninth in the number of publications (n = 188), it was cited 65.68 times on average, showing excellent research quality. The influence of papers in the United Kingdom (52.98), Canada (52.28) and Italy (52.45) was also significantly higher than the global average.

The map of the International Cooperation Network (Fig. 3E) shows that China and the United States constitute the dual hub structure of scientific research cooperation in this field, which radiates most countries. Other countries such as Japan, Germany and the United Kingdom also have certain cooperation links, but compared with the United States and China, their cooperation network is characterized by regionalization. The cooperation network diagram among countries/regions in Fig. 3F further confirms that there is significant knowledge flow between Sino-US cooperation hubs, and its nodal degree centrality is far greater than that of other countries. This highly interconnected mode of cooperation accelerates the global transformation of key technologies such as growth factor targeted therapy.

3.3 Author analysis

Author collaboration networks reveal key contributors in the field of GFs and OA. As listed in Table 2, Dutch researcher Van der Kraan, Peter M. leads with 38 publications, followed by American scholar Im Hee-Jeong (33) and Canadian researcher Martel-Pelletier, Johanne (32). Notably, four of the top 10 authors are affiliated with Canadian institutions, highlighting the country's pivotal role. Table 3 identifies the top 10 highly cited authors based on total citations and their prevalent growth factor research foci. Brown, Mark T. exhibited the strongest association with nerve growth factor (frequency = 18), while van den Berg, Wim B. and Martel-Pelletier, Johanne concentrated on growth-factor-beta (frequencies = 8 and 13, respectively). Im Hee-Jeong and Chen, Di demonstrated dual specializations in growth-factor (see Table 4).

The co-citation network (Fig. 4A) generated by VOSviewer identifies multiple research clusters. Node sizes indicate citation frequency, while colors distinguish clusters. Key authors from Table 2, such as Martel-Pelletier, Johanne and Im Hee-Jeong, occupy central positions. The collaboration network (Fig. 4B) further demonstrates strong partnerships among Université de Montréal researchers, including Martel-Pelletier, Johanne and Pelletier, Jean-Pierre.

Close

Fig. 4 (A) Bibliometric analysis of the co-cited authors by VOSviewer. (B) Network visualization map of collaborations among authors. (C) Three-field plot on biomarkers (left field: countries; middle field: authors; right field: keywords).

Export to PPT

The Three-field plot (Fig. 4C) integrates national, author, and thematic connections. Authors from specific countries align closely with distinct keywords—some emphasize mechanistic studies, while others focus on clinical translation. This transnational and interdisciplinary distribution underscores the field's diversity.

3.4 Analysis of publishing institutions

Fig. 5A reveals the University of California system as the top contributor with 133 publications, followed by Harvard University (118 publications). Notably, the University of California system demonstrates higher average citation rates (69.91 vs. Harvard's 58.7), with total citations reaching 9289 and 6927 respectively, indicating a non-linear relationship between quantity and impact.

Close

Fig. 5 (A) The number of article, average citation, total citation in the top 10 prolific institutions. (B) Agency Collaboration Network VOSviewer map.(C) The temporal view of institutional cooperation arising from citespace.

Export to PPT

The collaboration network map (Fig. 5B) identifies the University of California system and Harvard University as central hubs, forming intensive partnerships with institutions in the U.S., China, and other regions. Chinese research institutions exhibit particularly active transnational collaborations. The temporal evolution diagram (Fig. 5C) further shows strengthened long-term collaborations between these core institutions, alongside continuous integration of emerging research teams into the global network.

3.5 Literature sources and journal analysis

Journal analysis identifies key platforms in the GFs and OA field. Osteoarthritis and Cartilage leads with 356 publications (h-index 71, IF = 7.2, Q1), followed by Arthritis Research & Therapy (154 articles) and Arthritis & Rheumatology (115 articles). All top three journals are Q1-ranked, with impact factors ranging from 4.4 to 10.0, reflecting high academic relevance(Table 3).

Network mapping (Fig. 6A) highlights OA and Cartilage as the central hub. Density visualization (Fig. 6B) shows clustered journal distribution, predominantly in Europe and North America.

Close

Fig. 6 (A) Journals analysis network map drawing by VOSviewer. (B) Density map of journals distribution of published articles based on VOSviewer.(C) Dual-map overlay of journals on growth factor and OA.

Export to PPT

3.6 Analysis of literature sources

Analysis of highly cited references identifies pivotal contributions in this field. Fig. 7A lists the top 20 references with citation burst periods and strength values. Goldring MB (2007)¹⁹ and Lane NE (2010)²⁰ demonstrate significant influence during their active citation phases (2009-2012), driving disciplinary advancements.

Close

Fig. 7 (A) Top 20 references with the strongest citation bursts.(B) Visualization map of references analysis based on CiteSpace.(C)Total Number of publications of top 10 references (generated by Bibliometrix software).

Export to PPT

The CiteSpace-generated network (Fig. 7B) visualizes reference clusters through node size and interlink density. Early foundational works (e.g., Altman R, 1986) maintain strong connections with contemporary studies, illustrating knowledge continuity. Fig. 7C further confirms the enduring impact of seminal references like Kellgren JH (1957), with sustained citations (109 times) underscoring their paradigmatic role.

3.7 Keyword Co - occurrence, clustering, and burst analysis

Keywords are the core elements of the research field, and their citation and distribution characteristics can directly reflect the research hotspot and development trend of the field. Through in-depth analysis of key words, we can accurately grasp the key direction and evolution of the research on GFs and OA. Systematic categorization of growth factor constructs (Table 5) revealed the TGF-β superfamily as the predominant category, with cumulative keyword frequencies exceeding 700 occurrences. The VEGF family ranked second, followed by IGF and NGF families. High-frequency keywords (Fig. 8A) such as "β-growth factor” and “interleukin-6″ show continuous citation outbreaks, reflecting their central position. The trend topic graph (Fig. 8B) shows that the frequency of emerging topics such as “mesenchymal stem cells” and “angiogenesis” has increased significantly in recent years, suggesting a technological shift in research direction.

Close

Fig. 8 (A) Top 20 keywords with the strongest citation bursts.(B) Trend topics in growth factor and OA. (C) The chart is a two-dimensional scatter plot with “Relevance degree (Centrality)" on the x-axis and “Development degree (Density)" on the y-axis. It's divided into four quadrants: “Niche Themes (Low Centrality, High Density)," “Mature Themes (Low Centrality, High Density)," “Emerging or Declining Themes (Low Centrality, Low Density)," and “Basic Themes (High Centrality, Low Density)." (D) Application of co-occurrence cluster keyword networks in GFs and OA. (E)Keyword cloud of the top 50 keywords.

Export to PPT

The two-dimensional scatterplot (Fig. 8C) divides the research topics into niche areas, mature areas, emerging areas and basic areas. Niche areas include “double blindness,” “pain,” and “nerve growth factor.” These are specialized areas with a high research density, but are less important to the broader field. The mature area focuses on classic topics such as “articular cartilage repair”, the emerging area focuses on cutting-edge directions such as “stem cell therapy”, and the basic area covers theoretical cornerstones such as “gene expression regulation”. In the keyword co-occurrence network (Fig. 8D), "β-growth factor” is strongly associated with “inflammatory pathway”, revealing the cross-study characteristics of molecular mechanisms and pathological processes.

Keyword cloud map (Fig. 8E) visually presents the core framework and knowledge distribution of domain research. Growth factor family abbreviations (TGF-β, VEGF, IGF) appeared as prominent nodes, consistent with their high prevalence in Table 5. “ OA “and” GFs “as the largest nodes, constitute the theoretical cornerstone of the field. The secondary nodes such as cartilage metabolism and joint degeneration occupy a prominent position, confirming the dominant position of tissue-specific research. The high-frequency terms “gene expression” and “cell signaling” point to the depth of molecular mechanism exploration, while “inflammatory regulation” and “tissue repair” reflect the systematicness of pathological process research. Emerging concepts such as the dominant distribution of “mesenchymal stem cells” reveal academic heat in the direction of regenerative medicine. The persistence of foundational terms such as “disease model” indicates the dependence of translational research on theoretical support.

4.1 Global research trends and contributions

The exponential surge in publication volume and citation frequency over the past two decades underscores the escalating importance of GFs in OA research. This initial wave of publications was primarily driven by the recognition of GFs ' pivotal roles in regulating chondrocyte proliferation, differentiation, and ECM synthesis. As molecular mechanisms underlying OA pathology became clearer, research focus began to shift towards exploring the therapeutic potential of specific GFs, notably TGF-β and IGF-1.

A notable decline in publication numbers observed in 2023-2024 may reflect either transient fluctuations or a strategic maturation of the field, with research efforts increasingly concentrated on translating preclinical findings into clinical applications.

4.2 National and institutional contributions

The dominance of the United States and China in publication output underscores their leadership in this research domain. The United States demonstrates robust research capabilities and sustained academic excellence, evidenced by its superior H-index scores and total citation counts, reflecting decades of scholarly investment and institutional infrastructure. China's rapid growth in publication volume, coupled with extensive international collaborations, highlights its escalating prominence within global research ecosystems, aligning with its strategic focus on technological self-reliance and innovation-driven development.

Nations such as the Netherlands, the United Kingdom, and Canada exhibit exceptional research quality, as indicated by their elevated average citations per publication. This phenomenon likely stems from advanced research infrastructures, rigorous peer-review frameworks, and strategic global partnerships that foster knowledge exchange and interdisciplinary synergy.

Leading institutions like the ​University of California system and ​Harvard University exemplify research leadership through their exceptional scholarly output and collaborative networks. The University of California system, encompassing multiple research-intensive campuses, drives innovation through interdisciplinary initiatives. Harvard University's prominence is sustained by its cutting-edge medical research and global academic alliances, which amplify translational impact. Institutional collaboration networks further reveal the critical role of transregional partnerships in advancing scientific frontiers, with frameworks like cross-institutional data-sharing platforms and multinational R&D consortia serving as catalysts for high-impact discoveries.

4.3 Author and collaborative network insights

The data indicate that Canada, the United States, and the Netherlands are leading contributors to research on GFs and OA. Key authors such as van der Kraan, Im, and Martel-Pelletier have significantly advanced the field through their high publication output, citation metrics, and collaborative engagement. Crucially, our analysis of highly cited authors' thematic focus (Table 3) reveals distinct mechanistic specializations: while Brown, Mark T. dominated nerve growth factor research (frequency = 18)—potentially reflecting neuropathic pain interventions—Martel-Pelletier, Johanne and van den Berg, Wim B. concentrated on TGF-β signaling (frequencies = 13 and 8), aligning with cartilage homeostasis studies. This specialization pattern suggests strategic niche development within collaborative networks.

The research community exhibits remarkable dynamism, characterized by robust collaborative networks and a focused exploration of OA-associated biomarkers. Notably, authors like Im Hee-Jeong and Chen, Di demonstrate dual expertise in GFs pathways, exemplifying the cross-disciplinary integration essential for addressing OA's multifactorial pathology. Such convergence of growth factor expertise may accelerate combinatorial therapeutic approaches. These findings underscore the pivotal role of sustained academic productivity and interdisciplinary cooperation in driving scientific progress within this domain.

In summary, Canada, the United States, and the Netherlands emerge as frontrunners in this research area. The scholarly leadership of van der Kraan, Im, and Martel-Pelletier is evidenced by their prolific contributions, which are further supported by high citation impact and cross-institutional partnerships. The concentration of TGF-β and NGF research among top-cited authors (Table 3) additionally highlights these pathways as high-impact therapeutic targets, with translational potential warranting further clinical validation.

4.4 Journal and literature source analysis

Top-tier journals such as Osteoarthritis and Cartilage, Arthritis Research & Therapy, and Arthritis & Rheumatology play a pivotal role in disseminating high-quality research within this field. Their elevated impact factors and substantial publication volumes underscore their scholarly influence and broad coverage of OA-related innovations.

Bibliometric network mapping reveals the central positioning of Osteoarthritis and Cartilage within the research ecosystem, with dense interconnections to other key journals. This connectivity highlights the interdisciplinary nature of OA research, where molecular biology, biomechanics, and clinical therapeutics converge through collaborative frameworks. Density visualization further provide intuitive insights into publication distributions, delineating emerging thematic clustersalongside established research domains.

4.5 Keyword analysis and research hotspots

During the early research phase (2005–2015), dominant keywords such as “growth factor β," “interleukin-6,” and “chondrocytes” reflected a focus on elucidating the fundamental mechanisms by which GFs regulate chondrocyte behavior and inflammatory responses. The prevalence hierarchy revealed in Table 5 substantiates this pattern, with TGF-β superfamily constructs and VEGF-related terms dominating early publications—a trend persisting through subsequent phases due to their foundational roles in cartilage homeostasis. For instance, studies prioritized uncovering how GFs modulate chondrocyte proliferation, differentiation, and metabolic activity through cellular signaling pathways,^21,22 while simultaneously investigating the role of inflammatory cytokines in OA pathogenesis.²³ Keywords like “tumor necrosis factor-α" and “apoptosis” further underscored the emphasis on inflammation-driven cellular death processes within OA pathology.²⁴ As a core keyword of this era, “growth factor β" held pivotal significance in OA research. Extensive studies demonstrated that TGF-β family members, particularly through SMAD signaling cascades, play central roles in maintaining cartilage homeostasis by enhancing chondrocyte differentiation and ECM synthesis.²⁵ These factors not only stimulate collagen and proteoglycan production to improve cartilage mechanical resilience but also modulate inflammatory pathways to suppress cytokine release and mitigate joint inflammation.²⁶ Recent advancements have shifted toward optimizing growth factor β delivery systems to enhance in vivo stability and bioavailability, thereby maximizing therapeutic efficacy.

The period spanning 2015–2020 witnessed the emergence of keywords such as “mesenchymal stem cells (MSCs)" and “tissue engineering” as prominent research frontiers, marking a pivotal shift from purely mechanistic investigations of cellular and molecular pathways toward the development of therapeutic strategies and tissue regeneration approaches. Researchers increasingly focused on leveraging the dual capabilities of MSCs—their multipotent differentiation potential and immunomodulatory properties—in synergy with tissue engineering techniques to design biomimetic scaffolds for cartilage repair. Concurrently, persistent interest in “gene expression” and “signal transduction” reflected continued exploration of growth factor mechanisms, now recontextualized to align with novel therapeutic paradigms and provide theoretical foundations for clinical translation. As a dominant keyword in recent years, MSC-related research has evolved along two primary trajectories. First, investigations into the homing, differentiation, and survival mechanisms of MSCs within osteoarthritic microenvironments aim to optimize cellular therapy efficacy.²⁷

Second, studies emphasize how MSC- secreted GFs and cytokines interact with neighboring cells to modulate immune responses and enhance tissue repair.²⁸ For instance, paracrine signaling by MSCs facilitates cartilage regeneration and angiogenesis through synergistic interactions between cellular components, mediated by specific trophic factors.²⁹ Furthermore, advancements in gene-editing platforms have enabled functional enhancements of MSCs, such as targeted overexpression of therapeutic genes, representing a cutting-edge direction in regenerative medicine^30–32.

Recent research trends (2020–2025) reveal a marked increase in citation frequencies of keywords such as “bone marrow,” “repair,” and “angiogenesis,” signaling a paradigm shift toward investigating bone marrow microenvironment dynamics and vascularization in OA therapeutics.³³ This reflects an expanded focus on harnessing bone marrow-derived stem cells (BMSCs) for cartilage regeneration while optimizing nutrient delivery and microenvironmental regulation through enhanced vascular networks.³⁴ Concurrently, the emergence of terms like “double-blind” and “clinical trials” underscores the transition of foundational discoveries into rigorous clinical validation, accelerating the translation of OA therapies from bench to bedside. Spatial analysis of keyword distributions in bibliometric networks positions “mesenchymal stem cells,” “repair,” and “bone marrow” within emerging thematic clusters, highlighting their prominence as frontiers in OA research.³⁵ BMSCs, with their multipotent differentiation capacity, serve as pivotal cellular reservoirs for chondrogenic and osteogenic differentiation, offering structural and functional restoration of damaged cartilage.^36,37 It has been found that bone marrow stem cells can be guided to differentiate into chondrocytes and integrate into damaged cartilage tissue to achieve structural and functional repair through specific induction signals and microenvironment regulation. Angiogenesis has emerged as a critical enabler of tissue repair, with nascent vasculature facilitating nutrient transport, metabolic support, and paracrine signaling to sustain regenerative processes^38–40. Relevant studies aim to reveal the interaction mechanism between the bone marrow microenvironment and angiogenesis.⁴¹ The sustained prominence of VEGF-related keywords in this phase further validates vascularization as a linchpin for advanced regenerative strategies. Therapeutic strategies increasingly leverage exogenous interventions, including small-molecule agonists and physical stimuli, to amplify vascular sprouting and microenvironmental remodeling.

Collectively, these advancements illustrate a multidisciplinary convergence of stem cell biology, vascular engineering, and clinical trial design, positioning OA therapeutics at the threshold of transformative innovation.

4.6 Limitations

This study has several limitations inherent to bibliometric methodologies. First, the exclusive reliance on Web of Science Core Collection data may introduce database-specific selection bias, as clinical trial reports and regional journals indexed in other repositories were not systematically incorporated. Second, while our keyword-based approach effectively captured dominant growth factor families (TGF-β, VEGF, IGF, NGF, PDGF), it underrepresented emerging therapeutic candidates like BMP-7 that currently appear more frequently in clinical trial registries than academic literature. This reflects a broader disconnect between basic research output and translational applications. To address this, future bibliometric studies should integrate clinical registry terms with academic keywords to bridge the gap. Finally, despite algorithmic disambiguation, potential homonym errors in author/institution attribution remain possible.