Pathogenesis of osteoarthritis, rheumatoid arthritis, and hemophilic arthropathy: The role of angiogenesis

Abstract

Introduction

The term ‘chronic inflammatory arthritis’ (IA) can be used to define a group of heterogeneous diseases in which inflammation of the synovium is the common feature while having different pathogenesis and clinical outcomes. This condition can be found in osteoarthritis (OA), rheumatoid arthritis (RA), and hemophilic arthropathy (HA).

Aim

The objective is to try to highlight similarities and differences in the three pathological conditions and understand both molecular and physiological mechanisms.

Method

We have carried out a systematic review of the available literature following the guidelines Preferred Reporting Items for Systematic Reviews and Meta‐analysis (PRISMA).

Results

By comparing the data in the literature on OA, RA, and HA we have shown that the three pathologies differ in initial etiology but they motivate the same molecular pathways.

Conclusion

In this review we highlighted the similarities and differences between these diseases, creating ideas for future studies both in vivo and in vitro to develop new therapeutic agents and suggest possible biomarkers to follow the evolution and severity of the disease.

1. INTRODUCTION

Blood vessels consist of endothelial cells (EC), pericytes, vascular smooth muscle cells (vSMC), fibroblasts, basement membrane (BM) and extracellular matrix (ECM). ECs make the endothelium, a thin layer of squamous cells that lines the inner surface of blood vessels and maintains tissue homeostasis by regulating vascular permeability and chemical and mechanical signals. Under the stimulation of vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF) and angiopoietins 1 and 2 (Ang‐1 and Ang‐2) ECs develop new tubes that successively are surrounded by pericytes to become mature vessels thanks to platelet‐derived growth factor (PDGF) and Ang‐1 signals. ¹

Angiogenesis, namely the formation of new vessels, is a fundamental process both in the physiological field for tissue repair and regeneration, growth and embryogenesis and in pathological conditions, allowing the development of tumours and the progression of inflammatory arthritis (IA). ² IA is defined as a group of heterogeneous diseases characterised by synovium inflammation and a meaningful increase in angiogenesis despite having different pathogenesis and clinical courses, ³ the main ones are osteoarthritis (OA), rheumatoid arthritis (RA) and hemophilic arthropathy (HA). OA is due to stress signals, and biomechanical and metabolic factors, RA is determined by environment and genetic predisposition, while HA pathogenesis is caused by the accumulation of iron that starts chemical and inflammatory damage.

Angiogenesis is not one of the triggering factors of these pathologies but plays a significant role in their progression. OA is responsible for osteochondral junction damage and patients’ pain, RA causes the transformation of synovial in a ‘pannus’ that destruction the articulations. ² , ³ Different studies have shown that angiogenesis is an increase in HA and vascular remodelling plays a crucial role in the development of hemarthrosis. ⁴ , ⁵

This review aims to evaluate the differences in the pathogenesis and the molecular mechanisms involved in the three pathologies, investigating in particular the role of angiogenesis.

2. MATERIALS AND METHODS

This report provides an account of the reviews of the available literature conducted to achieve the aim of the research. Its reporting is an adaptation of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines [http://www.prisma‐statement.org/].

2.1. Identifying the research question

The research question identified for the literature review was first of all to evaluate the differences in the pathogenesis and the molecular mechanisms involved in the three pathologies OA, RA and HA, investigating in particular the role of angiogenesis.

2.2. Identifying relevant studies

A literature search was conducted to find all relevant studies on the topic. These were identified using diverse sources.

2.2.1. Electronic database search

The following electronic databases were searched, taking into consideration the chronological span between 2010 and 2023: PubMed and Scopus. The research strategy was designed to retrieve the most relevant results. Due to the specificity of the two databases employed, for each one, a different search string was built (1: PubMed search string; 2: Embase search string). In brackets, the number of the results is provided).

1. ((‘angiogenesis’[Journal] OR ‘angiogenesis’[All Fields] OR (‘synovitis’[MeSH Terms] OR ‘synovitis’[All Fields] OR ‘synovitides’[All Fields])) AND ((((‘haemophilic’[All Fields] OR ‘haemophilics’[All Fields] OR ‘hemophilic’[All Fields] OR ‘hemophilics’[All Fields]) AND (‘joint diseases’[MeSH Terms] OR (‘joint’[All Fields] AND ‘diseases’[All Fields]) OR ‘joint diseases’[All Fields] OR ‘arthropathies’[All Fields] OR ‘arthropathy’[All Fields])) OR (‘osteoarthritis’[MeSH Terms] OR ‘osteoarthritis’[All Fields] OR ‘osteoarthritides’[All Fields]) OR (‘rheumatoid’[All Fields] OR ‘rheumatoids’[All Fields])) AND (‘arthritis’[MeSH Terms] OR ‘arthritis’[All Fields] OR ‘arthritides’[All Fields] OR ‘polyarthritides’[All Fields]))) AND ((ffrft[Filter]) AND (fft[Filter]) AND (english[Filter]) AND (2010:2023[pdat])) [2386];

2. (angiogenesis OR synovitis) AND (hemophilic AND arthropathy OR osteoarthritis OR rheumatoid AND arthritis) AND (LIMIT‐TO (LANGUAGE, ‘English’)) [1118].

2.2.2. Other sources

Eight studies were also included, starting from a website and citation research. These articles were regarded to be relevant, even though they were not identified through the search strings.

2.3. Study inclusion criteria

Starting from the research question, inclusion and exclusion criteria for the objective selection of the studies identified were defined. Only studies published in the English language between 2010 and 2023 were eligible for inclusion. Titles and abstracts and full texts were screened by the research team—that is, two authors performed the study selection and the data extraction independently, and all disagreements were discussed between the authors.

2.4. Data extraction

A standardised data extraction sheet was prepared, where the main information on the studies was collected (e.g., first author's name, study title, publication year and DOI).

2.5. Study selection

Via the literature search, 26 studies were included in this literature review; 18 of them were identified via database searches and eight via websites or citation searching (Figure 1). Figure 1 shows the process of study selection in detail, covering the number of search records retrieved from the two database searches (n = 3504) and all other searches.

FIGURE 1.

PRISMA 2020 flow diagram for new systematic reviews which included searches of databases, registers and other sources. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta‐analysis.

(n = 21), the number of screened titles/abstracts (n = 2336), the number of finally included studies (n = 26).

3. RESULT

3.1. Molecular mechanisms compared in OA, RA and HA

Synovium is a specialised connective tissue find in diarthrodial joint and involved in the production of synovial fluid that fills the articular cavity. The normal synovial membrane is made of two layers: the intima (inner layer) which consists of a layer of 1−4 cells (20−40 µm thickness) and the subintima (outer layer) which is up to 5 mm thick. Between these two layers, there is a subtle layer of hyaluronic acid. The intima is characterised by the presence of two different types of synoviocytes: type A synoviocytes which are monocyte‐macrophage‐like cells and type B synoviocytes which are fibroblast‐like cells. The sub‐intima is constituted by lymphatic vessels and is highly vascularised. ⁶ , ⁷ , ⁸ Synovial inflammation (Synovitis) causes the transformation of connective tissue into an invading pannus characterised by interstitial resident macrophages, monocyte‐derived cells, luminal fibroblast‐like synoviocytes (FLS), and synovial FLS. Synovitis is the result of a complex combination of hypoxic, pro‐inflammatory, and pro‐angiogenic signalling pathways and it is characterised by hypertrophy, hypervascularization and hyperplasia. ⁹ Synovitis is a common feature of chronic inflammatory arthritis.

3.2. OA pathogenesis

OA is the most common arthritic disease and the leading cause of disability in the general population. It is characterised by synovial inflammation, osteophyte formation, and cartilage loss. Age, obesity, trauma, mechanical load, and modification of synovial biology are relevant to its pathogenesis. Angiogenesis is involved in the disease since it induces articular cartilage changes with loss and depletion of proteoglycans, deposition of collagen types I and X, and cartilage calcification or ossification. The formation of new vessels is also involved in the modulation of chondrocyte activity and the degradation of the cartilage matrix. ² OA synovium is characterised by inflammation, hypertrophy, and hyperplasia. At variance with other chronic inflammatory arthritis, OA is characterised by severe cartilage damage and mild synovial inflammation, due to two different molecular mechanisms: Toll‐like receptors (TLR) activated by endogenous products and the activation of the complement cascade due to some components of the ECM. TLRs activation induces different molecular pathway that stimulates chemokines and cytokines release, increase angiogenesis, and promote immune system activation, in particular macrophages that induce the production of interleukin 1 beta (IL‐1ß), tumour necrosis factor‐alpha (TNF‐α) and interleukin 6 (IL‐6). These cytokines trigger the inflammatory cascade, stimulate cartilage destruction by the phenotypic change in chondrocytes and stimulate proteolytic enzymes. While the complement cascade is responsible more for cartilage destruction than inflammation, focusing mainly on meniscal injury and phagocytosis. ⁸

3.3. RA pathogenesis

RA is a systemic autoimmune and complex chronic inflammatory disease affecting 1% of the population worldwide. RA is determined by two factors: environment and genetic predisposition. Environmental factors like cigarette smoke and stressors induce post‐translational epitope modifications (citrullination or carbamylation or acetylation) on different proteins including matrix proteins such as collagen, fibronectin, vimentin and intracellular proteins like histones that activate the immune system response: neutrophils, T and B cells and form lymphoid aggregates. This pathologic condition induces both mononuclear cell infiltration in endothelial tissue and produces pro‐inflammatory mediators. FLS and lymphocytes produce different cytokines, such as IL‐1, TNF, IL‐6, chemokine, and prostaglandins that cause synovial inflammation and synovial lining proliferation (‘pannus’), while neutrophils induce proteolytic enzymes that cause cartilage and bone damage, with hyperplasia of the intimal layer. The principal RA feature is a severe synovial inflammation while cartilage damage is less noticeable than OA and HA. ¹⁰ , ¹¹

3.3.1. HA pathogenesis

HA is the most common clinical complication of the natural history of haemophilia. It shows destruction of articular cartilage, stiffness, pain, hypertrophic and hyperplastic synovium and decreased range of motion as a result of very large limitations in physical activity and quality of life. ¹ HA is characterised by high inflammation like RA and severe cartilage damage like OA. HA pathogenesis starts from two main synovium damages: chemical damage (also called first hit) and inflammatory damage (second hit), both caused by the accumulation of iron. First hit begins with the inhibition of synovial cell apoptosis as well as secretion of pro‐inflammatory cytokines such as IL‐1β, TNFα, and IL‐6 and chemokines such as CCL2 and CXCL1. The second hit instead involves the activation of the inflammatory response through the migration of polymorphonuclear cells, monocytes and lymphocytes and the stimulation of neoangiogenesis through VEGF. ⁷ We report a summary scheme of the main cells involved and their mediators in Figure 2.

FIGURE 2.

Molecular mechanism involves in OA, RA, and HA pathogenesis. The image shows the pathways activated during OA, RA, and HA pathogenesis and the principal effects of these pathology at level of articulation. ANG‐1, angiopoietins 1; EC, endothelial cells; HA, hemophilic arthropathy; HIF, hypoxia‐inducible factor; IL‐1ß, cytokine interleukin‐1β; IL‐6, cytokine interleukin‐6; M1, macrophages involved in host defence; MMPs, matrix metalloproteinase; OA, osteoarthritis; RA, rheumatoid arthritis; TNF‐α, tumour necrosis factor; VEGF, vascular endothelial growth factor.

3.4. The angiogenesis involvement in chronic IA pathogenesis

3.4.1. Angiogenesis in OA

In OA, angiogenesis is increased in different joint sites, such as synovium, osteophytes, menisci and the osteochondral junction, but the sequence of pathological events is not completely understood. It increases inflammation and contributes to endochondral ossification. It is regulated by both proangiogenic and antiangiogenic factors found in the ECM environment. Proangiogenic factors localised in the osteoarthritic joint are prostaglandins, nitric oxide, regulatory peptides, cytokines, chemokines, growth factors, and VEGF. Antiangiogenic factors are protease inhibitors, matrix fragments and factors implicated in the resolution of inflammation. Synovial inflammation stimulates infiltrating macrophages, hypertrophic chondrocytes and osteoblasts to increase the production of VEGF, the major growth factor in angiogenesis. ²

Activated macrophages are of two different types: M1 macrophages (involved in host defence) which produce proinflammatory cytokines and M2 macrophages (involved in tissue repair) which produce anti‐inflammatory cytokines; both cell types produce VEGF. In OA, there is an imbalance between macrophage types, in favour of M1, causing increased production of inflammatory cytokines resulting in synovitis and angiogenesis. ¹² The formation of new vessels in the synovium generates a hypoxic condition with activation of hypoxia‐inducible factor (HIF) that stimulates different molecular pathways in favour of cell survival, including an increase in energy metabolism and oxygen supply by stimulating angiogenesis. ECs play a relevant role in this phase, as they interact with chondrocytes and osteoblasts inducing them to produce matrix metalloproteinases (MMPs) responsible for the degradation of the endothelial BM and the ECM. ¹³ Furthermore, blood vessel growth enhances inflammation, disruption of the osteochondral junction, and inappropriate sensory innervation of vulnerable joints contribute causing pain in patients. In OA, angiogenesis and sensory nerve growth are interrelated and would appear to explain the link between neangiogenesis and patient pain. ² By analysing the common pathways involving the release of proangiogenic factors such as VEGF, nerve growth factor β, and neuropeptides in OA patients, recent studies have shown that β‐NGF, a protein important for nervous system development, stimulates angiogenesis thanks to its Trk‐A receptor, present both on the surface of EC and sensory nerves and macrophages. At the level of nerve endings, the activation of the receptor induces the production of angiogenic neuropeptides, while at the level of the macrophages, it stimulates the release of VEGF. The released neuropeptides, together with VEGF and TrK‐A receptors present on EC, stimulate angiogenesis. ² Furthermore, angiogenesis appears to have a positive effect on the formation of new sensory vessels, as it has been observed that it may inhibit PKC δ, resulting in the upregulation of NGF and increased nerve fibre density. These results confirm the involvement of both angiogenesis and sensory nerves in the pain manifestation of OA patients ¹⁴ (Figure 3).

FIGURE 3.

Role of angiogenesis in pathogenesis of OA, RA, and HA. The image shows the pathways activated by angiogenesis in OA, RA, and HA and the principal effects. HA, hemophilic arthropathy; HIF, hypoxia‐inducible factor; MMPs, matrix metalloproteinase; PKC‐δ, protein kinase C δ; SMA‐α, α‐smooth muscle actin; ß‐NGF, nerve growth factor; OA, osteoarthritis; RA, rheumatoid arthritis; TNF‐α, tumour necrosis factor; VEGF, vascular endothelial growth factor.

3.4.2. Angiogenesis in RA

Angiogenesis is a crucial event of RA responsible for synovial hyperplasia, leucocyte recruitment and the transformation of synovial tissue in a ‘pannus’ that causes cartilaginous and bone damage. In RA synovium, the inflammation and hypoxia conditions, in association with the activation of M1 macrophages by TLR, induce macrophages and FLS cells to secrete pro‐inflammatory cytokines, such as TNF‐α, IL‐6, IL‐1β, responsible for angiogenesis regulation. These cytokines stimulate different pro‐angiogenetic mediators such as VEGF, in the first phase and ANG in the second phase. VEGF is responsible for the proliferation, migration, vascularization and permeability, while ANG allows the stability of new vessels and the EC connection. Cytokines also induce the activation of some MMPs: MMP‐1, MMP‐3, MMP‐9, and MMP‐13 to degrade the BM and ECM. In the synovium, inflammatory mediators, chemokines CXCL1, CXCL5, and CXCL8 increase the infiltration of the immune system and the inflammatory state. They stimulate the adhesion molecules, such as JAM and CAM, to promote endothelial adhesion. These pro‐inflammatory and pro‐angiogenic mediators recruit the EC, from local vascular structures and peripheral blood endothelial progenitor cells, to allow the migration and proliferation of EC in the synovium and the formation of the new vessel. Chronic inflammation, hyperplasia and increasing metabolite demands cause a hypoxia condition. The transcription factor HIF‐1α can regulate angiogenesis both with the stimulation of VEGF expression and the EC migration ¹⁵ , ¹⁶ (Figure 3).

3.4.3. Angiogenesis in HA

The endothelium plays an important role in HA, as it is involved both in the coagulation cascade, by regulating thrombosis, thrombolysis and platelet interaction, and in the regulation of angiogenesis by inducing blood vessel growth and regulating blood flow, leukocyte interaction and vascular tone. ¹⁷ Under physiological conditions, the vascular endothelium acts as a haemostatic barrier with anticoagulant properties, blocking platelet activation and aggregation, while in the presence of a lesion, the EC react by changing their characteristics to prothrombotic and procoagulant, to favour the activation of the coagulation cascade and clot formation. Through the activation of receptors present on the endothelial membrane, specific for various factors including proteins, lipids, hormones and cytokines, the endothelium also regulates the recruitment of leukocytes, inducing their rolling, arrest, and diffusion. ¹⁸ Several studies have hypothesised that at the level of the synovium, neo‐angiogenesis plays a relevant role in the pathogenesis of HA. High levels of pro‐angiogenic mediators (VEGF‐A, MMP‐9, and SDF‐1) compared to healthy controls were observed in the synovium and plasma of hemophilic joint disease (HJD) patients, and several infiltrated myeloid cells (CD68 and CD11b) were also detected in the synovium which express VEGF (VEGF⁺/CD68⁺ and VEGF⁺/CD11b⁺). Through in vitro studies it has been observed that hemophilic plasma patients induce chemotaxis of EC and stimulate the synoviocytes to express HIF‐1α, a hypoxic factor responsible for the activation of angiogenesis by the factor SDF‐1α. These results demonstrate that plasma from HJD patients can induce EC to a VEGF‐dependent angiogenic response. ¹⁹ Other in vitro studies analysed microvascular density, VEGF expression, and pericyte coverage in synovial tissue, synovial fluid, and blood samples from patients, showing an increase in microvascular density and VEGF expression in synovial tissue. No significant changes, such as pericyte coverage, were detected in synovial fluid and plasma. Although it is still not fully understood how angiogenesis develops over time in HJD, it would appear that vessel formation is relatively slow and deregulated in the disease. ¹ Research conducted on mouse models deficient in factor VIII, to study the synovial, vascular, stromal, and cartilaginous changes in response to a single hemarthrosis, has highlighted the presence of angiogenesis, hyperproliferation of soft tissues and an abnormal vascular architecture in the synovium. Increased α‐smooth muscle actin (SMA), endoglin (CD105), and VEGF expression were observed, suggesting a significant role of vascular remodelling in the propagation of bleeding and the development of HA. These changes are specific to hemophilic conditions as they were not found in healthy controls or mouse models of RA or OA ²⁰ (Figure 3).

4. DISCUSSION

Based on the literature, it is clear that in OA, RA and HA synovial tissue is characterised by hypertrophy, hyperplasia, and hypervascularization, although the etiopathogenesis of the three conditions seems to be different.

OA begins with mechanical damage due to several multifactorial events causing polarization of the immune system into M1 macrophages. This pathology is mainly characterised by extensive cartilage damage and the formation of new blood vessels in the joint. Even if in a less relevant way, it presents a local inflammation of the synovium which causes morphological modifications. ²¹

RA starts with immunological damage, characterised by hyperactivation of the immune system, mainly neutrophils, T, and B lymphocytes that cause a systemic and immune‐driven inflammation responsible for synovial changes and damage. Unlike OA and HA, this pathology presents little extensive cartilage damage caused by the release of proteolytic enzymes from neutrophils.

HA is caused by chemical and inflammatory damage generated by iron deposits in the joints as remnants of joint bleeds. HA shows peculiarity with OA, with extensive cartilage damage due to chondrocyte apoptosis, and RA, with prominent and reactive synovium inflammation resulting in immune system infiltration and neoangiogenesis. ²² Furthermore, the early stages of HA pathogenesis evolve very similarly to OA through the polarization of macrophages in M1.

Neoangiogenesis is key in the progression of all these diseases.

OA angiogenesis starts from the imbalance between pro‐ and anti‐angiogenetic factors. Little is known about the mechanisms behind such imbalance and further studies are needed to understand what the optimal balance between cytokines for the prevention of OA is and try to find possible therapeutic options. EC are crucial in this phase, they promote angiogenesis thank the interaction with VEGF and MMPs. ¹³

Unlike the other two pathologies, in RA angiogenesis is an initial and crucial event for the evolution of the disease. It is characterised by high levels of TLR 3 and TLR 2 that trigger the migration of ECs that produce metalloproteinases and proteolytic enzymes responsible for the degradation of the basement membrane. ²³

Pro‐angiogenic factors primarily involved in HA angiogenesis are VEGF, Ang‐1, and HIF. Blood deposits stimulate the chemotaxis of EC, which produces proteolytic enzymes and MMPs causing the degradation of the ECM and basement membrane. ECs promote the formation of new vessels, increasing the possibility of new synovium bleeding, with the consequent increase of blood deposits and joint damage, creating a continuous vicious cycle. ²⁴

The literature data collected show that OA, RA, and HA have different specific factors responsible for the pathophysiological mechanism of damage, but also present common factors, such as endothelium and angiogenesis, which play a crucial role in the progression of these three pathologies. These results are very interesting and quite complex, and further studies should be conducted both in vivo and in vitro to clarify all molecular pathways and the role of the numerous molecules involved given a potential therapeutic application.

The most used therapies for the treatment of knee OA patients are corticosteroid and non‐steroidal anti‐inflammatory drugs (NSAIDs) to reduce synovial inflammation and relieve the pain of patients. ⁶ Another interesting therapy opportunity is an angiogenic inhibitor to reduce the progression of joint damage, as reported by a study conducted with humanised monoclonal antibodies directly or indirectly directed against ß‐NGF. This study showed significant improvements in patients' walking and their general health. ²⁵

HA is one of the most common complications of haemophilia, therefore over the last decades bleed prevention has become the cornerstone of treatment aimed at abolishing all possible bleeds including subclinical bleeds. However, this goal is rather ambitious and not yet fully met by current available therapeutic options.

Concerning direct approaches to target synovial inflammation, a recent study by Haxaire observed that the inhibition of the iRhom2/TNF‐α pathway allowed a reduction of bone resorption and synovium inflammation. ²⁶

Currently, there is no RA therapy, only disease‐modifying antirheumatic drug (DMARD) treatment is available, which can prevent disease progression, inhibit pain, and improve the physical condition of patients. The most used is methotrexate, which combined with glucocorticoids has led to an improvement in the disease and some cases to remission. ²⁷ However, this treatment has several side effects and is only effective in 50% of cases, recent studies have hypothesised a new treatment by combining angiogenesis inhibitors with DMARDs, which would appear to make the therapy more effective. ¹⁵ Different studies show that RA and HA have a common progression of inflammation, suggesting inhibition of the iRhom2/TNF‐α pathway as a common treatment for both pathologies ²⁶ (Figure 4).

FIGURE 4.

Therapeutic treatment of OA, RA, and HA. For each chronic inflammatory arthritis, the current therapeutic treatments are shown in green and the treatments are still under study in fuchsia. The treatments under study for RA involve an amplification of those already existing (shown in yellow). ANG‐1, angiopoietins 1; EC, endothelial cells; HIF, hypoxia‐inducible factor; IL‐1ß, cytokine interleukin‐1β; IL‐6, cytokine interleukin‐6; M1, macrophages involved in host defence; MMPs, matrix metalloproteinase; TNF‐α, tumour necrosis factor; VEGF, vascular endothelial growth factor.

Since angiogenesis is a key factor in all these pathologies, it may be interesting to research new treatments in this field.

An interesting in vitro study conducted by Acharya showed that HJD plasma patients are rich in pro‐angiogenic precursors (such as VEGF that induce the formation and stabilization of new vessels) that increase the Hemarthrosis risk. Also was observed angiogenesis completely abrogation by a VEGF‐blocking peptide, suggesting that the disease severity is directly correlated with serum VEGF levels such as OA and RA. It will be interesting to evaluate an inhibitor of VEGF in an in vivo study to understand if it would be a new possible therapy for these diseases. ¹⁹

Analysing the data found in the literature, we could read innovative works of great scientific interest but unfortunately still too few to fully understand such a complex process.

5. CONCLUSION

This review compares for the first time the role of angiogenesis in OA, HA and RA and analyses the molecular pathways involved. These diseases show a different aetiology, but they activate the same molecular pathways. There are still many aspects to be clarified and it would be interesting to conduct in vivo and in vitro studies to identify a possible transversal therapy for these pathologies. Unfortunately, the limit of our work is that the literature data are limited and would need further studies to explain many aspects not yet fully clear and improve the quality of life of these patients.

AUTHOR CONTRIBUTIONS

Conceptualization: Laura Caliogna. Methodology: Camilla Torriani. Investigation: Micaela Berni. Writing—original draft preparation: Alice Maria Brancato. Writing—review and editing: Laura Caliogna and Micaela Berni. Visualization: Gianluigi Pasta. Supervision: Maria Elisa Mancuso, Matteo Nicola Dario Di Minno and Gianluigi Pasta. Validation: Eugenio Jannelli and Mario Mosconi. Project administration: Gianluigi Pasta. All authors have read and agreed to the published version of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors report no other conflict of interest.

ETHICS STATEMENT

The ethics statement does not apply to this article because it did not present human studies, animal studies, clinical trial registration or biosecurity.

Caliogna L, Berni M, Torriani C, et al. Pathogenesis of osteoarthritis, rheumatoid arthritis, and hemophilic arthropathy: The role of angiogenesis. Haemophilia. 2024;30:1256–1264. 10.1111/hae.15097

DATA AVAILABILITY STATEMENT

Data sharing does not apply to this article as no new data were created or analysed in this study.