Editorial Open Access
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. May 26, 2025; 17(5): 106934
Published online May 26, 2025. doi: 10.4252/wjsc.v17.i5.106934
Aberrant bone formation and dysregulated bone homeostasis in ankylosing spondylitis
Gun Woo Lee, Department of Orthopedic Surgery, Yeungnam University College of Medicine, Daegu 42415, South Korea
Gun Woo Lee, Institute for Quantitative Health Science & Engineering, East Lansing, MI 48824, United States
ORCID number: Gun Woo Lee (0000-0002-8441-0802).
Author contributions: Lee GW wrote, revised the manuscript, and approved the final manuscript published.
Supported by 2024 Yeungnam University Research Grant.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Gun Woo Lee, MD, PhD, Associate Professor, Department of Orthopedic Surgery, Yeungnam University College of Medicine, No. 170 Hyunchung-ro, Namgu, Daegu 42415, South Korea. gwlee1871@gmail.com
Received: March 11, 2025
Revised: April 3, 2025
Accepted: May 7, 2025
Published online: May 26, 2025
Processing time: 76 Days and 17.4 Hours

Abstract

Ankylosing spondylitis (AS) is a chronic, progressive, systemic autoimmune disease characterised by spinal stiffness and ocular, cardiac, intestinal, and peripheral joint involvements. Genetics, infectious agents, and immune-mediated inflammatory processes have all been hypothesized to contribute to AS pathogenesis, but the precise aetiology remains elusive. Recent studies have identified biological and cellular factors that correlate with the onset and progression of AS. This has provided avenues of research that may help elucidate disease mechanisms and lead to advances in therapeutic interventions. This study aimed to examine some of the findings from recent molecular studies, focusing on the molecular mechanism and associated factors such as interleukin-17, tumor necrosis factor-alpha, receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa B ligand/osteoprotegerin pathway, and related microRNAs to gain insight into aberrant bone formation in AS and potential approaches to its prevention. This editorial also addresses the contribution of osteoclasts to bone pathology in AS. The author examined the molecular pathways governing osteoclast differentiation and activity, with particular emphasis on relevant cytokines and immune cell interactions. A comprehensive understanding of these mechanisms is essential for the development of targeted therapies to mitigate excessive bone resorption and pathological skeletal remodeling in AS.

Key Words: Ankylosing spondylitis; Cytokines; Immune; Osteoclast; Pathway; Targeted therapy

Core Tip: In ankylosing spondylitis (AS), osteoclasts contribute significantly to pathological bone resorption and remodeling. The receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa B ligand/osteoprotegerin signaling axis, inflammatory cytokines such as interleukin-17 and tumor necrosis factor-alpha, and immune cells such as T helper type 17 and macrophages are central to osteoclastogenesis in AS. Elucidation of the mechanisms governing osteoclast differentiation, activation, and dysregulation in AS is essential for the development of targeted therapeutic strategies that modulate aberrant bone remodeling.



INTRODUCTION

Ankylosing spondylitis (AS) is a chronic inflammatory disease that primarily affects the spine. It begins with the sacroiliac joints and can also involve some joints in the extremities. Symptoms include pain, stiffness, disability, and limited range of motion. As the condition progresses, there is eventual fusion of the spinal joints[1]. Several factors contribute to the development and progression of AS. These include dysfunction of the immune system, dysregulation of the inflammatory process through the expression of inflammatory factors such as tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17), and genetic predisposition, particularly in those with the HLA-B27 gene. Other key drivers of AS progression include abnormal overactivation of bone cells, including osteoclasts and osteoblasts, and dysfunctional inflammation at the points where ligaments and bone meet.

The aberrant bone formation in AS can lead to a variety of comorbidities, including bamboo spine, severe secondary osteoarthritis, and pathologic fractures[2]. The condition is orchestrated by a complex interplay of inflammatory cytokines, signaling pathways, and osteogenic differentiation processes. The inflammatory cytokines TNF-α, IL-17, and IL-23 play pivotal roles in initiating and sustaining inflammation. This, in turn, activates the downstream osteogenic pathways. In addition to the cytokines, molecular abnormalities in the receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) signaling axis, the wingless-related integration site/beta-catenin signaling pathway, and immune cells such as T helper type 17 (Th17) and macrophages have been implicated in the facilitation of aberrant osteogenesis through the promotion of osteoblast differentiation and mineralization.

Current therapeutic approaches focus on inhibition of the aforementioned cytokines, but further research is necessary for future interventions. Unraveling the molecular mechanisms and pathways behind the aberrant bone formation in AS may help to identify new therapeutic targets and the development of treatments able to prevent excessive ossification without compromising bone integrity. This editorial aims to explore the molecular mechanisms underlying aberrant bone formation in AS, highlighting key signaling pathways and potential therapeutic implications.

KEY PATHWAYS AND MOLECULES IN AS OSTEOCLAST DYSFUNCTION

Osteoclasts are primarily responsible for breaking down bone tissue. These become overactive during the early and active stages of AS, leading to bone erosion, which is followed by abnormal bone formation and remodeling. These multinucleated cells play a crucial role in bone resorption, and their dysregulation is a major factor in the skeletal problems seen in AS. However, the exact molecular pathways involved in osteoclast functioning are not yet fully understood (Table 1).

Table 1 Mechanisms of osteoclast dysregulation in ankylosing spondylitis.
Category
Molecular mechanism
Effect on osteoclasts
Ref.
Inflammatory cytokinesTNF-α, IL-17, IL-23, IL-6Promotes osteoclast differentiation and activation[2-4]
RANK/RANKL/OPG pathwayIncreases RANKL expression and decreases OPGEnhances osteoclast formation and bone resorption[1,3]
TNF-α signalingActivates NF-κB and MAPK pathwaysEnhances osteoclast survival and activity[2-4]
T-helper cellsSecrete IL-17 and IL-23Stimulates RANKL production and osteoclastogenesis[2,8,14]
Wnt/β-catenin signalingInhibited by DKK-1 and sclerostinReduces bone formation, favors resorption[3,8,10]
Bone resorption factorsMMPs, CatKDegrades the bone matrix, increasing erosion[8,10]
The RANK/RANKL/OPG pathway

Studies have identified the key signaling molecules and pathways in AS osteoclast formation. The RANK/RANKL/OPG pathway, comprising RANK, RANKL, and OPG, is particularly important in regulating how osteoclasts differentiate in AS. Wang et al[3] investigated six single-nucleotide polymorphisms within these genes and found that variations in the RANKL gene are linked to the formation of syndesmophytes, which are bony spurs in spinal ligaments. They found that a specific combination of these variations, rs7984870C/rs9533155G/rs9525641C, reduces the risk of AS and protects against syndesmophyte formation. This suggests that the RANK/RANKL/OPG pathway influences osteoclast differentiation, which, in turn, may affect AS susceptibility and severity.

IL-17 and TNF-α inflammatory cytokines

Other studies have focused on inflammatory cytokines, primarily IL-17 and TNF-α, and the immune cells that produce them, such as Th17. IL-17 is a powerful cytokine that promotes osteoclast formation. Its receptors are found on many different types of cells[4], including neutrophils and mast cells. The presence of IL-17 activates RANK, and Th17 cells produce RANKL. This leads to the differentiation and proliferation of osteoclast precursors and the activation of osteoclasts. In a mouse model of arthritis, Pickens et al[5] found that those lacking the IL-17RA subunit showed less bone erosion and reduced levels of the chemokines C-X-C motif ligand 1 (CXCL1), CXCL2, CXCL5, C-C motif ligand 9 (CCL9), CCL7, and CCL20, the cytokines IL-1β, IL-6, and RANKL, and certain metal proteinases. TNF-α is known to increase the number of RANK receptors on osteoclast precursor cells, which encourages these cells to differentiate and become active. Recent study has shown that TNF-α and IL-17 work together to increase the production of RANKL[6] and further promote osteoclast formation.

Many different immune cells are also involved in osteoclast formation. As mentioned earlier, Th17 cells are the main source of IL-17, which can stimulate osteoclast differentiation through the RANKL and TNF-α pathways. Macrophages, B cells, and dendritic cells also play important roles in the activation and differentiation of osteoclasts[7]. However, a lack of evidence for direct relationships between abnormal bone formation and the RANKL and TNF-α pathways has led recent studies to direct their focus on other cells, pathways, and molecules to discover the mechanisms involved in aberrant osteogenesis and mineralization. These alternatives have included the wingless-related integration site/beta-catenin signaling pathway, bone morphogenetic proteins, the hedgehog signaling pathway, and osteoblasts[8-10].

Specific microRNAs

MicroRNAs (miRNAs) have been found to contribute to several AS processes, including ossification, the inflammatory response, differentiation of osteoblasts, and the control of immune cells such as lymphocytes and macrophages. Several studies have conducted microarray analyses to compare the profiles of long non-coding RNA, messenger RNA, and miRNA in biopsy samples obtained from patients with AS and healthy controls. Using pathway analysis, gene prediction, and network design, these studies have identified two miRNAs, miR-27b-3p and miR-17-5p, that appear to play significant roles in boosting the ability of ligament fibroblasts to differentiate into bone cells able to promote bone formation in AS[11-13]. MiRNA in extracellular vesicles known as exosomes have also emerged as promising candidates owing to their role in intercellular communication and their ability to transport a variety of bioactive molecules, including proteins, lipids, and nucleic acids. These exosomal miRNAs have also been implicated in the regulation of osteoclast differentiation and function. For example, miR-212-3p has been associated with dysregulated osteoclast activity[3]. Other studies have found specific exosomal miRNAs to play significant roles in osteoclastogenesis. These represent promising potential therapeutic targets in AS. Xie et al[6] discovered that miR-212-3p inhibits the phosphorylation of extracellular signal-regulated kinases 1 and 2, which decreases macrophage clumping and the release of inflammatory substances in AS patients. Manipulation of the miR-212-3p extracellular signal-regulated kinase pathway was shown to promote the differentiation and maturation of osteoclasts, potentially reducing inflammation and abnormal bone growth in AS[6]. A recent study by Liu et al[14] found that M2 macrophage-derived exosomes transfer miR-22-3p to recipient cells, where it modulates osteoclastogenesis. While the specific effects on AS are still under investigation, the effects of miR-22-3p on osteoclast differentiation suggest likely associated effects on the AS bone remodeling processes. Another recent study identified 22 miRNAs with increased expression and two with decreased expression in AS patient-derived exosomes compared with those from healthy controls[11]. These upregulated miRNAs may contribute to the dysregulation of osteoclast activity observed in AS and provide further potential therapeutic targets. Some studies have attempted to understand how osteoclasts become overactive or dysfunctional in AS, particularly in relation to the stiffening of the spine caused by inflammation where ligaments and bone meet. Nevertheless, the process of osteoclast formation in AS is still not well understood[15]. Because of this, only a few treatments aimed at reducing this increased activity have so far been developed. A study by Liu et al[13] made two important discoveries about osteoclast activity in AS. First, mesenchymal stem cells (MSCs) in patients with AS have higher levels of the fat mass obesity-associated protein (FTO). Second, FTO controls the ability of these MSCs to prevent osteoclast formation through a specific pathway involving miR-4284 and the long non-coding RNA non-coding RNA activated by DNA damage. The study concluded that FTO regulates how AS-MSCs function through the non-coding RNA activated by DNA damage/miR-4284 pathway, which could help explain how abnormal bone growth occurs and provide potential targets for AS treatment.

CURRENT LIMITATIONS AND FUTURE PERSPECTIVES

Despite significant advances in our understanding of the key pathways and molecular mechanisms of aberrant bone formation in AS, existing research has several limitations. Importantly, the specifics of the interaction between inflammation and osteogenesis have not been fully elucidated. This impedes the development of precise and efficacious therapeutic interventions. Current treatments are primarily TNF-α and IL-17 inhibitors. These focus on reducing inflammation, but they have only limited effects on the prevention of new bone formation. There is also insufficient information on reliable disease- or pathology-specific biomarkers for the prediction of disease progression and therapeutic response. Since all subtypes of AS otherwise follow the same course and exhibit the same activity, it is important to find a means of identifying which AS patients will experience aberrant bone formation so that preventive treatment can be provided. To overcome these current limitations and obtain a comprehensive understanding of AS pathophysiology, research is needed that utilizes methodology not usually utilized in AS research, such as genomics, transcriptomics, and metabolomics.

CONCLUSION

AS causes serious health problems and significantly impacts quality of life. While researchers have identified several potential mechanisms and molecular factors involved in the development and progression of AS, there is still a great deal we do not know. In particular, the overactivity and dysregulation of osteoclasts play a key role in AS bone problems like bamboo spine. To better understand the underlying molecular interactions and pathways, further research using the latest knowledge and technologies is essential. Addressing these limitations and knowledge gaps through advanced research technologies and innovative strategies is essential to improving our understanding of the disease and developing targeted therapeutics.

Footnotes

Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Cell and tissue engineering

Country of origin: South Korea

Peer-review report’s classification

Scientific Quality: Grade C, Grade C

Novelty: Grade C, Grade C

Creativity or Innovation: Grade C, Grade D

Scientific Significance: Grade C, Grade D

P-Reviewer: Tomsuk Ö S-Editor: Wang JJ L-Editor: A P-Editor: Zhao YQ

References
1.  Chen SR, Munsch MA, Chen J, Couch BK, Wawrose RA, Oyekan AA, Adjei J, Donaldson WF, Lee JY, Shaw JD. Spine Fractures of Patients with Ankylosing Spondylitis and Diffuse Idiopathic Skeletal Hyperostosis: Fracture Severity and Injury-Related Mortality at a Level I Trauma Center. Asian Spine J. 2023;17:549-558.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 5]  [Reference Citation Analysis (0)]
2.  Kim KT, Ha KY, Kim YC, Lee KH, Kim SI, Kim YH, Kim SM. Relationship between Sagittal Alignment and Anterior Bony Resorption of Cervical Vertebral Body in Patients with Ankylosing Spondylitis. Asian Spine J. 2022;16:361-368.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Reference Citation Analysis (0)]
3.  Wang CM, Tsai SC, Lin JC, Wu YJ, Wu J, Chen JY. Association of Genetic Variants of RANK, RANKL, and OPG with Ankylosing Spondylitis Clinical Features in Taiwanese. Mediators Inflamm. 2019;2019:8029863.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 9]  [Cited by in RCA: 7]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
4.  Rossini M, Viapiana O, Adami S, Idolazzi L, Fracassi E, Gatti D. Focal bone involvement in inflammatory arthritis: the role of IL17. Rheumatol Int. 2016;36:469-482.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 31]  [Cited by in RCA: 31]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
5.  Pickens SR, Volin MV, Mandelin AM 2nd, Kolls JK, Pope RM, Shahrara S. IL-17 contributes to angiogenesis in rheumatoid arthritis. J Immunol. 2010;184:3233-3241.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 131]  [Cited by in RCA: 146]  [Article Influence: 9.7]  [Reference Citation Analysis (0)]
6.  Xie J, Xu J, Chen H. Regulatory mechanisms of miR-212-3p on the secretion of inflammatory factors in monocyte-macrophages and the directed differentiation into osteoclasts in ankylosing spondylitis. Aging (Albany NY). 2023;15:13411-13421.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Reference Citation Analysis (0)]
7.  Xue P, Zhang W, Shen M, Yang J, Chu J, Wang S, Wan M, Zheng J, Qiu Z, Cao X. Proton-activated chloride channel increases endplate porosity and pain in a mouse spine degeneration model. J Clin Invest. 2024;134:e168155.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Reference Citation Analysis (0)]
8.  Whangbo M, Ko E, Kim D, Jeon C, Jo HR, Lee SH, Youn J, Jo S, Kim TH. Wnt5a exacerbates pathological bone features and trabecular bone loss in curdlan-injected SKG mice via osteoclast activation. BMB Rep. 2025;58:75-81.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 1]  [Cited by in RCA: 1]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
9.  Tang Y, Yang K, Liu Q, Ma Y, Zhu H, Tang K, Geng C, Xie J, Zhuo D, Wu W, Jin L, Xiao W, Wang J, Zhu Q, Liu J. Preosteoclast plays a pathogenic role in syndesmophyte formation of ankylosing spondylitis through the secreted PDGFB - GRB2/ERK/RUNX2 pathway. Arthritis Res Ther. 2023;25:194.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Reference Citation Analysis (0)]
10.  Zheng G, Peng X, Zhang Y, Wang P, Xie Z, Li J, Liu W, Ye G, Lin Y, Li G, Liu H, Zeng C, Li L, Wu Y, Shen H. A novel Anti-ROS osteoblast-specific delivery system for ankylosing spondylitis treatment via suppression of both inflammation and pathological new bone formation. J Nanobiotechnology. 2023;21:168.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 5]  [Reference Citation Analysis (0)]
11.  Mohammed OA, Alghamdi M, Adam MIE, BinAfif WF, Alfaifi J, Alamri MMS, Alqarni AA, Alhalafi AH, Bahashwan E, AlQahtani AAJ, Ayed A, Hassan RH, Abdel-Reheim MA, Abdel Mageed SS, Rezigalla AA, Doghish AS. miRNAs dysregulation in ankylosing spondylitis: A review of implications for disease mechanisms, and diagnostic markers. Int J Biol Macromol. 2024;268:131814.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Reference Citation Analysis (0)]
12.  Cui P, Zhang Y, Wang C, Xiao B, Wang Q, Zhang L, Li H, Wu C, Tian W. Crucial role of lncRNA NONHSAG037054.2 and GABPA, and their related functional networks, in ankylosing spondylitis. Exp Ther Med. 2024;27:237.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Reference Citation Analysis (0)]
13.  Liu WJ, Wang JX, Li QF, Zhang YH, Ji PF, Jin JH, Zhang YB, Yuan ZH, Feng P, Wu YF, Shen HY, Wang P. Fat mass and obesity-associated protein in mesenchymal stem cells inhibits osteoclastogenesis via lnc NORAD/miR-4284 axis in ankylosing spondylitis. World J Stem Cells. 2025;17:98911.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Reference Citation Analysis (0)]
14.  Liu C, Liang T, Zhang Z, Chen J, Xue J, Zhan X, Ren L. Transfer of microRNA-22-3p by M2 macrophage-derived extracellular vesicles facilitates the development of ankylosing spondylitis through the PER2-mediated Wnt/β-catenin axis. Cell Death Discov. 2022;8:269.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 1]  [Cited by in RCA: 16]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
15.  Chen W, Wang F, Wang J, Chen F, Chen T. The Molecular Mechanism of Long Non-Coding RNA MALAT1-Mediated Regulation of Chondrocyte Pyroptosis in Ankylosing Spondylitis. Mol Cells. 2022;45:365-375.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 4]  [Cited by in RCA: 9]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]