Published online May 26, 2025. doi: 10.4252/wjsc.v17.i5.106934
Revised: April 3, 2025
Accepted: May 7, 2025
Published online: May 26, 2025
Processing time: 76 Days and 17.4 Hours
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 patho
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.
- Citation: Lee GW. Aberrant bone formation and dysregulated bone homeostasis in ankylosing spondylitis. World J Stem Cells 2025; 17(5): 106934
- URL: https://www.wjgnet.com/1948-0210/full/v17/i5/106934.htm
- DOI: https://dx.doi.org/10.4252/wjsc.v17.i5.106934
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.
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).
Category | Molecular mechanism | Effect on osteoclasts | Ref. |
Inflammatory cytokines | TNF-α, IL-17, IL-23, IL-6 | Promotes osteoclast differentiation and activation | [2-4] |
RANK/RANKL/OPG pathway | Increases RANKL expression and decreases OPG | Enhances osteoclast formation and bone resorption | [1,3] |
TNF-α signaling | Activates NF-κB and MAPK pathways | Enhances osteoclast survival and activity | [2-4] |
T-helper cells | Secrete IL-17 and IL-23 | Stimulates RANKL production and osteoclastogenesis | [2,8,14] |
Wnt/β-catenin signaling | Inhibited by DKK-1 and sclerostin | Reduces bone formation, favors resorption | [3,8,10] |
Bone resorption factors | MMPs, CatK | Degrades the bone matrix, increasing erosion | [8,10] |
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.
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].
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, me
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 me
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.
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