Single-cell RNA sequencing identifies a senescence-related BMSC subpopulation with dual senescence and hyperactive metabolism phenotype as the predominant population in AS patients with advanced syndesmophytes, suggesting JAK inhibitors may serve as effective agents to reverse this pathogenic BMSC signature.
Key Findings
Methods
Single-cell RNA sequencing of BMSCs from AS patients revealed eight distinct subpopulations forming a continuum from progenitors to lineage-committed cells.
BMSCs were obtained from 12 AS patients stratified into severe structural damage (SSD, n=9) and no structural damage (NSD, n=3) groups
Stratification was based on mSASSS and SPARCC-SSS assessments
After quality control, 47,628 cells were analyzed by unsupervised clustering
Analysis methods included trajectory inference, metabolic profiling, pathway enrichment, and in silico drug screening
Results
A distinct senescence-related cluster (SRC) was identified as the predominant BMSC subpopulation in AS patients with advanced syndesmophytes.
The SRC was specifically enriched in the severe structural damage (SSD) group compared to the no structural damage (NSD) group
The SRC displayed a dual phenotype combining cellular senescence and hyperactive metabolism
This subpopulation was closely associated with structural progression in AS
The SRC represented a specific differentiation state within the eight identified BMSC subpopulations
Results
The senescence-related BMSC cluster exhibited elevated glycolysis and oxidative phosphorylation supporting secretion of matrix-remodeling and inflammatory factors.
The SRC was characterized by elevated glycolysis and oxidative phosphorylation
This hyperactive metabolic state supported secretion of matrix-remodeling factor MMP2
Inflammatory cytokine IL-6 was also identified as a secreted product of the SRC
The metabolic phenotype was described as 'hyperactive metabolism' co-occurring with cellular senescence markers
Results
A five-gene signature linking oxidative stress to aberrant differentiation trajectory was identified in the senescence-related cluster.
The specific gene signature consisted of CDR1, PLPPR2, CMBL, SRXN1, and PPP1R3C
These genes were identified as linking oxidative stress to the aberrant differentiation trajectory of the SRC
This signature was associated with the pathological bone-forming phenotype
The signature was derived from pathway enrichment analysis of the SRC subpopulation
Results
Computational in silico drug screening predicted JAK inhibitors baricitinib and filgotinib as potential therapeutics to attenuate the senescence-related cluster phenotype.
In silico drug screening was performed to identify therapeutic candidates targeting the SRC
Both baricitinib and filgotinib were highlighted as candidate agents
These JAK inhibitors were predicted to reverse the pathogenic BMSC signature
The computational prediction suggested these agents may attenuate the dual senescence and hypermetabolic phenotype of the SRC
Discussion
The study provides a cellular basis for pathological bone formation in AS by identifying a senescence-associated, hypermetabolic BMSC subpopulation closely associated with structural progression.
The findings establish that BMSCs are pathologically reprogrammed under chronic inflammation in AS
The SRC represents a mechanistic link between cellular senescence, hypermetabolism, and aberrant new bone formation
Structural damage was quantified using mSASSS and SPARCC-SSS scores to stratify patients
The study characterizes molecular features of pathogenic subpopulations and identifies potential therapeutic targets
What This Means
Ankylosing spondylitis (AS) is an inflammatory arthritis that causes abnormal new bone growth in the spine, eventually fusing vertebrae together. Scientists have long suspected that bone marrow stem cells — cells that normally help maintain and repair the skeleton — might be misbehaving in AS patients, but the details were unclear. This research used a powerful technology called single-cell RNA sequencing to read the genetic activity of nearly 48,000 individual bone marrow stem cells from 12 AS patients, allowing researchers to identify distinct cell subpopulations and compare those from patients with severe bone damage versus those without.
The study found eight different bone marrow stem cell subtypes, including one specific group called the 'senescence-related cluster' (SRC) that was far more abundant in patients with advanced spine fusion. This cluster showed an unusual combination of cellular aging (senescence) and highly revved-up energy metabolism, and these cells were actively producing proteins known to remodel the tissue matrix (MMP2) and drive inflammation (IL-6). A five-gene fingerprint — CDR1, PLPPR2, CMBL, SRXN1, and PPP1R3C — was also identified as linking oxidative stress to the abnormal bone-forming behavior of these cells. Using computer-based drug screening, the researchers predicted that two existing JAK inhibitor drugs, baricitinib and filgotinib, could potentially reverse this harmful stem cell state.
This research suggests that a specific 'senescent' stem cell population plays a key role in driving the abnormal bone growth seen in ankylosing spondylitis, and that targeting these cells' activity — potentially with already-approved JAK inhibitors — could be a strategy to slow structural damage. The findings provide new insight into why some AS patients develop severe spinal fusion while others do not, and may help guide future research into more targeted treatments for the disease.
Luo X, Li J, Qi J, Lin C, Wu J, Jin O, et al.. (2026). Single-cell profiling reveals senescent bone marrow mesenchymal stem cell subpopulations driving pathological ossification in ankylosing spondylitis.. Rheumatology (Oxford, England). https://doi.org/10.1093/rheumatology/keag429