Brucella melitensis clinical isolate modulates osteoclast differentiation to drive pathological bone destruction in brucellar arthritis
Bibliographic record
Abstract
Background Brucellosis is a widespread zoonosis that is acquired by humans from infected animals. Articular complications, particularly brucellar spondylitis, are the most prevalent and disabling manifestations of human brucellosis. Inflammation-mediated osteoclast activation is implicated in Brucella -induced bone destruction, but the direct cellular tropism of Brucella within bone tissue and the specific effects of infection on osteoclasts remain poorly understood. This study aims to characterize the osteoclast tropism of Brucella melitensis biovar 3 clinical isolates and their direct regulatory effects on osteoclast-mediated bone destruction in Brucella -induced arthritis. Methods Brucella clinical isolates were obtained from the bone tissues of human brucellar spondylitis patients in Gansu Province, China. Whole-genome sequencing and biotyping identified their specific biovars. These isolates were used to generate arthritis in immunodeficient NCG mice; bone homeostasis in these mice was assessed via ELISA. We assessed their cellular tropism and osteoclast-modulating effects through intracellular survival assays, immunofluorescence, histopathology, TRAP staining, and resorption pit analysis. Results Three clinical isolates of B. melitensis biovar 3 were obtained from arthritis lesions in patients from Gansu. Genomic analysis revealed homology with geographically diverse Chinese Brucella strains. Although these isolates reached splenic bacterial loads similar to the virulent strain 16M, they did not cause splenomegaly by two weeks post-infection. The isolates displayed strong tropism for human and murine osteoclasts, achieving significantly higher intracellular loads compared to osteoblasts or osteocytes. Infection at the osteoclast precursor/bone marrow macrophage stage enhanced early osteoclastogenesis while inhibiting late-stage apoptosis and fusion, leading to prolonged osteoclast survival and aggravated bone resorption and defects. In contrast, conditioned medium from infected osteoblasts or osteocytes had minimal impact on late-stage osteoclast differentiation. Conclusions These findings elucidate the mechanisms underlying pathological bone defects in brucellar arthritis. The direct bacterial effects, together with the formation of an osteoclast-derived pro-survival niche, account for the prevalence of brucellar arthritis as the most common complication of chronic brucellosis. Targeting the interaction between B. melitensis and osteoclasts may thus offer a novel therapeutic strategy for preventing and treating Brucella -induced osteolytic lesions.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".