Journal Article

Brucella melitensis clinical isolate modulates osteoclast differentiation to drive pathological bone destruction in brucellar arthritis

Su, Mengru, Chen, Jinlei, Zhi, Feijie, Tuo, Junyun, Song, Wei, Chu, Yuefeng, Zhang, Haihong, Zhao, Guanghai

2025

Overview

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 -induced bone destruction, but the direct cellular tropism of within bone tissue and the specific effects of infection on osteoclasts remain poorly understood. This study aims to characterize the osteoclast tropism of biovar 3 clinical isolates and their direct regulatory effects on osteoclast-mediated bone destruction in -induced arthritis. 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. Three clinical isolates of biovar 3 were obtained from arthritis lesions in patients from Gansu. Genomic analysis revealed homology with geographically diverse Chinese 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. 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 and osteoclasts may thus offer a novel therapeutic strategy for preventing and treating -induced osteolytic lesions.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animals / Apoptosis / Arthritis / Arthritis - microbiology / Arthritis - pathology / Arthritis, Infectious - microbiology / Arthritis, Infectious - pathology / B. melitensis biovar 3 / Biotyping / Bone and Bones - microbiology / Bone and Bones - pathology / Bone resorption / Bone Resorption - microbiology / Bone Resorption - pathology / Bone turnover / Bones / Brucella / Brucella melitensis / Brucella melitensis - genetics / Brucella melitensis - isolation & purification / Brucella melitensis - pathogenicity / Brucella melitensis - physiology / brucellar arthritis / Brucellosis / Brucellosis - microbiology / Brucellosis - pathology / Cell Differentiation / China / Clinical isolates / Disease Models, Animal / Enzyme-linked immunosorbent assay / Female / Genomic analysis / Homeostasis / Homology / Humans / Immunodeficiency / Immunofluorescence / Infections / Intracellular / Livestock / Macrophages / Male / Medical prognosis / Mice / Osteoblastogenesis / Osteoblasts / osteoclast differentiation and function / Osteoclastogenesis / Osteoclasts / Osteoclasts - microbiology / Osteocytes / pathological bone destruction / Patients / Phylogenetics / Public health / Research centers / Splenomegaly / Spondylitis / Tropism / Whole Genome Sequencing / Zoonoses