Objective: Over-activity of transforming growth factor β1 in subchondral bone has a direct causal role in rodent models of knee osteoarthritis (OA), which can be blocked by β1 neutralisation. In this study, we investigated whether the spatially distributed level of active β 1 in human subchondral bone associates with the characteristic structural, cellular and molecular parameters of human knee OA. Design: Subchondral bone samples (35 OA arthroplasty patients, aged 69±9 years) were obtained from regions below either macroscopically present or denuded cartilage. Bone samples were processed to determine the concentration of active β 1 (ELISA) and gene-specific mRNA expression (RT-PCR). Synchrotron micro-CT imaging was utilised to assess the bone microstructure, bone mineralization, the osteocyte lacunar network and bone matrix vascularity. Finally, samples were histologically examined for cartilage OARSI grading, quantification of tartrate resistant acid phosphatase positive cells and bone marrow micro-vasculature. Results: Subchondral bone below severely degenerated/depleted cartilage, characterised by impaired bone matrix quality due to sclerotic microarchitecture, disorganised collagen, high heterogeneity of the mineral distribution, contained increased concentrations of active β 1, compared to adjacent areas with more intact cartilage. In addition, increased levels of active β 1 related directly to increased bone volume while increased OARSI grade associated directly with morphometric characteristics (size, shape and orientation) of osteocyte lacunae. Conclusion: These results indicate that increased active β 1 associates spatially with impaired bone quality and the disease severity of human OA. This study therefore suggests that β 1 could be a therapeutic target to prevent or reduce human disease progression.
Elevated levels of active Transforming Growth Factor β1 in the subchondral bone relate spatially to cartilage loss and impaired bone quality in human knee osteoarthritis
