Single-cell RNA-sequencing analysis reveals the molecular mechanism of subchondral bone cell heterogeneity in the development of osteoarthritis

Abstract

The cellular composition and underlying spatiotemporal transformation processes of subchondral bone in osteoarthritis (OA) remain unknown. Herein, various cell subsets from tibial plateau of patients with OA are identified, and the mechanism of subchondral microstructure alteration is elaborated using single-cell RNA sequencing technique. We identified two novel endothelial cell (EC) populations characterised by either exosome synthesis and inflammation response or vascular function and angiogenesis. Three osteoblast (OB) subtypes are introduced, separately related to vascularisation, matrix manufacturing and matrix mineralisation. The distinct roles and functions of these novel phenotypes in OA development are further discussed as well as interaction network between these subpopulations. The variation tendency of each population is testified in a destabilisation of the medial meniscus mouse model. The identification of cell types demonstrates a novel taxonomy and mechanism for ECs and OBs inside subchondral bone area provides new insights into the physiological and pathological behaviours of subchondral bone in OA pathogenesis.

Endothelial Stat3 activation promotes osteoarthritis development

“…Meanwhile, subchondral bone abnormal angiogenesis is observed in OA samples 11,25 . Therefore, we collected tibial plateaus from two OA patients to investigate the underlying mechanisms regulating subchondral bone ECs 26 . We selected the medial tibial plateau where severe cartilage injury occurred as the OA group and the almost intact lateral plateau as the control group (Figure S1).…”

Single‐cell RNA sequencing in osteoarthritis

“…112 Our group used scRNA-seq to further identify the cell-cell communication networks in the subchondral bone. 113 Notably, the coupling of osteogenesis and angiogenesis between OBs and ECs (endothelial cells in subchondral bone) may contribute to subchondral bone remodelling. 114 (Figure 6) Previous evidence has shown that the crosstalk between OBs and type-H ECs aggravates subchondral bone remodelling.…”

“…Prevent ECM degradation and promote reparative anabolic processes [72] Cartilage tissue from 10 OA patients CPCs Repair cartilage [53] HTC Human articular cartilage samples GPX4 Anti-ferroptotic effect of Trpv1 in OA cartilage [76] Human meniscus samples FCP Progenitors in OA meniscus [100] ALPN Antiapoptotic maintaining vascular activity in the red-zone of meniscus [106] Human subchondral bone samples Pre-ECs and EC Pathological angiogenesis coupling with aberrant osteogenesis to accelerate OA progression in the subchondral bone [113] Synovial joint tissue ACKR4 Decrease chondrocyte catabolism [85] Human F I G U R E 8 scRNA-seq links potential clinical applications with pre-clinical studies on OA. Singlecell RNA sequencing is a promising technology in preclinical studies to identify potential molecular mechanisms or targets in OA and will be applied as a fundamental method in all aspects of OA clinical studies in the future.…”

Insights into osteoarthritis development from single-cell RNA sequencing of subchondral bone

“…In a current study published in RMD Open , Hu et al 37 analysed the SB of tibial plateaus that were removed from two patients with OA. Through unbiased clustering, 10 clusters were identified.…”

“…Finally, since OA is ‘a disease of the joint as an organ’, it would be exciting to build a comprehensive silicon 3D structure of a diarthrodial joint. This model could be based on scRNA-seq data from joint tissues including AC, 27–29 SB 37 , meniscus, 30 31 synovium membrane 32 33 and even bone marrow microenvironment. 34 It could delineate the alterations in cellular composition and function from the healthy state to various OA stages at the single-cell level.…”