Abstract
Osteoarthritis (OA), the most common joint disorder, is characterised by progressive structural changes in both the cartilage and the underlying subchondral bone. In late disease stages, subchondral bone sclerosis has been linked to heightened osteogenic commitment of bone marrow stromal cells (BMSCs). This study utilised cell sorting and immunohistochemistry to identify a phenotypically-distinct, osteogenically-committed BMSC subset in human OA trabecular bone. Femoral head trabecular bone tissue digests were sorted into CD45-CD271+CD56+CD146-, CD45-CD271+CD56-CD146+ and CD45-CD271+CD56-CD146-(termed double-negative, DN) subsets, and CD45+CD271-hematopoietic-lineage cells served as control. Compared to the CD146+ subset, the CD56+ subset possessed a lower-level expression of adipocyte-associated genes and significantly over 100-fold higher-level expression of many osteoblast-related genes including osteopontin and osteocalcin, whilst the DN subset presented a transcriptionally ‘intermediate’ BMSC population. All subsets were tri-potential following culture-expansion and were present in control non-OA trabecular bone. However, while in non-OA bone CD56+ cells only localised on the bone surface, in OA bone they were additionally present in the areas of new bone formation rich in osteoblasts and newly-embedded osteocytes. In summary, this study reveals a distinct osteogenically-committed CD271+CD56+ BMSC subset and implicates it in subchondral bone sclerosis in hip OA. CD271+CD56+ subset may represent a future therapeutic target for OA and other bone-associated pathologies.
Highlights
Osteoarthritis (OA) is recognised as a disease of the whole joint characterised by pathological changes to cartilage, subchondral bone and the s ynovium[1,2]
We have previously shown an accumulation of CD271+ bone marrow stromal cells (BMSCs) in the damaged femoral head areas of hip OA patients marked by the presence of bone marrow lesions[8], which are known to be associated with cartilage loss and bone s clerosis[16]
hematopoietic-lineage cells (HLCs) followed by the separation of BMSCs into the three distinct subsets: CD56+ (CD45-CD271+CD56+), CD146+ (CD45-CD271+CD146+) and DN (CD45-CD271+CD56-CD146-). (b) Dendrogram showing hierarchical cluster analysis of the BMSCs subsets and HLCs gene expression from OA trabecular bone; the colour scale reflects the log transformed fold differences relative to HPRT1; grey—missing data. (c) Osteogenesis-related genes expressed at significantly higher levels in CD56+ subset compared to CD146+ subset. (d) Genes expressed at lower levels in CD56+ subset compared to CD146+ subset. (e) Chondrogenesis associated genes and CXCL12
Summary
Osteoarthritis (OA) is recognised as a disease of the whole joint characterised by pathological changes to cartilage, subchondral bone and the s ynovium[1,2]. At this bone-lining location, CD56 expression was independently documented in a flat thin cell layer of c ells[23], and in active osteoblasts that coincided with their deposition of collagen I and alkaline phosphatase activity[24] In accumulation, this indicated that CD56 could be acquired by BMSCs as they progressed along the osteogenic lineage, and could, be a potential marker of osteogenically-committed BMSCs. Given the accelerated bone remodelling and sclerosis that is characteristic of OA, it could be predicted that such a BMSC subset might be increased at this location
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