Background/Purpose: Bone marrow mesenchymal stromal cells (BM-MSCs) are multipotent stem cells that can differentiate into chondrocytes, osteoblasts and adipocytes. SLE has been implicated as a stem cell disorder with impaired immunomodulatory function of SLE BM-MSCs and improvement of lupus nephritis with healthy MSCs transplantation has been suggested. However, the exact differentiation defects of SLE BM-MSCs have not been addressed, nor are the potential interventions studied. Our previous work indicates upregulation of IFNβ specific genes in human SLE bone marrow derived MSCs compared to normal bone marrow MSC. In addition, our data also suggest that IFNβ and MAVS (Mitochondrial antiviral-signaling protein) form a positive feedback loop which leads to a senescence-like phenotype in SLE BM-MSCs and impairs MSC immunomodulatory function. Here we set out to investigate the differentiation defects of SLE BM-MSCs and potential intervention approaches.

Methods: The SLE patients recruited in this proposal satisfy the ACR classification criteria for SLE. BM-MSCs were isolated with Ficoll centrifugation (1.073 g/ml) and phenotyped using flow cytometry. In vitro studies included real-time PCR, western blotting and osteoblastogenesis analysis.

Results: We compared 3 age paired BM aspirates from healthy controls and SLE patients. BM-MSCs from SLE patients and healthy controls were isolated and cultured. The MSC surface markers are positive for CD73, CD90 and CD105, but negative for CD34 and CD45 in both healthy and SLE BM-MSCs after culture. No difference was observed in the surface markers between SLE and healthy BM-MSCs. However, SLE MSCs display significantly reduced osteoblastogenesis markers, such ALP (6 fold, p<0.05), RUNX2 (8 fold, p<0.05), OCN (4 fold, p<0.05) and BSP (4 fold, p<0.05). The osteoblast induction and ALP staining analysis for osteoblastogenesis also suggested a reduced differentiation with the SLE BM-MSCs. In contrast to the downregulation of osteoblast markers, the expression of IFNb is increased 5 fold (p<0.05) in SLE BM-MSCs. When BM-MSCs from healthy controls were treated with IFNb for 6 hours, reduced ALP (12 fold, p<0.05), RUNX2 (11 fold, p<0.05), OCN (8 fold, p<0.05) and BSP (7 fold, p<0.05) were observed, suggesting that IFNb plays an important role in inhibiting SLE BM-MSC differentiation into osteoblasts. Conversely, when IFNb neutralizing antibody was applied to SLE BM-MSCs, the osteoblastogenesis markers were significantly enhanced.

Conclusion: IFN-I signature is an important feature of SLE. IFNb has distinct features as compared to IFNα, higher affinity binding to IFN-I receptors, distinct gene transcripts and induction of senescence in non-hematopoietic cells. Our present work suggests that SLE BM-MSCs produce IFNb, mediating a decrease in osteoblastogenesis capacity. Our work sheds lights on the SLE BM pathogenesis. Moreover, the successful rescue of the SLE BM-MSCs osteoblastogenesis defect with an IFNb neutralizing antibody highlights IFNb as a new potential therapeutic target for SLE treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interferon-b-blockade-rescues-human-bm-msc-osteoblastogenesis-defects-in-systemic-lupus-erythematosus/