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Stimulatory Effect of Tofacitinib on Bone Marrow Adipocytes Differentiation
Jean-Guillaume Letarouilly1, Julien Paccou1, Sammy Badr2
1Université de Lille, Centre Hospitalier Universitaire CHU CENTRE HOSPITALIER UNIVERSITAIRE (CHU) Lille, MABLab ULR 4490, Service de Rhumatologie, Lille, France.
Background:
Systemic inflammation is the main factor underlying secondary osteoporosis in patients with rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi), such as tofacitinib (Tofa), can control systemic inflammation and may have beneficial effects on bone in various models. This might be due to direct effects on the bone microenvironment and not exclusively based on their anti-inflammatory function. Bone marrow adipocytes (BMAds) are abundant in the bone microenvironment. The effect of JAKi on BMAds is unknown, but evidence suggests that there is competition between human bone marrow-derived stromal cell (hBMSC) differentiation routes towards BMAds and osteoblasts (Ob) in osteoporosis.
Objectives:
The aims of the study are to determine whether Tofa influences BMAds and Ob derived from hBMSCs and to investigate the potential effects of Tofa on bone marrow adiposity in RA patients.
Methods:
To determine the effect of Tofa on cellular commitment, hBMSCs were differentiated to BMAds or OBs for 3 days together with Tofa at 200, 400, or 800 nM and TNFα. This study was also conducted using differentiated BMAds. The impact of Tofa was determined by gene and protein expression analysis and cell density monitoring. In parallel, in a pilot study of 9 RA patients treated with Tofa 5 mg twice a day (NCT04175886), the proton density fat fraction (PDFF) was measured using MRI at the lumbar spine at baseline and at 6 months.
Results:
In non-inflammatory conditions, the gene expression of Runx2 and Dlx5 decreased in Ob treated with Tofa (p <0.05). The gene expression of PPARγ2, C/EBPα, and Perilipin 1 were increased compared to controls (p <0.05) in BMAds treated with Tofa. Under inflammatory conditions, Tofa did not change the expression profiles of Ob compared to TNFα controls. In contrast, Tofa limited the negative effect of TNFα on BMAd differentiation (p <0.05). An increase in the density of differentiated BMAds treated with Tofa under TNFα was noted (p <0.001). These findings were consolidated by an increase in PDFF at 6 months of treatment with Tofa in RA patients (46.3 ± 7.0% versus 53.2 ± 9.2% p <0.01).
Conclusion:
Together, these results suggest a stimulatory effect of Tofa on BMAd commitment and differentiation, which does not support a positive effect of Tofa on bone.
Insights
Tofacitinib (Tofa) may increase bone marrow fat cells, potentially worsening osteoporosis in rheumatoid arthritis (RA) patients. This janus kinase inhibitor (JAKi) stimulates bone marrow adipocyte differentiation, contrary to expectations for bone health.
Area of Science:
- Rheumatology
- Bone Biology
- Pharmacology
Background:
- Rheumatoid arthritis (RA) systemic inflammation drives secondary osteoporosis.
- Janus kinase inhibitors (JAKi), like tofacitinib (Tofa), target inflammation but may directly impact bone.
- Bone marrow adipocytes (BMAds) and osteoblasts (Ob) compete for stromal cell differentiation, crucial in osteoporosis.
Purpose of the Study:
- Investigate tofacitinib's effect on bone marrow adipocyte and osteoblast differentiation from human bone marrow-derived stromal cells (hBMSCs).
- Assess tofacitinib's impact on bone marrow adiposity in RA patients.
Main Methods:
- hBMSCs were differentiated into BMAds or Ob with Tofa and TNFα, followed by gene/protein analysis.
- Differentiated BMAds were treated with Tofa.
- Pilot study in RA patients measured lumbar spine fat fraction (PDFF) via MRI before and after Tofa treatment.
Main Results:
- Tofa decreased osteoblast differentiation markers (Runx2, Dlx5) and increased adipocyte markers (PPARγ2, C/EBPα, Perilipin 1) in non-inflammatory conditions.
- Tofa enhanced BMAd differentiation under inflammatory conditions (TNFα), increasing BMAd density.
- RA patients on Tofa showed increased lumbar spine PDFF after 6 months.
Conclusions:
- Tofacitinib appears to stimulate bone marrow adipocyte commitment and differentiation.
- These findings suggest Tofa may not have a beneficial effect on bone density in RA patients.
- Further research is needed to clarify the net effect of JAKi on bone metabolism in RA.
