Bone Formation In Rheumatoid Arthritis Research Articles

TNF-Polarized Macrophages Produce Insulin-like 6 Peptide to Stimulate Bone Formation in Rheumatoid Arthritis in Mice.

The risk of osteoporosis is increased in rheumatoid arthritis (RA). Anti-tumor necrosis factor (TNF) therapy has markedly improved the outcomes of RA patients but does not improve osteoporosis in some reports. This could be a combined result of disease severity and other therapeutic agents, such as glucocorticoids that accelerate osteoporosis progression. We evaluated the effects of anti-TNF therapy on osteoporosis in an animal model of RA and explored the possible mechanisms involved. Six-week-old TNF transgenic (TNF-Tg) mice with early stage erosive arthritis were treated with TNF antibody (Ab) or control immunoglobulin (IgG) weekly for 4 weeks. We found that TNF Ab completely blocked the development of erosive arthritis in TNF-Tg mice, but only slightly increased vertebral bone mass, associated with reduction in parameters of both bone resorption and formation. Similarly, TNF Ab slightly increased trabecular bone mass in tibias of 8-month-old TNF-Tg mice with advanced erosive arthritis. Interestingly, TNFα increased osteoblast differentiation from mouse bone marrow stromal cells (BMSCs) containing large number of macrophages but not from pure mesenchymal progenitor cells (MPCs). TNFα-polarized macrophages (TPMs) did not express iNos and Arginase 1, typical markers of inflammatory and resident macrophages. Interestingly, TPMs stimulated osteoblast differentiation, unlike resident and inflammatory macrophages polarized by IL-4 and interferon-λ, respectively. RNA-seq analysis indicated that TPMs produced several anabolic factors, including Jagged1 and insulin like 6 (INSL6). Importantly, inhibition of either Jagged1 or INSL6 blocked TNFα-induced osteoblast differentiation. Furthermore, INSL6 Ab significantly decreased the expansion of TNF-induced MPCs in BMSCs, and anti-TNF Ab reduced INSL6 expression by macrophages in vitro and in TNF-Tg mice in vivo. We conclude that TPMs produce INSL6 to stimulate bone formation and anti-TNF Ab blocks not only enhanced bone resorption but also the anabolic effect of TPMs on bone, limiting its effect to increase bone mass in this model of RA. © 2021 American Society for Bone and Mineral Research (ASBMR).

Osteoblastic PLEKHO1 contributes to joint inflammation in rheumatoid arthritis.

BackgroundOsteoblasts participating in the inflammation regulation gradually obtain concerns. However, its role in joint inflammation of rheumatoid arthritis (RA) is largely unknown. Here, we investigated the role of osteoblastic pleckstrin homology domain-containing family O member 1 (PLEKHO1), a negative regulator of osteogenic lineage activity, in regulating joint inflammation in RA.MethodsThe level of osteoblastic PLEKHO1 in RA patients and collagen-induced arthritis (CIA) mice was examined. The role of osteoblastic PLEKHO1 in joint inflammation was evaluated by a CIA model and a K/BxN serum-transfer arthritis (STA) model which were induced in osteoblast-specific Plekho1 conditional knockout mice and mice expressing high Plekho1 exclusively in osteoblasts, respectively. The effect of osteoblastic PLEKHO1 inhibition was explored in a CIA mice model and a non-human primate arthritis model. The mechanism of osteoblastic PLEKHO1 in regulating joint inflammation were performed by a series of in vitro studies.ResultsPLEKHO1 was highly expressed in osteoblasts from RA patients and CIA mice. Osteoblastic Plekho1 deletion ameliorated joint inflammation, whereas overexpressing Plekho1 only within osteoblasts exacerbated local inflammation in CIA mice and STA mice. PLEKHO1 was required for TRAF2-mediated RIP1 ubiquitination to activate NF-κB for inducing inflammatory cytokines production in osteoblasts. Moreover, osteoblastic PLEKHO1 inhibition diminished joint inflammation and promoted bone formation in CIA mice and non-human primate arthritis model.ConclusionsThese data strongly suggest that the highly expressed PLEKHO1 in osteoblasts contributes to joint inflammation in RA. Targeting osteoblastic PLEKHO1 may exert dual therapeutic action of alleviating joint inflammation and promoting bone formation in RA.

B cells inhibit bone formation in rheumatoid arthritis by suppressing osteoblast differentiation

The function of B cells in osteoblast (OB) dysfunction in rheumatoid arthritis (RA) has not been well-studied. Here we show that B cells are enriched in the subchondral and endosteal bone marrow (BM) areas adjacent to osteocalcin+ OBs in two murine RA models: collagen-induced arthritis and the TNF-transgenic mice. Subchondral BM B cells in RA mice express high levels of OB inhibitors, CCL3 and TNF, and inhibit OB differentiation by activating ERK and NF-κB signaling pathways. The inhibitory effect of RA B cells on OB differentiation is blocked by CCL3 and TNF neutralization, and deletion of CCL3 and TNF in RA B cells completely rescues OB function in vivo, while B cell depletion attenuates bone erosion and OB inhibition in RA mice. Lastly, B cells from RA patients express CCL3 and TNF and inhibit OB differentiation, with these effects ameliorated by CCL3 and TNF neutralization. Thus, B cells inhibit bone formation in RA by producing multiple OB inhibitors.

Differential mechanisms of de-regulated bone formation in rheumatoid arthritis and spondyloarthritis.

The inflammatory arthropathies share in common their tendency to produce marked alterations in skeletal remodelling and architecture. This review will focus on RA and the seronegative spondyloarthopathies (SpA), which share common features with respect to their tendency to produce localized bone destruction at sites of articular and peri-articular inflammation. However, there are significant differences in the skeletal pathology in these conditions, which include the unique involvement of the axial skeleton and the presence of inflammation in the extra-articular entheses in SpA. There also are differences in the pattern of bone formation and repair associated with the articular and peri-articular inflammation. This review will highlight the molecular and cellular processes that are involved in the pathogenesis of the skeletal pathology in these two forms of inflammatory arthritis with specific focus on the pathogenic mechanisms underlying the differential patterns of bone formation and repair.

Insulin-Like Growth Factor I Does Not Drive New Bone Formation in Experimental Arthritis

IntroductionInsulin like growth factor (IGF)-I can act on a variety of cells involved in cartilage and bone repair, yet IGF-I has not been studied extensively in the context of inflammatory arthritis. The objective of this study was to investigate whether IGF-I overexpression in the osteoblast lineage could lead to increased reparative or pathological bone formation in rheumatoid arthritis and/or spondyloarthritis respectively.MethodsMice overexpressing IGF-I in the osteoblast lineage (Ob-IGF-I+/-) line 324–7 were studied during collagen induced arthritis and in the DBA/1 aging model for ankylosing enthesitis. Mice were scored clinically and peripheral joints were analysed histologically for the presence of hypertrophic chondrocytes and osteocalcin positive osteoblasts.Results90–100% of the mice developed CIA with no differences between the Ob-IGF-I+/- and non-transgenic littermates. Histological analysis revealed similar levels of hypertrophic chondrocytes and osteocalcin positive osteoblasts in the ankle joints. In the DBA/1 aging model for ankylosing enthesitis 60% of the mice in both groups had a clinical score 1<. Severity was similar between both groups. Histological analysis revealed the presence of hypertrophic chondrocytes and osteocalcin positive osteoblasts in the toes in equal levels.ConclusionOverexpression of IGF-I in the osteoblast lineage does not contribute to an increase in repair of erosions or syndesmophyte formation in mouse models for destructive and remodeling arthritis.

WNT5A is a novel regulator of cytokine and chemokine expression in bone marrow stromal cells

WNT5A is a novel regulator of cytokine and chemokine expression in bone marrow stromal cells

TNF-α and IL-1β inhibit RUNX2 and collagen expression but increase alkaline phosphatase activity and mineralization in human mesenchymal stem cells

Aims Joint inflammation leads to bone erosion in rheumatoid arthritis (RA), whereas it induces new bone formation in spondyloarthropathies (SpAs). Our aims were to clarify the effects of tumour necrosis factor α (TNF-α) and interleukin 1β (IL-1β) on osteoblast differentiation and mineralization in human mesenchymal stem cells (MSCs). Main methods In MSCs, expression of osteoblast markers was assessed by real-time PCR and ELISA. Activity of tissue-nonspecific alkaline phosphatase (TNAP) and mineralization were determined by the method of Lowry and alizarin red staining respectively. Involvement of RUNX2 in cytokine effects was investigated in osteoblast-like cells transfected with a dominant negative construct. Key findings TNF-α (from 0.1 to 10 ng/ml) and IL-1β (from 0.1 to 1 ng/ml) stimulated TNAP activity and mineralization in MSCs. Addition of 50 ng/ml of IL-1 receptor antagonist in TNF-α-treated cultures did not reverse TNF-α effects, indicating that IL-1 was not involved in TNF-α-stimulated TNAP activity. Both TNF-α and IL-1β decreased RUNX2 expression and osteocalcin secretion, suggesting that RUNX2 was not involved in mineralization. This hypothesis was confirmed in osteoblast-like cells expressing a dominant negative RUNX2, in which TNAP expression and activity were not reduced. Finally, since mineralization may merely rely on increased TNAP activity in a collagen-rich tissue, we investigated cytokine effects on collagen expression, and observed that cytokines decreased collagen expression in osteoblasts from MSC cultures. Significance The different effects of cytokines on TNAP activity and collagen expression may therefore help explain why inflammation decreases bone formation in RA whereas it induces ectopic ossification from collagen-rich entheses during SpAs.