TO THE EDITOR—Chow et al [1] recently implicated interleukin 6 (IL-6) in the persistent arthralgia that occurs in some patients following infection with chikungunya virus (CHIKV). They observed that plasma IL-6 concentrations in patients with persistent arthralgia were higher than those in fully recovered patients; the significance of this observation is supported by the known role of IL-6 in causing joint pain [2]. A role for IL-6 in persistent arthralgia is further supported by the finding by Hoarau et al [3] that IL-6 is specifically expressed in the affected joint during chronic chikungunya disease. Nevertheless, the plasma IL-6 concentration in patients with chronic disease is low (interquartile range, 4–40 pg/mL) and close to normal values [1]. IL-6 is expressed by a variety of cell types, including osteoblasts, and the low circulating levels suggest the joint as a potential source of this cytokine. IL-6 stimulates the release of RANKL [4] and inhibits the one of its decoy receptor osteoprotegerin (OPG) [5] by osteoblasts, therefore promoting osteoclastogenesis and bone resorption [6]. The RANKL/ OPG ratio indeed drives osteoclastogenesis and osteoclast activation [7]. This raises the possibility that dysregulation of IL-6, RANKL, and OPG during CHIKV infection may contribute to joint pathology. In this context, we aimed to determine whether osteoblasts may be involved in CHIKV induced chronic rheumatic syndromes. First, we tested whether primary human osteoblasts are susceptible to CHIKV infection in vitro. Osteoblast cultures were prepared from bone samples obtained from a healthy male subject during a knee operation for a cause unrelated to arthritis. The patient’s medical history indicated no autoimmune disorders, metabolic diseases, intake of immune suppressant/stimulating drugs, or immunotherapy for 3 months before surgery. Bone fragments were cultured in α minimum essential medium supplemented with 10% fetal calf serum, 100 mM ascorbic acid, 20 mM HEPES, and 2 mM L-glutamine. After 2 weeks, confluent cells surrounding fragments were collected and subcultured. Osteoblast characterization by osteocalcin staining and measurement of alkaline phosphatase activity showed >98% purity [8]. Cell monolayers were infected with CHIKV at a multiplicity of infection of 0.1 for 1 hour at 37°C, washed, and fed with fresh media. As shown in Figure 1A, CHIKV replicated in osteoblasts between days 1 and 20 after infection, at levels comparable to that described for macrophages [9]. The decrease in virus production with

/pdf/interleukin-6-rankl-and-osteoprotegerin-expression-by-3mmp7j0gst.pdf

Interleukin 6, RANKL, and Osteoprotegerin Expression by Chikungunya Virus–Infected Human Osteoblasts

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

Re-directing mesenchymal stromal cell (MSC) chondrogenesis towards a non-hypertrophic articular chondrocyte-(AC)-like phenotype is important for improving articular cartilage neogenesis to enhance clinical cartilage repair strategies. This study is the first to demonstrate that high levels of non-canonical WNT5A followed by WNT11 and LEF1 discriminated MSC chondrogenesis from AC re-differentiation. Moreover, β-catenin seemed incompletely silenced in differentiating MSCs, which altogether suggested a role for WNT signaling in hypertrophic MSC differentiation. WNT inhibition with the small molecule IWP-2 supported MSC chondrogenesis according to elevated proteoglycan deposition and reduced the characteristic upregulation of BMP4, BMP7 and their target ID1, as well as IHH and its target GLI1 observed during endochondral differentiation. Along with the pro-hypertrophic transcription factor MEF2C, multiple hypertrophic downstream targets including IBSP and alkaline phosphatase activity were reduced by IWP-2, demonstrating that WNT activity drives BMP and hedgehog upregulation, and MSC hypertrophy. WNT inhibition almost matched the strong anti-hypertrophic capacity of pulsed parathyroid hormone-related protein application, and both outperformed suppression of BMP signaling with dorsomorphin, which also reduced cartilage matrix deposition. Yet, hypertrophic marker expression under IWP-2 remained above AC level, and in vivo mineralization and ectopic bone formation were reduced but not eliminated. Overall, the strong anti-hypertrophic effects of IWP-2 involved inhibition but not silencing of pro-hypertrophic BMP and IHH pathways, and more advanced silencing of WNT activity as well as combined application of IHH or BMP antagonists should next be considered to install articular cartilage neogenesis from human MSCs.

Regulation of WNT5A and WNT11 during MSC in vitro chondrogenesis: WNT inhibition lowers BMP and hedgehog activity, and reduces hypertrophy.

Osteochondral defects remain a major clinical challenge mainly due to the combined damage to the articular cartilage and the underlying bone, and the interface between the two tissues having very d...

https://journals.sagepub.com/doi/pdf/10.1177/2041731419896068

Biomimetic gradient scaffold of collagen–hydroxyapatite for osteochondral regeneration:

Multiple pharmacological inhibitors targeting the epigenetic suppressor enhancer of zeste homolog 2 (Ezh2) accelerate osteoblast differentiation.

Myocyte Enhancer Factor 2C, an Osteoblast Transcription Factor Identified by Dimethyl Sulfoxide (DMSO)-enhanced Mineralization

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Myocyte Enhancer Factor 2C, an Osteoblast Transcription Factor Identified by Dimethyl Sulfoxide (DMSO)-enhanced Mineralization