The peripheral blood (PB) monocyte pool contains osteoclast progenitors (OCPs), which contribute to osteoresorption in inflammatory arthritides and are influenced by the cytokine and chemokine milieu. We aimed to define the importance of chemokine signals for migration and activation of OCPs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). PB and, when applicable, synovial fluid (SF) samples were collected from 129 patients with RA, 53 patients with PsA, and 110 control patients in parallel to clinical parameters of disease activity, autoantibody levels, and applied therapy. Receptors for osteoclastogenic factors (CD115 and receptor activator of nuclear factor-κB [RANK]) and selected chemokines (CC chemokine receptor 1 [CCR1], CCR2, CCR4, CXC chemokine receptor 3 [CXCR3], CXCR4) were determined in an OCP-rich subpopulation (CD3−CD19−CD56−CD11b+CD14+) by flow cytometry. In parallel, levels of CC chemokine ligand 2 (CCL2), CCL3, CCL4, CCL5, CXC chemokine ligand 9 (CXCL9), CXCL10, and CXCL12 were measured using cytometric bead array or enzyme-linked immunosorbent assay. Sorted OCPs were stimulated in culture by macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand, and they were differentiated into mature osteoclasts that resorb bone. Selected chemokines (CCL2, CCL5, CXCL10, and CXCL12) were tested for their osteoclastogenic and chemotactic effects on circulatory OCPs in vitro. The OCP population was moderately enlarged among PB cells in RA and correlated with levels of tumor necrosis factor-α (TNF-α), rheumatoid factor, CCL2, and CCL5. Compared with PB, the RANK+ subpopulation was expanded in SF and correlated with the number of tender joints. Patients with PsA could be distinguished by increased RANK expression rather than total OCP population. OCPs from patients with arthritis had higher expression of CCR1, CCR2, CCR4, CXCR3, and CXCR4. In parallel, patients with RA had increased levels of CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10, with significant elevation in SF vs PB for CXCL10. The subset expressing CXCR4 positively correlated with TNF-α, bone resorption marker, and rheumatoid factor, and it was reduced in patients treated with disease-modifying antirheumatic drugs. The CCR4+ subset showed a significant negative trend during anti-TNF treatment. CCL2, CCL5, and CXCL10 had similar osteoclastogenic effects, with CCL5 showing the greatest chemotactic action on OCPs. In our study, we identified distinct effects of selected chemokines on stimulation of OCP mobilization, tissue homing, and maturation. Novel insights into migratory behaviors and functional properties of circulatory OCPs in response to chemotactic signals could open ways to new therapeutic targets in RA.

25-Hydroxyvitamin D (25-OHD) may have a prognostic value in colorectal cancer (CRC) patients. However, as 25-OHD concentration is strongly impacted by surgery, it is uncertain what is the most reliable time-point for 25-OHD assessment, pre- or post-operative. Therefore, we examined 515 CRC patients (AJCC I-III) who underwent surgery. Blood samples were collected either pre-operatively (n = 286; median = 1 day before surgery) or post-operatively (n = 229; median = 8 days). Serum 25-OHD concentration was determined by liquid chromatography–tandem mass spectrometry. Association between 25-OHD and survival was tested in the whole cohort, followed by stratified analyses in pre- and post-operatively sampled. Median 25-OHD in the cohort was 36.7 nmol/L and median follow-up time was 5.9 years. There were no differences between pre- and post-operative cohort in age, sex, 25-OHD, AJCC stage, or localization of tumor. After adjustment, higher 25-OHD (>50 nmol/L) was associated with better overall survival only in post-operative (HR = 0.53; 95% CI: 0.33–0.84; P = 0.006), but not in pre-operative cohort (HR = 1.13; 95% CI: 0.77–1.65; P = 0.53). In conclusion, higher post-operative 25-OHD levels were associated with better survival outcome in CRC patients, while no such association was found for pre-operative levels. Time-point of blood collection should be addressed carefully in future research as it might affect the prognostic value of 25-OHD in CRC.

Recent studies have established a concept of tumour necrosis factor‐α (TNF‐α)/Fas signalling crosstalk, highlighting TNF‐α as a critical cytokine in sensitizing hepatocytes to death induced by Fas activation. However, in the exact inflammatory response, besides TNF‐α, many other mediators, that might modulate apoptotic response differentially, are released. To resolve the issue, we studied the effects of lipopolysaccharide (LPS), one of the crucial inductors of inflammation in the liver, on apoptotic outcome. We show that LPS‐induced inflammation diminishes the sensitivity of hepatocytes to Fas stimulus in vivo at caspase‐8 level. Analysis of molecular mechanisms revealed an increased expression of various pro‐inflammatory cytokines in non‐parenchymal liver cells and hepatocyte‐specific increase in Bcl‐xL, associated with signal transducer and activator of transcription 3 (Stat3) phosphorylation. Pre‐treatment with ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, prevented the LPS‐induced Stat3 phosphorylation and restored the sensitivity of hepatocytes to Fas‐mediated apoptosis. Furthermore, ruxolitinib pre‐treatment diminished the LPS‐induced Bcl‐xL up‐regulation without an inhibitory effect on LPS‐induced expression of pro‐inflammatory cytokines. In summary, although the reports are showing that the effects of isolated pro‐inflammatory mediators, such as TNF‐α or neutrophils, are pro‐apoptotic, the overall effect of inflammatory milieu on hepatocytes in vivo is Stat3‐dependent desensitization to Fas‐mediated apoptosis.

Rheumatoid arthritis (RA) is an inflammatory joint disease that eventually leads to permanent bone and cartilage destruction. Fas has already been established as the regulator of inflammation in RA, but its role in bone formation under arthritic conditions is not completely defined. The aim of this study was to assess the effect of Fas inactivation on the bone damage during murine antigen‐induced arthritis. Subchondral bone of wild‐type (WT) and Fas‐knockout (Fas ^−/− ) mice was evaluated by histomorphometry and microcomputerized tomography. Proportions of synovial bone and cartilage progenitors were assessed by flow cytometry. Synovial bone and cartilage progenitors were purified by fluorescence‐activated cell sorting and expression of Fas and Fas‐induced apoptosis were analyzed in vitro . Results showed that Fas ^−/− mice developed attenuated arthritis characterized by preserved epiphyseal bone and cartilage. A proportion of the earliest CD200 ⁺ bone and cartilage progenitors was reduced in WT mice with arthritis and was unaltered in Fas ^−/− mice. During osteoblastic differentiation in vitro , CD200 ⁺ cells express the highest levels of Fas and are removed by Fas ligation. These results suggest that Fas‐induced apoptosis of early CD200 ⁺ osteoprogenitor population represents potential mechanism underlying the impaired bone formation in arthritis, so their preservation may represent the bone‐protective mechanism during arthritis.—Lazić Mosler, E., Lukač, N., Flegar, D., Fadljević, M., Radanović, I., Cvija, H., Kelava, T., Ivčević, S., Šućur, A., Markotić, A., Katavić, V., Marušić, A., Grčević, D., Kovačić, N. Fas receptor induces apoptosis of synovial bone and cartilage progenitor populations and promotes bone loss in antigen‐induced arthritis. FASEB J. 33, 3330–3342 (2019). www.fasebj.org

While increased serum concentrations of CXCL9/10 are associated with acute cellular rejection (ACR) occurrence, the association between CXCL9/10 single nucleotide polymorphisms (SNPs) and ACR after liver transplantation (LT) remains unknown. In the present case-control study, polymorphisms of CXCL9 (rs10336) and CXCL10 (rs3921) were determined by polymerase chain reaction in 215 liver transplant recipients. ACR was defined as biopsy proven within 6 months after LT. As selected SNPs were in 3’-UTR region, their possible association with protein synthesis was assessed by measuring the plasma concentration of CXCL9/10 in a cohort of 40 new transplant patients using ELISA. There was no association between CXCL9/10 genotypes and overall incidence of ACR. However, patients with CXCL9 genotype AA developed ACR earlier than patients with GG genotype (P = .003), with similar results for CXCL10 gene (CC vs GG; P = .005). There was no statistically significant difference in plasma concentrations of CXCL9/10 between the rejectors and the non-rejectors. Of note, patients with AA CXCL9 genotype had significantly higher CXCL9 plasma concentrations than patients with AG (P = .01) or GG genotype (P = .045). In conclusion, the SNPs of CXCL9 (rs10336) and CXCL10 (rs3921) are not associated with the incidence of ACR. However, patients with CXCL9 genotype AA developed ACR earlier and the same genotype was associated with greater plasma concentrations suggesting the involvement of CXCL9 mediated processes in ACR development.

Pain remains one of the most burdensome symptoms in rheumatoid arthritis (RA), often persisting despite inflammatory remission and profoundly impairing quality of life. This review aimed to evaluate the clinical efficacy and mechanistic pathways by which Janus kinase (JAK) inhibitors alleviate RA-related pain. Evidence from randomized clinical trials demonstrates that JAK inhibitors have demonstrated rapid and significant pain relief, often exceeding that of methotrexate or biologic DMARDs. Improvements in patient-reported pain scores seem to typically emerge within 1–2 weeks and are sustained over time. Beyond anti-inflammatory effects, JAK inhibitors modulate central sensitization and nociceptive signaling by attenuating IL-6 and GM-CSF activity, reducing astrocyte and microglial activation, and downregulating nociceptor excitability in dorsal root ganglia and spinal pathways. Preclinical models further suggest that JAK inhibition interrupts neuroimmune feedback loops critical to chronic pain maintenance. Comparative and network meta-analyses consistently position JAK inhibitors among the most effective agents for pain control in RA. However, individual variability in response, partly due to differential JAK-STAT activation and cytokine receptor uncoupling, underscores the need for biomarker-guided treatment approaches. JAK inhibitors represent a mechanistically distinct and clinically impactful class of therapies that target both inflammatory and non-inflammatory pain in RA. Their integration into personalized pain management strategies offers a promising path to address one of RA’s most persistent unmet needs.