Sodium chloride induces and amplifies human T _H 2 cell responses, potentially shaping the atopic skin microenvironment.

Th cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here, we demonstrate that high-NaCl conditions induced a stable, pathogen-specific, antiinflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and IL-17A expression in high-NaCl conditions. The NaCl-induced acquisition of an antiinflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high-NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a proinflammatory and TGF-β–low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.

Dysregulated actions of bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) result in several inherited diseases, such as X-linked hypophosphatemia (XLH), and contribute substantially to the mortality in kidney failure. Mechanisms governing FGF23 production are poorly defined. We herein found that ablation of the G _q/11 α–like, extralarge Gα subunit (XLαs), a product of GNAS , exhibits FGF23 deficiency and hyperphosphatemia in early postnatal mice (XLKO). FGF23 elevation in response to parathyroid hormone, a stimulator of FGF23 production via cAMP, was intact in XLKO mice, while skeletal levels of protein kinase C isoforms α and δ (PKCα and PKCδ) were diminished. XLαs ablation in osteocyte-like Ocy454 cells suppressed the levels of FGF23 mRNA, inositol 1,4,5-trisphosphate (IP3), and PKCα/PKCδ proteins. PKC activation in vivo via injecting phorbol myristate acetate (PMA) or by constitutively active Gqα-Q209L in osteocytes and osteoblasts promoted FGF23 production. Molecular studies showed that the PKC activation–induced FGF23 elevation was dependent on MAPK signaling. The baseline PKC activity was elevated in bones of Hyp mice, a model of XLH. XLαs ablation significantly, but modestly, reduced serum FGF23 and elevated serum phosphate in Hyp mice. These findings reveal a potentially hitherto-unknown mechanism of FGF23 synthesis involving a G protein–coupled IP3/PKC pathway, which may be targeted to fine-tune FGF23 levels.

Since the field-changing invention of noncemented hip arthroplasty fixation in the 1980s, noncemented fixation has been progressively replacing cemented fixation. However, analyses of fixation frequencies reveal new patterns in cement versus noncemented preferences. Although cementation is again gaining ground in the United States, noncemented models remain the dominant fixation mode, seen in more than 90% of all hip arthroplasties. This stark preference is likely driven by concerns regarding implant durability and patient safety. Although advances in surgical techniques, intensive perioperative care, and improved instrument have evolved in both methods, data from large arthroplasty registries reveal shifting risks in contemporary hip arthroplasty, calling the use of noncemented fixation into question. Varying risk profiles regarding sex, age, or health comorbidities and morphological and functional differences necessitate personalized risk assessments. Furthermore, certain patient populations, based on the literature and data from large registries, have superior outcomes from cemented hip arthroplasty techniques. Therefore, we wanted to critically evaluate the method of arthroplasty fixation in primary hip arthroplasties for unique patient populations.

Fibroblast growth factor-23 (FGF23) is critical for phosphate and vitamin D homeostasis. Cellular and molecular mechanisms underlying FGF23 production remain poorly defined. The extra-large Gα subunit (XLαs) is a variant of the stimulatory G protein alpha-subunit (Gsα), which mediates the stimulatory action of parathyroid hormone in skeletal FGF23 production. XLαs ablation causes diminished FGF23 levels in early postnatal mice. Herein we found that plasma FGF23 levels were comparable in adult XLαs knockout (XLKO) and wild-type littermates. Upon adenine-rich diet-induced renal injury, a model of chronic kidney disease, both mice showed increased levels of plasma FGF23. Unexpectedly, XLKO mice had markedly higher FGF23 levels than WT mice, with higher blood urea nitrogen and more severe tubulopathy. FGF23 mRNA levels increased substantially in bone and bone marrow in both genotypes; however, the levels in bone were markedly higher than in bone marrow. In XLKO mice, a positive linear correlation was observed between plasma FGF23 and bone, but not bone marrow, FGF23 mRNA levels, suggesting that bone, rather than bone marrow, is an important contributor to severely elevated FGF23 levels in this model. Upon folic acid injection, a model of acute kidney injury, XLKO and WT mice exhibited similar degrees of tubulopathy; however, plasma phosphate and FGF23 elevations were modestly blunted in XLKO males, but not in females, compared to WT counterparts. Our findings suggest that XLαs ablation does not substantially alter FGF23 production in adult mice but increases susceptibility to adenine-induced kidney injury, causing severe FGF23 elevations in plasma and bone.

Background/Objectives: Limb malalignment disrupts physiological joint forces and predisposes individuals to the development of osteoarthritis. Surgical interventions such as distal femur or high tibial osteotomy aim to restore mechanical balance on weight-bearing joints, thereby reducing long-term morbidity. Accurate alignment is crucial since it cannot be adjusted after stabilization with plates and screws. Recent advances in personalized medicine offer the opportunity to tailor surgical corrections to each patient’s unique anatomy and biomechanical profile. This study evaluates the benefits of 3D planning and patient-specific cutting guides over traditional 2D planning with standard implants for alignment correction procedures. Methods: We assessed limb alignment parameters pre- and postoperatively in patients with varus and valgus lower limb malalignment undergoing acute realignment surgery. The cohort included 23 opening-wedge high tibial osteotomies and 28 opening-wedge distal femur osteotomies. We compared the accuracy of postoperative alignment parameters between patients undergoing traditional 2D preoperative X-ray planning and those using 3D reconstructions of CT data. Outcome measures included mechanical axis deviation and tibiofemoral angles. Results: 3D reconstructions of computerized tomography data and patient-specific cutting guides significantly reduced the variation in postoperative limb alignment parameters relative to preoperative goals. In contrast, traditional 2D planning with standard non-custom implants resulted in higher deviations from the targeted alignment. Conclusions: Utilizing 3D CT reconstructions and patient-specific cutting guides enhances the accuracy of postoperative limb realignment compared to traditional 2D X-ray planning with standard non-custom implants. Patient-specific instrumentation and personalized approaches represent a key step toward precision orthopedic surgery, tailoring correction strategies to individual patient anatomy and potentially improving long-term joint health. This improvement may reduce the morbidity associated with lower limb malalignment and delay the onset of osteoarthritis. Level of Evidence: Therapeutic Level III.