Systemic Jak1 activation provokes hepatic inflammation and imbalanced FGF23 production and cleavage

Abstract

Fibroblast growth factor 23 (FGF23) is a main regulator of mineral homeostasis. Low and high circulating FGF23 levels are associated with bone, renal, cardiovascular diseases, and increased mortality. Understanding the factors and signaling pathways affecting FGF23 levels is crucial for the management of these diseases and their complications. Here, we show that activation of the Jak1/Stat3 signaling pathway leads to inflammation in liver and to an increase in hepatic FGF23 synthesis, a key hormone in mineral metabolism. This increased synthesis leads to massive C‐terminal FGF23 circulating levels, the inactive C‐terminal fragment, and increased intact FGF23 levels, the active form, resulting in imbalanced production and cleavage. Liver inflammation does not lead to activation of the calcineurin‐NFAT pathway, and no signs of systemic inflammation could be observed. Despite the increase of active intact FGF23, excessive C‐terminal FGF23 levels block the phosphaturic activity of FGF23. Therefore, kidney function and renal αKlotho expression are normal and no activation of the MAPK pathway was detected. In addition, activation of the Jak1/Stat3 signaling pathway leads to high calcitriol levels and low parathyroid hormone production. Thus, JAK1 is a central regulator of mineral homeostasis. Moreover, this study also shows that in order to assess the impact of high FGF23 levels on disease and kidney function, the source and the balance in FGF23 production and cleavage are critical.

Systemic Jak1 activation causes extrarenal calcitriol production and skeletal alterations provoking stunted growth

“…Our previous studies found that calcitriol is elevated in mice following Jak1/Stat3 activation 26 . Here, we confirmed these changes using another independent group of mice (Figure 1A).…”

“…Furthermore, MAP kinase signaling plays a major role in bone formation and remodeling, 35,50,51 and we showed here that systemic Jak1/Stat3 activation led to lower Erk1/2 activation in bone. Moreover, we observed that Il‐6 expression is higher in long bones after Jak1/Stat3 activation indicating local inflammation, as observed previously in the liver 26 . As mentioned previously, Il‐6 (and Il‐1) had been reported to increase osteoclast differentiation, 16,17 and may play a role in the alterations observed here.…”

“…25,26 Examining these mice at young age, before the appearance of the autoimmune disease, revealed that Jak1 also plays a role in mineral homeostasis showing increased total and cleaved FGF23 and calcitriol levels in plasma and decreased PTH, with no alterations in calcium and phosphate levels in plasma. 26 JAK inhibitors (jakinibs) represent a promising therapy in inflammatory and immune diseases. First generation jakinibs are already in use for the treatment of rheumatoid arthritis (RA), myelofibrosis, and ulcerative colitis and many clinical trials are ongoing for a much wider range of diseases including SLE, juvenile arthritis, psoriasis, and various cancers.…”

Serum Fibroblast Growth Factor 23 Level and Liver Fat Content in MAFLD: A Community-Based Cohort

“…7 The emerging evidence shows that the activation of JAK1/STAT3 signaling pathway leads to liver inflammation and liver fat deposition, which can significantly increase the synthesis of FGF23 in the liver, suggesting a bidirectional effect between liver fat deposition and FGF23. 37 To the best of our knowledge, this is the first study of the associations of serum FGF23 level and MAFLD. However, this study had a few limitations.…”

“… 7 The emerging evidence shows that the activation of JAK1/STAT3 signaling pathway leads to liver inflammation and liver fat deposition, which can significantly increase the synthesis of FGF23 in the liver, suggesting a bidirectional effect between liver fat deposition and FGF23. 37 …”