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 … Show more
“…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).…”
Section: Resultssupporting
confidence: 89%
“…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.…”
Section: Discussionsupporting
confidence: 89%
“…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.…”
Mineral homeostasis is regulated by a complex network involving endocrine actions by calcitriol, parathyroid hormone (PTH), and FGF23 on several organs including kidney, intestine, and bone. Alterations of mineral homeostasis are found in chronic kidney disease and other systemic disorders. The interplay between the immune system and the skeletal system is not fully understood, but cytokines play a major role in modulating calcitriol production and function. One of the main cellular signaling pathways mediating cytokine function is the Janus kinase (JAK)––signal transducer and activator of transcription (STAT) pathway. Here, we used a mouse model (Jak1S645P+/−) that resembles a constitutive activating mutation of the Jak1/Stat3 signaling pathway in humans, and shows altered mineral metabolism, with higher fibroblast growth factor 23 (FGF23) levels, lower PTH levels, and higher calcitriol levels. The higher calcitriol levels are probably due to extrarenal calcitriol production. Furthermore, systemic Jak1/Stat3 activation led to growth impairment and skeletal alterations. The growth plate in long bones showed decreased chondrocyte proliferation rates and reduced height of terminal chondrocytes. Furthermore, we demonstrate that Jak1 is also involved in bone remodeling early in life. Jak1S645P+/− animals have decreased bone and cortical volume, imbalanced bone remodeling, reduced MAP kinase signaling, and local inflammation. In conclusion, Jak1 plays a major role in bone health probably both, directly and systemically by regulating mineral homeostasis. Understanding the role of this signaling pathway will contribute to a better knowledge in bone growth and in mineral physiology, and to the development of selective Jak inhibitors as osteoprotective agents.
“…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).…”
Section: Resultssupporting
confidence: 89%
“…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.…”
Section: Discussionsupporting
confidence: 89%
“…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.…”
Mineral homeostasis is regulated by a complex network involving endocrine actions by calcitriol, parathyroid hormone (PTH), and FGF23 on several organs including kidney, intestine, and bone. Alterations of mineral homeostasis are found in chronic kidney disease and other systemic disorders. The interplay between the immune system and the skeletal system is not fully understood, but cytokines play a major role in modulating calcitriol production and function. One of the main cellular signaling pathways mediating cytokine function is the Janus kinase (JAK)––signal transducer and activator of transcription (STAT) pathway. Here, we used a mouse model (Jak1S645P+/−) that resembles a constitutive activating mutation of the Jak1/Stat3 signaling pathway in humans, and shows altered mineral metabolism, with higher fibroblast growth factor 23 (FGF23) levels, lower PTH levels, and higher calcitriol levels. The higher calcitriol levels are probably due to extrarenal calcitriol production. Furthermore, systemic Jak1/Stat3 activation led to growth impairment and skeletal alterations. The growth plate in long bones showed decreased chondrocyte proliferation rates and reduced height of terminal chondrocytes. Furthermore, we demonstrate that Jak1 is also involved in bone remodeling early in life. Jak1S645P+/− animals have decreased bone and cortical volume, imbalanced bone remodeling, reduced MAP kinase signaling, and local inflammation. In conclusion, Jak1 plays a major role in bone health probably both, directly and systemically by regulating mineral homeostasis. Understanding the role of this signaling pathway will contribute to a better knowledge in bone growth and in mineral physiology, and to the development of selective Jak inhibitors as osteoprotective agents.
“…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.…”
Section: Discussionmentioning
confidence: 88%
“… 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 …”
Purpose
Although fibroblast growth factor-23 (FGF23) is involved in the development of metabolic diseases, its association with metabolic-associated fatty liver disease (MAFLD) remains unknown. We explored the relationship between serum fibroblast growth factor-23 level, metabolic associated fatty liver disease, and liver fat content.
Patients and Methods
Participants were enrolled from communities in Shanghai. Serum fibroblast growth factor-23 level was determined using two-side sandwich enzyme-linked immunosorbent assays. MAFLD was diagnosed using the international expert consensus (2020) criteria. Liver fat content was assessed using ultrasound.
Results
We enrolled 1827 individuals aged 30–80 years (mean age, 59.4±7.3 years). MAFLD was diagnosed in 445/1393 (31.9%) non-diabetic participants and 245/434 (56.5%) diabetic participants. After adjusting for confounders, one standard deviation increase in serum FGF23 was associated with MAFLD in diabetic (odds ratio, 1.27; 95% confidence interval, 1.15–1.49;
P
<0.001) and non-diabetic (odds ratio, 1.28; 95% confidence interval, 1.07–1.74;
P
=0.030) groups. In a fully adjusted linear regression model, serum FGF23 emerged as a positive determinant of liver fat content in both diabetic and non-diabetic groups (
P
=0.039;
P
=0.034).
Conclusion
Participants with MAFLD had higher serum fibroblast growth factor-23 level than those without MAFLD, regardless of diabetes status. Serum fibroblast growth factor-23 was independently related to MAFLD and liver fat content.
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