The Role of Bone-Derived Hormones in Glucose Metabolism, Diabetic Kidney Disease, and Cardiovascular Disorders

Abstract

Bone contributes to supporting the body, protecting the central nervous system and other organs, hematopoiesis, the regulation of mineral metabolism (mainly calcium and phosphate), and assists in respiration. Bone has many functions in the body. Recently, it was revealed that bone also works as an endocrine organ and secretes several systemic humoral factors, including fibroblast growth factor 23 (FGF23), osteocalcin (OC), sclerostin, and lipocalin 2. Bone can communicate with other organs via these hormones. In particular, it has been reported that these bone-derived hormones are involved in glucose metabolism and diabetic complications. Some functions of these bone-derived hormones can become useful biomarkers that predict the incidence of diabetes and the progression of diabetic complications. Furthermore, other functions are considered to be targets for the prevention or treatment of diabetes and its complications. As is well known, diabetes is now a worldwide health problem, and many efforts have been made to treat diabetes. Thus, further investigations of the endocrine system through bone-derived hormones may provide us with new perspectives on the prediction, prevention, and treatment of diabetes. In this review, we summarize the role of bone-derived hormones in glucose metabolism, diabetic kidney disease, and cardiovascular disorders.

The roles of hepatokine and osteokine in liver-bone crosstalk: Advance in basic and clinical aspects

“…Several studies have demonstrated a protective effect of osteocalcin against NAFLD ( 35 , 36 ). In wild-type mice fed a western diet, osteocalcin increased the secretion and sensitivity of insulin ( 8 , 100 ), reduced hepatic sterol regulatory element-binding protein-1 ( 101 ), triglyceride accumulation, malondialdehyde as well as the ratio of oxidized to reduced glutathione ( 102 ). Osteocalcin robustly reduced the expression of proinflammatory and profibrotic genes in liver of Ldlr -/- mice fed with a high-fat, high-cholesterol diet for 12 weeks to induce metabolic syndrome and NASH ( 103 ).…”

“…In clinical research, higher blood level of LCN2 was linked to obesity, insulin resistance, and dyslipidemia in people with type 2 diabetes ( 124 , 125 ). In patients with alcoholic hepatitis (AH), hepatic LCN2 expression and serum LCN2 levels both dramatically increased and were connected with disease severity and portal hypertension ( 45 , 126 , 127 ) LCN2 levels in the blood are a biomarker for metabolic diseases as a result and are expected to be a new therapeutic target to control appetite and obesity ( 8 ). Further investigation is needed in both experimental and clinical studies.…”

“…For instance, osteocytes and osteoblasts secreted FGF23 is positively correlated with liver fat content ( 7 ). Furthermore, osteoblasts-expressed osteocalcin (OCN) has also been reported to increase insulin secretion and sensitivity ( 8 ). The secreted bone factor LCN2 conditional knockout mice in osteoblasts showed increased blood glucose levels and body fat ( 9 ).…”

Bone-kidney axis: A potential therapeutic target for diabetic nephropathy

“…However, recent studies have shown that bone not only acts as the target organ of several endocrine glands or tissues through hormone regulation, but also produces and secretes a large number of bioactive substances, such as bone regulatory proteins, active peptides, growth factors and hormones ( 35 ). These substances can regulate bone homeostasis in both autocrine and paracrine manners and act on the distal target organs in an endocrine manner, thus playing a role in regulating their biological activity ( 36 ). Cellular active substances secreted by bone as an endocrine organ and their relationship with kidney diseases are described below ( Figure 1 ).…”

Renal osteodystrophy: A historical review of its origins and conceptual evolution

“…Notably that of the fibroblast growth factor-23 (FGF23), that suppresses renal phosphate reabsorption and calcitriol synthesis, and of its receptor α-Klotho of the family of enzymes involved in aging termed Klotho, after the Greek mythological figure of Fate who controlled the thread of life ( Ketteler et al, 2018 ; Ott, 2017 ; Patlak and Teitelbaum, 2001 ). Additional hormones secreted from bone include uncarboxylated osteocalcin, that acts on the pancreas to increase insulin production, on fat to regulate metabolism, and on the testis to regulate male fertility; sclerostin that regulates insulin and adipose tissue; and lipocalin 2 that suppresses appetite ( Lee, 2008 ; Takashi and Kawanami, 2022 ).…”