Endocrine role of bone in the regulation of energy metabolism

Abstract

Bone mainly functions as a supportive framework for the whole body and is the major regulator of calcium homeostasis and hematopoietic function. Recently, an increasing number of studies have characterized the significance of bone as an endocrine organ, suggesting that bone-derived factors regulate local bone metabolism and metabolic functions. In addition, these factors can regulate global energy homeostasis by altering insulin sensitivity, feeding behavior, and adipocyte commitment. These findings may provide a new pathological mechanism for related metabolic diseases or be used in the diagnosis, treatment, and prevention of metabolic diseases such as osteoporosis, obesity, and diabetes mellitus. In this review, we summarize the regulatory effect of bone and bone-derived factors on energy metabolism and discuss directions for future research.

Fig. 1

The cells that make up bone mainly include osteocytes, osteoblasts, osteoclasts, and chondrocytes in bone tissue, as well as bone marrow mesenchymal cells and bone marrow adipocytes in the bone marrow cavity. Different cells can produce different endocrine factors, which can enter the blood circulation to regulate multiple organs in the body

Fig. 2

Metabolic regulation of factors derived from cells in bone tissue. a OCN can be decarboxylated in osteoblasts, transformed into unOCN, and secreted into the blood. It can primarily bind to the GPRC6A receptor on the cell membrane and activate downstream PI3K/mTOR/Akt signals to affect gene expression. OPG, as a competitive ligand of RANK and TRAIL receptors, can combine with RANK and TRAIL to reduce the distribution of RANK/RANKL and TRAILR/TRAIL on the cell membrane and further affect gene expression. FGF23 can regulate energy metabolism by forming a feedback regulation loop with 1,25(OH)₂D₃ and PTH. BMP is mainly derived from osteocytes. Different kinds of BMPs can combine with type I and type II serine/threonine kinase receptors on the cell membrane and can interfere with important downstream pathways, such as MAPK, PI3K/Akt, Wnt, hedgehog, and notch, through Smad protein-dependent or Smad-independent pathways, playing a role in regulating metabolism. b The BMP family influences the key steps of fat production and preadipocyte differentiation into WAT and BAT and regulates the function of adipocytes

Fig. 3

Exosomes and inflammatory factors are mainly secreted by BMSCs. After forming vesicles containing various active substances, exosomes are released into the extracellular matrix. The inflammatory factors released by BMSCs can be divided into proinflammatory factors and anti-inflammatory factors. Exosomes and inflammatory factors can regulate distant target organs, thus leading to an inflammatory response, obesity, insulin resistance, etc

Fig. 4

MAT can secrete RANKL, the ligand of RANK. RANKL regulates metabolism by binding with RANK on the cell membrane. In addition, MAT can also secrete the adipokines leptin and adiponectin. Leptin and adiponectin combine with ADIPOR and OBR on the cell membrane of peripheral tissue, regulating cellular sugar metabolism. They also act on the central nervous system, leading to reduced food intake and energy consumption

Fig. 5

The network relationship between bone and whole-body energy metabolism. Aging is one of the main causes of bone and whole-body metabolism disorder, and exercise training can alleviate it. Changes in bone metabolism will affect multiple organs and tissues, including the brain (a potential research direction in the future), and lead to metabolic diseases. Metabolic diseases, as well as changes in circulating endocrine factors, can in turn affect bone. On the other hand, bone-derived factors can also be used as autocrine factors to regulate their own metabolic state