Bone and the regulation of global energy balance

Abstract

The skeleton, populated by large numbers of osteoblasts and long-lived osteocytes, requires a constant supply of energy-rich molecules to fuel the synthesis, deposition, and mineralization of bone matrix during bone modeling and remodeling. When these energetic demands are not met, bone acquisition is suppressed. Recent findings suggest that key developmental signals emanating from WNT- low-density lipoprotein-related receptor 5 and Hypoxia-inducible factor pathways impact osteoblast bioenergetics to accommodate the energy requirements for bone cells to fulfill their function. In vivo studies in several mutant mouse strains have confirmed a link between bone cells and global metabolism, ultimately leading to the identification of hormonal interactions between the skeleton and other tissues. The hormones insulin and leptin affect postnatal bone acquisition, while osteocalcin produced by the osteoblast in turn stimulates insulin secretion by the pancreas. These observations have prompted additional questions regarding the nature of the mechanisms of fuel sensing and processing in the osteoblast and their contribution to overall energy utilization and homeostasis. Answers to such questions should advance our understanding of metabolic diseases and may ultimately improve management of affected patients. In this review we highlight recent studies in this field and offer a perspective on the evolutionary implications of bone as a metabolic endocrine organ.

Sclerostin antibody treatment improves fracture outcomes in a Type I diabetic mouse model

“…However, reduced osteocalcin has also recently been implicated in metabolic activity of osteoblasts, in which reduced insulin signaling in osteoblasts and reduced Runx2 expression may fail to activate osteocalcin to promote local and systemic metabolic homeostasis in STZ diabetes (57) . In STZ diabetic mice, osteoblasts are no longer able to depend on glucose as an energy source, but must rely on lipid metabolism to generate ATP (57) . LRP5, a Wnt co-receptor, has been implicated in this process, and mice lacking Lrp5 develop metabolic imbalance with increased adiposity.…”

Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner

“…The formation and maintenance of the vertebrate skeleton are energy-intensive processes that impact global energy expenditure and are influenced by metabolic hormones like insulin, leptin, and adiponectin (1)(2)(3)(4)(5). In states of extreme malnourishment, bone growth ceases and a reduction in bone mass is associated with increased fracture risk (6)(7)(8).…”

Determining the Role of Sost and Sostdc1 During Fracture Healing

“…However, reduced osteocalcin has also recently been implicated in metabolic activity of osteoblasts, in which reduced insulin signaling in osteoblasts and reduced Runx2 expression may fail to activate osteocalcin to promote local and systemic metabolic homeostasis in STZ diabetes [158]. In STZ diabetic mice, osteoblasts are no longer able to depend on glucose as an energy source, but must rely on lipid metabolism to generate ATP [158]. LRP5, a Wnt co-receptor, has been implicated in this process, and mice lacking Lrp5 develop metabolic imbalance with increased adiposity.…”