Volume 28, Issue 1 - Special issue: Endocrine Functions of Bone: New (Patho)-Physiological and Clinical Insights / Editors: Gérard S. Chetrite and Bruno Féve

Bone has always been regarded as a merely structural tissue, a “hard” scaffold protecting all of its “soft” fellows, while they did the rest of the work. In the last few decades this concept has totally changed, and new findings are starting to portray bone as a very talkative tissue that is capable not only of being regulated, but also of regulating other organs. In this review we aim to discuss the endocrine regulation that bone has over whole-body homeostasis, with emphasis on energy metabolism, male fertility, cognitive functions and phosphate (Pi) metabolism. These delicate tasks are mainly carried out by two known hormones, osteocalcin (Ocn) and fibroblast growth factor 23 (FGF23) and possibly other hormones that are yet to be found. The extreme plasticity and dynamicity of bone allows a very fine tuning over the actions these hormones exert, portraying this tissue as a full-fledged endocrine organ, in addition to its classical roles. In conclusion, our findings suggest that bone also has a “soft side”, and is daily taking care of our entire organism in ways that were unknown until the last few years.

White adipose tissue (WAT) is a major endocrine organ, secreting a diverse range of hormones, lipid species, cytokines and other factors to exert diverse local and systemic effects. These secreted products, known as ‘adipokines’, contribute extensively to WAT’s impact on physiology and disease. Adipocytes also exist in the bone marrow (BM), but unlike WAT, study of this bone marrow adipose tissue (MAT) has been relatively limited. We recently discovered that MAT contributes to circulating adiponectin, an adipokine that mediates cardiometabolic benefits. Moreover, we found that MAT expansion exerts systemic effects. Together, these observations identify MAT as an endocrine organ. Additional studies are revealing further secretory functions of MAT, including production of other adipokines, cytokines and lipids that exert local effects within bone. These observations suggest that, like WAT, MAT has secretory functions with diverse potential effects, both locally and systemically. A major limitation is that these findings are often based on in vitro approaches that may not faithfully recapitulate the characteristics and functions of BM adipocytes in vivo. This underscores the need to develop improved methods for in vivo analysis of MAT function, including more robust transgenic models for MAT targeting, and continued development of techniques for non-invasive analysis of MAT quantity and quality in humans. Although many aspects of MAT formation and function remain poorly understood, MAT is now attracting increasing research focus; hence, there is much promise for further advances in our understanding of MAT as an endocrine organ, and how MAT impacts human health and disease.

Dietary protein represents an important nutrient for bone health and thereby for the prevention of osteoporosis. Besides its role as a brick provider for building the organic matrix of skeletal tissues, dietary protein stimulates the production of the anabolic bone trophic factor IGF-I (insulin-like growth factor I). The liver is the main source of circulating IGF-I. During growth, protein undernutrition results in reduced bone mass and strength. Genetic defect impairing the production of IGF-I markedly reduces bone development in both length and width. The serum level of IGF-I markedly increases and then decreases during pubertal maturation in parallel with the change in bone growth and standing height velocity. The impact of physical activity on bone structure and strength is enhanced by increased dietary protein consumption. This synergism between these two important environmental factors can be observed in prepubertal boys, thus modifying the genetically determined bone growth trajectory. In anorexia nervosa, IGF-I is low as well as bone mineral mass. In selective protein undernutrition, there is a resistance to the exogenous bone anabolic effect of IGF-I. A series of animal experiments and human clinical trials underscore the positive effect of increased dietary intake of protein on calcium-phosphate economy and bone balance. On the contrary, the dietary protein-induced acidosis hypothesis of osteoporosis is not supported by several experimental and clinical studies. There is a direct effect of amino acids on the local production of IGF-I by osteoblastic cells. IGF-I is likely the main mediator of the positive effect of parathyroid hormone (PTH) on bone formation, thus explaining the reduction in fragility fractures as observed in PTH-treated postmenopausal women. In elderly women and men, relatively high protein intake protects against spinal and femoral bone loss. In hip fracture patients, isocaloric correction of the relatively low protein intake results in: increased IGF-I serum level, significant attenuation of postsurgical bone loss, improved muscle strength, better recovery, and shortened hospital stay. Thus, dietary protein contributes to bone health from early childhood to old age. An adequate intake of protein should be recommended in the prevention and treatment of osteoporosis.

The function of fibroblast growth factor (FGF) 23 has been suggested to be multifaceted beyond its canonical function as a regulator of mineral metabolism. FGF23 was originally shown to play a central role in phosphate (Pi) and vitamin D metabolism, and a number of diseases associated with dysregulated Pi metabolism have been attributed to abnormal FGF23 signaling activities. The discovery of Klotho as a co-receptor for FGF23 signaling has also accelerated understanding on the molecular mechanisms underlying Pi and vitamin D metabolism. In addition to these canonical functions, FGF23 has recently been implicated in a number of metabolic diseases including chronic kidney disease-associated complications, cardiovascular diseases, and obesity-related disorders; however, the physiological significance and molecular mechanisms of these emerging roles of FGF23 remain largely unknown. Molecular and functional insights into the FGF23 pathway will be discussed in the present review, with an emphasis on its role in human disorders related to dysregulated Pi metabolism as well as metabolic disorders.