Preface to special issue on ‘Endocrine functions of bone: new (patho)-physiological and clinical insights’

Bone is a very singular tissue that challenges both the medical and human sciences and has even been engaged in the mythical origin of a part of our civilization.

As an example, for archeologists and anthropologists, bone is a particular and unique tissue as it can be the subject of studies long after our death and burial because of its physico-chemical structure, where inorganic mineral molecules represent two thirds of bone mass, and because regulation of bone growth, bone turnover, bone homeostasis and/or bone remodeling and resorption, carried out by osteoblasts/osteoclasts/osteocytes cellular skeletal system, is a specific, constant and continuous mechanism during several stages throughout life. In this way, bone is one marker of our existence, a witness which can notably attest and reveal to our progeny some precious knowledge about us, such as age at death, gender, type of diseases suffered, nutritional habits, way of life and even part of our personal history. Bone is a crucial element to explain the scale of evolution, especially in humans. From another perspective, bone was understood as a symbolic image, an allegory of creation (for half of humanity), as reported by some occidental spiritual currents of thought and theologists.

Far away from these considerations, one central point of all “living” organisms is communication. This is true at all levels, for all hierarchical systems, macroscopic or microscopic, either for the efficient organization of our societies, or for the well-being of our human body. Molecular, hormonal and cellular communication within and/or between organs is an essential and widespread mechanism, because exchange of rapid and renewed information allows the multiplication of specific and acute biological checkpoints and signaling pathways with interdependent regulation, in order to exercise a better adaptative response to the punctual physiological needs and requirements of the organism.

During the last decades, there has been a steadily growing body of evidence suggesting that bone is no longer regarded as a traditional “passive” and isolated biomechanical support tissue having only a limited function as a “static” (but relatively flexible and plastic) structure of the skeleton with independent regulation of bone metabolism, but is now considered, with bone marrow adipose tissue (MAT), a very fascinating, communicative, active and complex connective tissue with large systemic endocrine, paracrine, autocrine and intracrine functions. Bone, as is also the case for adipose tissue, is now recognized as a “great communicator” through developing numerous dynamic interactions and crosstalk, either with the close neighboring cells within the skeleton and/or with the distant target cells in other organs, such as skeletal muscle, adipose deposits, parathyroid gland, liver, pancreas, kidney, brain, testis, and can exert endocrine capabilities by regulating glucose homeostasis and energy metabolism, reproduction and male fertility, cognitive function, inflammation, the immune system, phosphate metabolism and their related disturbances, including metabolic syndrome, type 2 diabetes, obesity, chronic kidney disease, hypertension, cardiovascular damage, male infertility, depression, bone disorders and osteoporosis.

It is well known that bone possesses a highly specialized structure, corresponding to its role as the body’s skeleton (framework). As such, bone assumes numerous unique or specific functions including support of softer tissues and attachment points for skeletal muscle to assist in movement, mechanical protection of internal organs, storage and release of minerals (99% of all calcium in the body is found in the skeleton and teeth), production of blood cells (hematopoiesis) from red bone marrow, storage reserve of fatty acids (chemical energy) with the increase of fat cells (adipocytes) with aging in yellow bone marrow.

For this reason, bone is clearly a target tissue for various hormones. Hence, local bone metabolism (osteoanabolic/osteocatabolic effects) can be regulated by gonadal steroids (estrogen, testosterone), glucocorticoids, thyroid and parathyroid hormone, growth hormone/insulin-like growth factor-1 (IGF-I) axis, vitamin D (calcitriol), calcitonin, or by some new effectors, such as incretin hormones (namely the glucagon-like peptide one and the gastric inhibitory peptide), angiotensin and peroxisome proliferator-activated receptor gamma. However, recent interesting observations have demonstrated that bone is also an endocrine/paracrine/autocrine organ producing specific secretory factors either for the control of its own local metabolism (bone formation, resorption, modeling and remodeling) or for the regulation of some extra-skeletal physiological functions and participation in whole body homeostasis. Among these specific effectors, hormones, growth factors and cytokines, that bind to and modulate skeletal and/or extra-skeletal receptors, we can cite: osteocalcin, skeletal endocannabinoids, bone morphogenetic proteins, fibroblast-growth factor 23 (FGF 23), monocyte chemoattractant protein-1.

This special issue on “Endocrine functions of bone: new (patho)-physiological and clinical insights” (HMBCI, Volume 28, Issues 1–3) provides a very interesting state-of-the-art overview on a new vision of bone. This volume has been compiled by leading scientists recognized in their field, and assembles a group of 11 reviews and one original article that highlight new important information concerning the pivotal role of the crosstalk of bone with peripheral and/or central organs, on their (patho)-physiological outcome and clinical and therapeutical perspectives. The reviews covered in Topic A (Endocrine functions of bone and bone marrow adipose tissue: hormonal, molecular, nutritional mechanisms) include: the mechanistic and complex regulation of the “soft side” of the endocrine function of bone (Rucci team); the endocrine and paracrine secretion of adipokines, cytokines, lipids species by MAT and their clinical relevance (Sulston and Cawthorn); the beneficial contribution of dietary protein to bone health by stimulating the IGF-1 axis, and to the prevention of osteoporosis (Bonjour); analysis of the FGF 23 pathway, associated to its co-receptor Klotho, implicated in phosphate and vitamin D metabolism and their dysregulation, but also in chronic kidney disease-associated complications, cardiovascular diseases, and obesity-related disorders (Kawai).

On the other hand, Topic B (Neuro-endocrine aspects of bone-brain interactions) emphasizes the original and new field of the relation between bone and the central nervous system. Interesting observations in the first review show the central regulation of bone mass and, moreover, how the osteoblast-derived factor, osteocalcin, can be implicated in brain development, behavioral functions and brain pathologies such as depression and schizophrenia (Oury’s team). The discovery that pituitary hormones possess some of their receptors on the skeleton suggests that these molecules, such as: growth hormone, follicle stimulating hormone, thyroid stimulating hormone, adrenocorticotrophic hormone, prolactin, oxytocin and arginine vasopressin, can have direct skeletal action with possible therapeutic effects on bone metabolism or osteoporosis (Zaidi’s team). In this context, oxytocin is more precisely appreciated in relation to its control of bone and fat mass and the potential therapeutic effect of oxytocin in the treatment of obesity-associated diseases and osteoporosis (Amri and Pisani). Finally, an original article reports the presence of luteinizing hormone-releasing hormone (LHRH) receptors in sarcomas of bone, which could be of potential therapeutic importance to inhibit tumor cells by LHRH agonists and antagonists, or by targetting these receptors with peptides conjugated with anti-cancer drugs (Schally’s team).

To conclude, Topic C (Bone patho-physiology and related disorders: therapeutic and clinical impacts) concerns reviews which deal with: regenerative/cell therapy for the treatment of osteoarthritis by using adipose tissue-derived mesenchymal stem cells because of their biological capacity, such as mesodermal differentiation, immunosuppression (Pers and Jorgensen); the influence of eating disorders, anorexia nervosa and obesity, on the variation of bone metabolism and bone marrow adipose tissue via, notably, the modification of adipokine levels and consequent alteration in bone-derived factors, resulting in increased risk of fracture (Migliaccio’s team); the incidence of obesity treatment, bariatric surgery, weight loss pharmaceuticals, and dietary restriction alone, seem deleterious for bone health by decreasing bone mineral density of the hip with a higher fracture risk and by increasing bone turnover (Sainsbury’s team); vitamin D is greatly engaged in the regulation of bone mineralization and calcium, phosphorus homeostasis, but also has extra-skeletal receptors, notably in the male reproductive system with the possibilty to modify calcium and cholesterol content of spermatozoa and sperm capacitation (Costanzo and Knoblovits).

We express our sincere thanks to the distinguished and internationally reknowned scientists, researchers and clinicians, who kindly accepted the invitation to contribute with their expertise to this special issue, and provide a state-of-the-art update on endocrine functions of bone, an exciting new topic that has profound and promising clinical consequences on the health and well-being of millions of individuals around the world. We sincerely hope that readers of Hormone Molecular Biology and Clinical Investigation will enjoy finding some answers and perhaps more importantly, elaborating new pertinent questions that will encourage submission of interesting original articles related to this new highly dynamic medical field.

We warmly thank Ms S.Y. MacDonald for the quality of her help in the editorial process.