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Several factors converge to induce evolution of malignant cells in hematological myeloid malignancies. Such factors accumulate with aging, can be intrinsic or extrinsic to mutation-carrying hematopoietic stem cell clones and in the latter case can be exerted by their microenvironment. The bone marrow microenvironment has emerged as a critical regulator of the development of hematological myeloid malignancies acting as a permissive niche required for the emergence of tumor cells or influencing their progression or resistance to treatment. Identifying mechanisms that mediate functions of the stromal niche on disease development or progression may provide novel targets of therapeutic potential.

The homeostatic role of the skeleton has expanded beyond the regulation of bone growth and remodeling to fulfill two novel endocrine functions: regulation of energy metabolism and male fertility. Bone regulates energy metabolism by favoring insulin secretion, insulin sensitivity, and energy expenditure. In a tight regulatory mechanism, insulin targets the osteoblast to control bone remodeling and through it to promote insulin production by the pancreas. Similar to every endocrine organ, skeletal endocrinology is also under the control of other organs. The fat–brain axis acts through leptin to regulate both the remodeling and endocrine functions of the skeleton. In an opposing and balancing mode of action the brain and the gut exert opposite effects on bone mass accrual, remarkably, through the same protein, serotonin. The intercommunication between the skeleton and its regulating or regulatory organs is mainly mediated by three transcription factors CREB, FoxO1 and ATF4.

Publisher Summary Control of bone remodeling by estrogen results from attenuating effects on the birth rate of osteoblast and osteoclast progenitors as well as from suppressing the production and action of cytokines that are responsible for osteoclastogenesis and osteoblastogenesis. These effects result, in part, from the transcriptional regulation of genes responsible for osteoclastogenesis and mesenchymal cell replication and/or differentiation. Direct effects on osteoblast differentiation and osteoclast lifespan may also be involved. In parallel, estrogen and androgens regulate the lifespan of osteoclasts, osteoblasts and osteocytes. Indeed, maintenance of the balance between bone formation and resorption depends on two parallel actions. In addition, the estrogen receptor (ER) controls the survival of osteocytes, former osteoblasts that are entombed in the mineralized matrix. Appreciation of the adverse effects of estrogen and androgen deficiency on the skeleton has launched a quest for the elucidation of the mechanism of the skeletal actions of sex steroids and the pathogenesis of the bone loss resulting from sex steroid deficiency. This chapter aims to provide a perspective on the advances that have been made in understanding the cellular and molecular mechanisms by which estrogens and androgens influence adult bone homeostasis. By extension, the pathogenetic mechanisms responsible for the development of osteoporosis following sex steroid deficiency have become clearer.

Publisher Summary This chapter focuses on the cellular effects of parathyroid hormone (PTH) on the skeleton. PTH is essential for the maintenance of calcium homeostasis through direct actions on its principal target organs, bone and kidney, and through indirect actions on the gastrointestinal tract. PTH acts directly on the skeleton to promote calcium release from bone and on the kidney to enhance calcium reabsorption. The indirect effects of PTH on the gastrointestinal tract lead to greater calcium absorption through its actions to facilitate the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Actions of PTH at these three sites (the kidney, the skeleton, and the gastrointestinal tract) result in restoration of the extracellular calcium concentration. Furthermore, PTH helps to regulate phosphorus metabolism. An increase in phosphorus leads to a reduction in the circulating calcium concentration. The resultant increase in PTH leads to phosphaturia, a classical physiological effect of the hormone and restoration of the serum phosphorus concentration. Finally, cellular responsiveness to PTH occurs via receptor mediated activation of intracellular events and several major biochemical pathways, which are elucidated in the study.