The Central Regulation of Bone Mass: Genetic Evidence and Molecular Bases
The alternation of resorption of preexisting bone by the osteoclasts followed by de novo bone formation by osteoblasts is called bone modeling during childhood and bone remodeling during adulthood. A central question raised by this physiological process t
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Contents 1 Introduction: Why Should Bone Have a Coordinating Role? 2 Leptin Is a Negative Regulator of Bone Mass Accrual 2.1 Bone Mass Increases in the Absence of Leptin Signaling 2.2 Leptin Action on Bone Mass Accrual Is Independent of its Effect on Body Weight 3 Mechanism of the Regulation of Bone Remodeling by Leptin 3.1 Leptin Regulates Bone Remodeling by a Central Mechanism 3.2 Leptin Regulates the Bone Through a Serotonin Relay 3.3 Leptin Regulation of Bone Mass Accrual Is Mediated by Serotonin Signaling to VMH Neurons Via the Htr2c Receptor 4 Establishing the Efferent Mediators of the Central Regulation of Bone Remodeling by Leptin 4.1 Sympathetic Tone Mediates Regulation of Bone Formation and Resorption by Leptin 4.2 A Second Potential Leptin Mediator: Leptin Regulation of Cart Expression in the Hypothalamus Affects Bone Resorption 5 Leptin Actions on Bone Remodeling as Related to Human Bone Biology References
Abstract
The alternation of resorption of preexisting bone by the osteoclasts followed by de novo bone formation by osteoblasts is called bone modeling during childhood and bone remodeling during adulthood. A central question raised by this physiological process that is fundamental to longitudinal growth during childhood and adolescence and that is attacked at the other end of life in the context of osteoporosis is to know how it is regulated. This question was rejuvenated in the late G. Karsenty (*) Departments of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA e-mail: [email protected] # Springer Nature Switzerland AG 2020 Handbook of Experimental Pharmacology, https://doi.org/10.1007/164_2020_378
G. Karsenty
1990s and early 2000s years when the application of mouse genetics made it feasible to test whether there were new endocrine determinants of bone (re)modeling. Addressing this question, taking into account fundamental cell biology features of bone led to the hypothesis that there should be a coordinated control of bone growth/mass, energy metabolism, and reproduction. Testing genetically and molecularly, this hypothesis revealed that, in vivo, the adipocyte-derived hormone leptin is a powerful inhibitor of bone mass accrual following its signaling in the brain. This chapter details the molecular bases and biological relevance of this regulation of bone mass accrual by leptin. Keywords
Bone formation · Bone resorption · Brain serotonin · CART · CREB · RANKL · Sympathetic tone
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Introduction: Why Should Bone Have a Coordinating Role?
A striking cell biological feature of the bone is that it is the only tissue in our body that houses a cell type, the osteoclast, whose only function is to actively destroy the host tissue. This destruction that is energetically demanding occurs daily, from birth to death in hundreds of locations in the skeleton of all bony vertebrates including of course humans. Remarkably, from an energetic vantage point, this destruction is followed, also daily, by de novo bone formation, which is also an ener
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