More about FSH and bone: TNF comes into the game
Postmenopausal osteoporosis is traditionally attributed to declining estrogen levels. However, a recent study showed that follicle-stimulating hormone (FSH), the secretion of which is under estrogenic feedback, directly enhances osteoclast formation and function. The deletion of one of its subunits protects against bone loss despite severe hypogonadism. This finding suggests that elevated FSH contributes to the genesis of postmenopausal osteoporosis.
However, hypogonadal bone loss is accompanied by alterations in bone and bone marrow, notably enhanced bone formation, increased T lymphocyte production, and macrophage activation. The alterations in immune function have been attributed to an increase in TNFα production that is thought to arise from estrogen deficiency.
Constitutive activity of the osteoblast calcium-sensing receptor promotes loss of cancellous bone
Remodeling of the skeleton is a physiological process crucial for the maintenance of skeletal integrity and systemic calcium homeostasis. Local extracellular calcium concentration ([Ca2+]e) fluctuates dramatically within bone multicellular units, from ~0.5 mM during bone formation, when the extracellular matrix is being mineralized, to ≥2 mM during bone resorption and matrix degradation. Osteoblasts sense and respond to fluctuations in [Ca2+]e independently of systemic factors: high [Ca2+]e promote osteoblast chemotaxis, proliferation, maturation, gene expression, and matrix mineralization. Osteoblasts express the calcium receptor (CaR) that detects and responds to changes in [Ca2+]e. Important physiological functions of the CaR have been shown in the parathyroid and kidney cells.
Inhibin A stimulates bone mass and strength: news from the ovary-bone axis
Bone turnover is tightly regulated to maintain sufficient bone mass and strength to prevent fracture during normal physical activity. In diseases of bone loss, such as osteoporosis, decreased bone mass and strength, leading to nontraumatic fractures of the spine, hip, and other bones, are common and the result of an imbalance in bone turnover.
Towards elucidation of the central nervous system network involved in leptin control of bone formation
Once it was known that leptin acts on the central nervous system, the next step was to identify leptin-sensitive neurons controlling bone formation. This was achieved through chemical lesioning in wild-type and leptin signaling-deficient mice, and the use of other genetically modified mouse models. These experiments established that hypothalamic neural networks regulate bone formation. The final proof that leptin was the mediator came when ob/ob mice, which lack leptin, with destroyed arcuate or ventromedial hypothalamic (VMH) neurons received leptin ICV (intracerebroventricular) infusion. In this situation, leptin ICV infusion decreased body weight but did not affect bone formation parameters or bone mass. Thus, VMH neurons regulate bone formation under the control of leptin [1, 2].
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Leptin: in search of a hormonal regulation of bone formation
Two major features of osteoporosis are that osteoporosis invariably follows gonadal failure, and that obesity protects from it. These two observations suggest the existence of a common regulation of body weight (or appetite), reproduction, and bone mass. Since appetite and reproduction are governed by the hypothalamus, this hypothesis implies that the control of bone remodeling may also, in part, originate from the hypothalamus.
 Download here the slide set presented by Prof. Friedlander, on Thursday, March 29th. |
