HIFα couples angiogenesis to osteogenesis during skeletal development

Skeletal development and turnover occur in close spatial and temporal association with angiogenesis. Osteoblasts are ideally situated in bone to sense oxygen tension and respond to hypoxia by activating the hypoxia inducible factor α (HIFα) pathway. An elegant study [1] provides evidence that HIFα promotes angiogenesis and osteogenesis by elevating vascular endothelial growth factor (VEGF) levels in osteoblasts. Mice overexpressing HIFα in osteoblasts through selective deletion of the von Hippel¿Lindau gene (Vhl), a factor which usually promotes degradation of HIFα , expressed high levels of Vegf and developed extremely dense, heavily vascularized long bones.
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Regulation of bone resorption by leptin

The assumption that identical classes of molecules might regulate the two aspects of bone remodeling, formation, and resorption, prompted the investigators to look for neural regulation of bone resorption.

The answer came from mice lacking the adrenergic receptor [1]. These mutant mice not only present an increase in bone formation, but also a decrease in bone resorption. This latter abnormality, which contributes to the Adrβ2-deficient mice high bone mass, cannot be corrected by leptin ICV infusion, indicating that leptin regulates bone resorption via the sympathetic tone.

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Overexpression of y-glutamyltransferase accelerates bone resorption and causes osteoporosis

Genetic studies in human patients as well as mutant mice have disclosed critical molecules involved in osteoclast development, including cytokines, intracellular signaling molecules, and nuclear transcription factors. Among these, the osteoclastogenic cytokines have received special attention, because they represent novel targets for the development of both diagnostic tools and antiresorptive drugs. For example RANKL, belonging to the TNF family, was identified as an essential cytokine for osteoclastogenesis, and mice deficient in RANKL were found to lack osteoclasts and to exhibit severe osteopetrosis. In an attempt to identify new cytokines that stimulate osteoclast differentiation, expression cloning was used and led to identify y-glutamyltransferase (GGT) as such a stimulator. Mice deficient in GGT exhibit growth retardation, cataracts, and severe osteoporosis and die at 10 ¿18 wk of age. Purified GGT is capable of inducing osteoclast formation in bone marrow cultures, which raises the possibility that its excess may also be involved in the bone and joint pathology characterized by enhanced osteoclastic bone resorption.
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CD40 ligand is a modulator of osteoclastogenesis

Patients with X-linked hyper-IgM syndrome (XHIM), an inherited immune deficiency disorder caused by mutations in the gene encoding CD40 ligand (CD40L), have prominent osteopenia, leading to low-energy fractures, of unknown mechanism. This clinical observation prompted the investigators to ask whether CD40L deficiency may contribute to an imbalance in bone mineral homeostasis [1]. In this study, they show that, compared with age- and sex-matched normal controls, XHIM patients have significantly lower bone mineral density (BMD) and have elevated levels of N-terminal telopeptides of type I collagen (NTX), a urinary marker indicative of osteoclast activity.

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