Tuesday, September 28, 2010


Central Depletion of Brain-Derived Neurotrophic Factor in Mice Results in High Bone Mass and Metabolic Phenotype.

"BDNF and its receptor are expressed in osteoblasts and chondrocyte. BDNF in vitro has a positive effect on bone; whether central BDNF affects bone mass in vivo is not known. We therefore examined bone mass and energy use in brain-targeted BDNF conditional knockout mice (Bdnf(2lox/2lox)/93). The deletion of BDNF in the brain led to a metabolic phenotype characterized by hyperphagia, obesity, and increased abdominal white adipose tissue. Central BDNF deletion produces a marked skeletal phenotype characterized by increased femur length, elevated whole bone mineral density, and bone mineral content. The skeletal changes are developmentally regulated and appear concurrently with the metabolic phenotype, suggesting that the metabolic and skeletal actions of BDNF are linked. The increased bone development is evident in both the cortical and trabecular regions. Compared with control, Bdnf(2lox/2lox)/93 mice show greater trabecular bone volume (+50% for distal femur; +35% for vertebral body) and midfemoral cortical thickness (+11 to 17%), measured at 3 and 6 months of age. The skeletal and metabolic phenotypes were gender dependent, with female being more affected than male mice. However, uncoupling protein-1 expression in brown fat, a marker of sympathetic tone, was not different between genotypes. Deletion of central BDNF expression in mice results in increased bone mass and white adipose tissue, with no significant changes in sympathetic signaling or peripheral serotonin, associated with hyperphagia, obesity, and leptin resistance."

"BDNF acts on central and peripheral neurons through binding to the product of tyrosine kinase receptor type B/neurotrophic tyrosine kinase, receptor, type 2, a high-affinity tyrosine kinase receptor"

"BDNF levels in bone are not significantly different between the mutant and control mice"

"Bdnf2lox/2lox/93 mice at 3 and 6 months of age had longer femurs ( 6–10%)"

Growth plate thickness was about 10 to 15% greater at six months age.

The problem is that the blood brain barrier is the most selective barrier so anything that would reduce BDNF in the brain would also affect the bone.

BDNF alters ERK/p38 MAPK activity ratios to promote differentiation in growth plate chondrocytes.

"Using primary bovine growth plate chondrocytes and murine ATDC5 cells, we demonstrate that the ERK and p38 pathways have opposing effects on proliferation but are both absolutely required for differentiation. Two factors that promote chondrocyte differentiation, brain-derived neurotrophic factor (BDNF) and C-type natriuretic peptide, increase p38 activity while decreasing, but not completely inhibiting, ERK activity. The attenuation of ERK activity by BDNF occurs via p38-dependent raf-1 inhibition{raf1 is downregulated by LSJL}. The inhibition of raf-1 by p38 is direct, because purified p38 protein inhibits the kinase activity of purified active raf-1 as well as raf-1 immunoprecipitated from chondrocyte lysates. Moreover, IGF-I, which stimulates proliferation, suppresses p38 activation. Unopposed IGF-I promotes high ERK/p38 activity ratios favoring proliferation, whereas BDNF signals a transition to differentiation by decreasing the ERK/p38 activity ratio without completely inhibiting ERK, which involves the direct inhibition of raf-1 by p38."

"The receptor families activating one or more MAPK cascades include receptor tyrosine kinases, cytokine receptors, G protein-coupled receptors, and serine-threonine kinase receptors. The three major MAPK cascades consist of the classic ERK1/2 cascade, which is responsive to mitogens such as IGF-I, and the c-Jun N-terminal kinase (JNK) and p38 MAPK cascades"

"In the case of ERK1/2, the module consists of the MAPK p44 ERK1 and p42 ERK2, the immediate upstream kinases MAPK kinase (MEK)1 and MEK2 that activate ERK1/2 by phosphorylating the dual TEY motif in the ERK kinase domain, and the kinase that activates MEK1/2, raf-1; raf-1, in turn, is activated by the recruitment of the small G protein Ras by Grb/SOS complex formation after receptor tyrosine kinase activation. In the p38 MAPK module, the MAPK kinases 3/6 phosphorylate the TGY motif in the kinase domain of p38, and are themselves activated by upstream kinases, such as MEK kinases 2 and 3. Activation of the p38 pathway often follows cellular stress, such as that caused by UV light or osmotic changes, but the pathway is also activated by a variety of extracellular stimuli"

"brain-derived neurotrophic factor (BDNF), stem cell factor, and growth arrest-specific gene 6 as factors that block IGF-I-stimulated proliferation but enhance differentiation in growth plate chondrocytes and showed that ERK activity is required for chondrocyte proliferation. The three factors, as well as CNP, inhibit chondrocyte proliferation by reducing ERK activity but do not affect IGF-I-dependent phosphorylation of the IGF-I receptor or the immediate downstream signaling molecules Shc1{down in LSJL} and Grb2, suggesting that these factors act on the ERK pathway downstream of the Shc1/Grb2 complex."

"p38 activation by IGF-I plus CNP was 8.1 ± 1.3-fold greater than seen with IGF-I alone."

"IGF-I-stimulated chondrocyte proliferation requires ERK1/2 activation, which is reduced by both BDNF and CNP"

"ERK activity must be high during proliferation but must be low (but not nil) for differentiation to proceed."<-Note this may not be true for initial differentiation of stem cells into chondrocytes.

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