The benefits of adipocyte metabolism in bone health and regeneration.

Patients suffering from musculoskeletal diseases must cope with a diminished quality of life and an increased burden on medical expenses. The interaction of immune cells and mesenchymal stromal cells during bone regeneration is one of the key requirements for the restoration of skeletal integrity. While stromal cells of the osteo-chondral lineage support bone regeneration, an excessive accumulation of cells of the adipogenic lineage is thought to promote low-grade inflammation and impair bone regeneration. Increasing evidence indicates that pro-inflammatory signaling from adipocytes is responsible for various chronic musculoskeletal diseases. This review aims to summarize the features of bone marrow adipocytes by phenotype, function, secretory features, metabolic properties and their impact on bone formation. In detail, the master regulator of adipogenesis and prominent diabetes drug target, peroxisome proliferator-activated receptor γ (PPARG), will be debated as a potential therapeutic approach to enhance bone regeneration. We will explore the possibilities of using clinically established PPARG agonists, the thiazolidinediones (TZDs), as a treatment strategy to guide the induction of a pro-regenerative, metabolically active bone marrow adipose tissue. The impact of this PPARG induced bone marrow adipose tissue type on providing the necessary metabolites to sustain osteogenic-as well as beneficial immune cells during bone fracture healing will be highlighted.

A comprehensive molecular profiling approach reveals metabolic alterations that steer bone tissue regeneration.

Bone regeneration after fracture is a complex process with high and dynamic energy demands. The impact of metabolism on bone healing progression and outcome, however, is so far understudied. Our comprehensive molecular profiling reveals that central metabolic pathways, such as glycolysis and the citric acid cycle, are differentially activated between rats with successful or compromised bone regeneration (young versus aged female Sprague-Dawley rats) early in the inflammatory phase of bone healing. We also found that the citric acid cycle intermediate succinate mediates individual cellular responses and plays a central role in successful bone healing. Succinate induces IL-1ß in macrophages, enhances vessel formation, increases mesenchymal stromal cell migration, and potentiates osteogenic differentiation and matrix formation in vitro. Taken together, metabolites-here particularly succinate-are shown to play central roles as signaling molecules during the onset of healing and in steering bone tissue regeneration.

Compromised Bone Healing in Aged Rats Is Associated With Impaired M2 Macrophage Function.

Fracture repair is initiated by a multitude of immune cells and induction of an inflammatory cascade. Alterations in the early healing response due to an aged adaptive immune system leads to impaired bone repair, delayed healing or even formation of non-union. However, immuno-senescence is not limited to the adaptive immunity, but is also described for macrophages, main effector cells from the innate immune system. Beside regulation of pro- and anti-inflammatory signaling, macrophages contribute to angiogenesis and granulation tissue maturation. Thus, it seems likely that an altered macrophage function due to aging may affect bone repair at various stages and contribute to age related deficiencies in bone regeneration. To prove this hypothesis, we analyzed the expression of macrophage markers and angiogenic factors in the early bone hematoma derived from young and aged osteotomized Spraque Dawley rats. We detected an overall reduced expression of the monocyte/pan-macrophage markers CD14 and CD68 in aged rats. Furthermore, the analysis revealed an impaired expression of anti-inflammatory M2 macrophage markers in hematoma from aged animals that was connected to a diminished revascularization of the bone callus. To verify that the age related disturbed bone regeneration was due to a compromised macrophage function, CD14+ macrophage precursors were transplanted locally into the osteotomy gap of aged rats. Transplantation rescued bone regeneration partially after 6 weeks, demonstrated by a significantly induced deposition of new bone tissue, reduced fibrosis and significantly improved callus vascularization.

Structural abnormality of the substantia nigra in children with attention-deficit hyperactivity disorder.

BACKGROUND: Structural abnormality of the substantia nigra can be detected by transcranial sonography in neuropsychiatric disorders such as Parkinson disease and restless legs syndrome. We investigated echogenicity of the substantia nigra as a potential structural marker for dysfunction of the nigrostriatal dopamine system in children with attention-deficit hyperactivity disorder (ADHD). METHODS: We used a blinded design and determined echogenicity of the substantia nigra by use of transcranial sonography in 22 children with ADHD and 22 healthy controls matched for age and sex. RESULTS: The echogenic substantia nigra area was significantly larger in ADHD patients than in healthy controls (F(1,42) = 9.298, p = 0.004, effect size = 0.92). We found no effects of age or sex. LIMITATIONS: Owing to a lack of dimensional assessment, we could not analyze the correlation between echogenicity and clinical symptoms. CONCLUSION: Our results support the hypothesis that the nigrostriatal dopaminergic system is abnormal in children with ADHD.

The auxin-induced K(+) channel gene Zmk1 in maize functions in coleoptile growth and is required for embryo development.

The transcript level and in turn protein density of the K(+)-uptake channel ZMK1 in maize (Zea mays) coleoptiles is controlled by the phytohormone auxin. ZMK1 is involved in auxin-regulated coleoptile elongation as well as gravi- and phototropism. To provide unequivocal evidence for the role of ZMK1 in these elementary processes we screened for maize plants containing a Mutator-tagged Zmk1 gene. In a site-selected approach, we were able to identify three independent alleles of Mutator-transposon insertions in Zmk1. zmk1-m1::Mu1 plants were characterised by a Mu1 transposon inside intron 1 of ZMK1. When we analysed the Zmk1-transcript abundance in growing coleoptiles of these homozygous mutants, however, we found the K(+)-channel allele overexpressed. In consequence, elevated levels of K(+)-channel transcripts resulted in a growth phenotype as expected from more efficient K(+)-uptake, representing a central factor for turgor formation. Following Zmk1 expression during maize embryogenesis, we found this K(+)-channel gene constitutively expressed throughout embryo development and upregulated in late stages. In line with a vital role in embryogenesis, the mutations of exon 2 and intron 2 of Zmk1-zmk1-m2::Mu8 and zmk1-m3::MuA2-caused a lethal, defective-kernel phenotype. Thus, these results demonstrate the central role of the auxin-regulated K(+)-channel gene Zmk1 in coleoptile growth and embryo development.