Mitofusin 2 plays a critical role in maintaining the functional integrity of the neuromuscular-skeletal axis.

Purpose: Mitofusin 2 (Mfn2) is one of two mitofusins involved in regulating mitochondrial size, shape and function, including mitophagy, an important cellular mechanism to limit oxidative stress. Reduced expression of Mfn2 has been associated with impaired osteoblast differentiation and function and a reduction in the number of viable osteocytes in bone. We hypothesized that the genetic absence of Mfn2 in these cells would increase their susceptibility to aging-associated metabolic stress, leading to a progressive impairment in skeletal homeostasis over time.

An Unanticipated Role for Sphingosine Kinase-2 in Bone and in the Anabolic Effect of Parathyroid Hormone.

Sphingosine-1-phosphate (S1P) is an anabolic clastokine. Sphingosine kinase (SPHK) is the rate-limiting enzyme in S1P production and has 2 isoforms. To evaluate the roles of SPHK1 and SPHK2 in bone, we examined the skeletal phenotype of mice with selective deletion of SPHK1 in osteoclasts (SPHK1-Oc-/-) and mice in which the SPHK2 gene was deleted in all tissues (SPHK2-/-).

Selective deletion of the receptor for CSF1, c-fms, in osteoclasts results in a high bone mass phenotype, smaller osteoclasts in vivo and an impaired response to an anabolic PTH regimen.

The receptor for Colony Stimulating Factor 1 (CSF1), c-fms, is highly expressed on mature osteoclasts suggesting a role for this cytokine in regulating the function of these cells. Consistent with this idea, in vitro studies have documented a variety of effects of CSF1 in mature osteoclasts. To better define the role of CSF1 in these cells, we conditionally deleted c-fms in osteoclasts (c-fms-OC-/-) by crossing c-fmsflox/flox mice with mice expressing Cre under the control of the cathepsin K promoter.

The contribution of cross-talk between the cell-surface proteins CD36 and CD47-TSP-1 in osteoclast formation and function.

Antibody-mediated blockade of cluster of differentiation 47 (CD47)-thrombospondin-1 (TSP-1) interactions blocks osteoclast formation and attenuates parathyroid hormone (PTH)-induced hypercalcemia in mice. Hypercalcemia in this model reflects increased bone resorption. TSP-1 has two cell-associated binding partners, CD47 and CD36.

AgRP Neurons Regulate Bone Mass.

The hypothalamus has been implicated in skeletal metabolism. Whether hunger-promoting neurons of the arcuate nucleus impact the bone is not known. We generated multiple lines of mice to affect AgRP neuronal circuit integrity.

The transcription factor T-box 3 regulates colony-stimulating factor 1-dependent Jun dimerization protein 2 expression and plays an important role in osteoclastogenesis.

Colony-stimulating factor 1 (CSF1) is known to promote osteoclast progenitor survival, but its roles in osteoclast differentiation and mature osteoclast function are less well understood. In a microarray screen, Jun dimerization protein 2 (JDP2) was identified as significantly induced by CSF1. Recent reports indicate that JDP2 is required for normal osteoclastogenesis and skeletal metabolism.

Measurement of plasma, serum, and platelet serotonin in individuals with high bone mass and mutations in LRP5.

It has recently been suggested that the low-density lipoprotein receptor-related protein 5 (LRP5) regulates bone mass by suppressing secretion of serotonin from duodenal enterochromaffin cells. In mice with targeted expression of a high bone mass-causing (HBM-causing) LRP5 mutation and in humans with HBM LRP5 mutations, circulating serotonin levels have been reported to be lower than in controls whereas individuals with loss-of-function mutations in LRP5 have high blood serotonin. In contrast, others have reported that conditionally activating a knock-in allele of an HBM-causing LRP5 mutation in several tissues, or genetic deletion of LRP5 in mice has no effect on serum serotonin levels.

Increasing dietary protein acutely augments intestinal iron transporter expression and significantly increases iron absorption in rats.

Iron (Fe) deficiency is endemic worldwide. Little data are available regarding acute effects of dietary protein on intestinal Fe absorption. The current study evaluated the short-term effects of increasing dietary protein on Fe absorption and expression of genes involved in Fe homeostasis.

The effect of dietary protein on intestinal calcium absorption in rats.

Increasing dietary protein intake in humans acutely increases urinary calcium. Isotopic absorption studies have indicated that, at least in the short term, this is primarily due to increased intestinal Ca absorption. To explore the mechanisms underlying dietary protein's effect on intestinal Ca absorption, female Sprague Dawley rats were fed a control (20%), low (5%), or high (40%) protein diet for 7 d, and Ca balance was measured during d 4-7.

Dominant role of CD47-thrombospondin-1 interactions in myeloma-induced fusion of human dendritic cells: implications for bone disease.

Lytic bone disease in myeloma is characterized by an increase in multinucleate osteoclasts in close proximity to tumor cells. However, the nature of osteoclast precursors and the mechanisms underlying multinuclearity are less understood. Here we show that culture of myeloma cell lines as well as primary myeloma cells with human dendritic cells (DCs) but not monocytes or macrophages leads to spontaneous cell-cell fusion, which then leads to the facile formation of multinucleate bone-resorbing giant cells.

Targeted overexpression of the two colony-stimulating factor-1 isoforms in osteoblasts differentially affects bone loss in ovariectomized mice.

Colony-stimulating factor-1 (CSF1) is one of two cytokines required for normal osteoclastogenesis. There are two major isoforms of CSF1, the cell-surface or membrane-bound isoform (mCSF1) and soluble CSF1 (sCSF1). Whether these isoforms serve nonredundant functions in bone is unclear.

The anabolic response to parathyroid hormone is augmented in Rac2 knockout mice.

PTH is the only currently available anabolic therapy for osteoporosis. In clinical practice, the skeletal response to PTH varies and because therapy is limited to 2 yr, approaches to maximize the therapeutic response are desirable. Rac2 is a small GTPase that is expressed only in hematopoietic tissue.

Expression and synthesis of bone morphogenetic proteins by osteoclasts: a possible path to anabolic bone remodeling.

Skeletal remodeling is a finely orchestrated process coupling bone formation to bone resorption. The dynamics of coupling is regulated by the microenvironment at the bone remodeling site, which in turn is influenced by the intercellular communication between cells like osteoclasts and osteoblasts. Understanding the dynamics of coupling is important in devising new therapeutic approaches to the treatment of skeletal diseases characterized by disturbances in the bone remodeling process.

[Weed biodiversity in winter wheat field of loess soil under different fertilization regimes].

Employing an inverted 'W' investigation procedure with 9 sampling locations and adopting a biodiversity analysis approach integrated with typical statistic method, this paper studied the effects of different long-term stationary fertilization regimes on the weed biodiversity in winter wheat fields on loess soil. The results showed that in the experimental plots, there were 16 weed species belonging to 10 family and 16 genera, occupying about 34% of the total number of weed species in winter wheat fields in Shaanxi Province. The weed biodiversity was decreased with the improvement of soil nutrient status.

The effect of aging on the skeletal response to intermittent treatment with parathyroid hormone.

Little is known about the modifying effects of age on the skeletal response to intermittent treatment with PTH. We therefore compared the response of 63 aged (18 month old) and 61 young-adult (3 month old) C57BL/6 mice to 4 wk of daily sc injections of either vehicle or h(1-34)PTH at a dose of 95 ng/g body weight. The increase in total body bone mineral density (BMD), compared with vehicle-treated animals, was similar in aged and young-adult mice (+5.

The cell surface form of colony-stimulating factor-1 is biologically active in bone in vivo.

The specific biological function of the cell surface or membrane-bound isoform of colony-stimulating factor-1 (mCSF-1) is not well understood. To help define the role of this isoform in bone, we developed a transgenic mouse in which targeted expression of human mCSF-1 in osteoblasts was achieved under the control of the 2.4-kb rat collagen type I alpha promoter.