Bone marrow adipose tissue composition and glycemic improvements after gastric bypass surgery.

Fracture risk is increased in type 2 diabetes, which may in part be due to altered bone marrow adiposity. Cross sectional studies have reported that people with type 2 diabetes have lower unsaturated BMAT lipid levels than people without diabetes, although there are limited data on longitudinal changes. We hypothesized that Roux-en-Y gastric bypass (RYGB), which dramatically improves glycemic status, would have differential effects on BMAT composition, with increases in the unsaturated lipid index in people with diabetes.

Female-Specific Role of Progranulin to Suppress Bone Formation.

Progranulin (PGRN) is best known as a glial protein for which deficiency leads to the most common inherited form of frontotemporal dementia. Recently, PGRN has been found to be an adipokine associated with diet-induced obesity and insulin resistance. Therefore, PGRN may have homeostatic effects on bone because PGRN is reported to promote the differentiation of bone-resorbing osteoclasts.

Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones.

Central estrogen signaling coordinates energy expenditure, reproduction, and in concert with peripheral estrogen impacts skeletal homeostasis in females. Here, we ablate estrogen receptor alpha (ERα) in the medial basal hypothalamus and find a robust bone phenotype only in female mice that results in exceptionally strong trabecular and cortical bones, whose density surpasses other reported mouse models. Stereotaxic guided deletion of ERα in the arcuate nucleus increases bone mass in intact and ovariectomized females, confirming the central role of estrogen signaling in this sex-dependent bone phenotype.

Sirtuin-3 Promotes Adipogenesis, Osteoclastogenesis, and Bone Loss in Aging Male Mice.

Sirtuin-3 (Sirt3) is an essential metabolic regulatory enzyme that plays an important role in mitochondrial metabolism, but its role in bone marrow and skeletal homeostasis remains largely unknown. In this study, we hypothesize that increased expression of Sirt3 plays a role in skeletal aging. Using mice that overexpress Sirt3 [i.

Role of Osteoblast Gi Signaling in Age-Related Bone Loss in Female Mice.

Age-related bone loss is an important risk factor for fractures in the elderly; it results from an imbalance in bone remodeling mainly due to decreased bone formation. We have previously demonstrated that endogenous G protein-coupled receptor (GPCR)-driven Gi signaling in osteoblasts (Obs) restrains bone formation in mice during growth. Here, we launched a longitudinal study to test the hypothesis that Gi signaling in Obs restrains bone formation in aging mice, thereby promoting bone loss.

Osteoblast-derived FGF9 regulates skeletal homeostasis.

FGF9 has complex and important roles in skeletal development and repair. We have previously observed that Fgf9 expression in osteoblasts (OBs) is regulated by G protein signaling and therefore the present study was done to determine whether OB-derived FGF9 was important in skeletal homeostasis. To directly test this idea, we deleted functional expression of Fgf9 gene in OBs using a 2.

Investigating the cellular origin of rotator cuff muscle fatty infiltration and fibrosis after injury.

Background: rotator cuff muscle atrophy, fibrosis and fatty infiltration are common complications after large and massive rotator cuff tears. Currently, there are no effective treatments for these muscle pathologies after injury. Furthermore, the cellular source for fibrotic and adipose tissues in rotator cuff muscle after injury remains unknown.

Dietary dried plum increases bone mass, suppresses proinflammatory cytokines and promotes attainment of peak bone mass in male mice.

Nutrition is an important determinant of bone health and attainment of peak bone mass. Diets containing dried plum (DP) have been shown to increase bone volume and strength. These effects may be linked to the immune system and DP-specific polyphenols.

Negative Skeletal Effects of Locally Produced Adiponectin.

Epidemiological studies show that high circulating levels of adiponectin are associated with low bone mineral density. The effect of adiponectin on skeletal homeostasis, on osteoblasts in particular, remains controversial. We investigated this issue using mice with adipocyte-specific over-expression of adiponectin (AdTg).

Loss of Gi G-Protein-Coupled Receptor Signaling in Osteoblasts Accelerates Bone Fracture Healing.

G-protein-coupled receptors (GPCRs) are key regulators of skeletal homeostasis and are likely important in fracture healing. Because GPCRs can activate multiple signaling pathways simultaneously, we used targeted disruption of G(i) -GPCR or activation of G(s) -GPCR pathways to test how each pathway functions in the skeleton. We previously demonstrated that blockade of G(i) signaling by pertussis toxin (PTX) transgene expression in maturing osteoblastic cells enhanced cortical and trabecular bone formation and prevented age-related bone loss in female mice.

Effects of blockade of endogenous Gi signaling in Tie2-expressing cells on bone formation in a mouse model of heterotopic ossification.

Available evidence indicates that some Tie2-expressing (Tie2(+) ) cells serve as multipotent progenitors that have robust BMP-dependent osteogenic activity and mediate heterotopic ossification (HO). Since signaling through the G protein Gi is required for cell motility, we hypothesized that blockade of endogenous Gi signaling in Tie2(+) cell populations would prevent HO formation. Blockade of Gi signaling in Tie2(+) cells was accomplished in transgenic mice with expression of pertussis toxin (PTX) under the control of the Tie2 promoter (Tie2(+) /PTX(+) ).

Assessing the osteoblast transcriptome in a model of enhanced bone formation due to constitutive Gs-G protein signaling in osteoblasts.

G protein-coupled receptor (GPCR) signaling in osteoblasts (OBs) is an important regulator of bone formation. We previously described a mouse model expressing Rs1, an engineered constitutively active Gs-coupled GPCR, under the control of the 2.3 kb Col I promoter.

Novel mouse model of spinal cord injury-induced heterotopic ossification.

Heterotopic ossification (HO) develops in about 20% to 30% of patients with spinal cord injury (SCI) and significantly impairs their rehabilitation. There is no effective prevention or treatment for this condition at this time. Our current understanding of its etiology and pathophysiology is limited partially due to the lack of clinically relevant animal models.

A novel mouse model of trauma induced heterotopic ossification.

Severe soft tissue trauma is associated with heterotopic ossification (HO), the abnormal deposition of bone at extra-skeletal sites. The pathophysiology of the development of trauma-induced HO remains largely unknown due in part to the lack of appropriate animal models. In this study, we sought to develop a new trauma-induced HO mouse model using muscle impact injury combined with low dose BMP-2.

CXCL12/CXCR4 signaling in the osteoblast regulates the mesenchymal stem cell and osteoclast lineage populations.

The chemokine CXCL12 and its receptor CXCR4 play a key role in regulation of hematopoietic stem cells and cell migratory function during morphogenesis. Osteoblasts express both the ligand and the receptor, but little is known about the role of CXCL12-CXCR4 signaling in maintaining skeletal homeostasis. Using Cre-Lox technology to delete CXCR4 in mature osteoblasts in mice, we show here a significant decrease in bone mass and alterations in cancellous bone structure.

Increased bone mass in mice lacking the adipokine apelin.

Adipose tissue plays an important role in skeletal homeostasis, and there is interest in identifying adipokines that influence bone mass. One such adipokine may be apelin, a ligand for the Gi-G protein-coupled receptor APJ, which has been reported to enhance mitogenesis and suppress apoptosis in MC3T3-E1 cells and primary human osteoblasts (OBs). However, it is unclear whether apelin plays a physiological role in regulating skeletal homeostasis in vivo.

Constitutive protein kinase A activity in osteocytes and late osteoblasts produces an anabolic effect on bone.

Osteocytes have been implicated in the control of bone formation. However, the signal transduction pathways that regulate the biological function of osteocytes are poorly defined. Limited evidence suggests an important role for the Gs/cAMP pathway in osteocyte function.

Cyclic AMP signaling in bone marrow stromal cells has reciprocal effects on the ability of mesenchymal stem cells to differentiate into mature osteoblasts versus mature adipocytes.

Stimulatory G protein-mediated cAMP signaling is intimately involved in skeletal homeostasis. However, limited information is available on the role of the cAMP signaling in regulating the differentiation of mesenchymal stem cells into mature osteoblasts and adipocytes. To investigate this, we treated primary mouse bone marrow stromal cells (BMSCs) with forskolin to stimulate cAMP signaling and determined the effect on osteoblast and adipocyte differentiation.

Lamellar spacing in cuboid hydroxyapatite scaffolds regulates bone formation by human bone marrow stromal cells.

Background: A major goal in bone engineering is the creation of large volume constructs (scaffolds and stem cells) that bear load. The scaffolds must satisfy two competing requirements--they need be sufficiently porous to allow nutrient flow to maintain cell viability, yet sufficiently dense to bear load. We studied the effect of scaffold macroporosity on bone formation and scaffold strength, for bone formed by human bone marrow stromal cells.

Blockade of receptor-activated G(i) signaling in osteoblasts in vivo leads to site-specific increases in cortical and cancellous bone formation.

Osteoblasts play a critical role in the maintenance of bone mass through bone formation and regulation of bone resorption. Targeted expression of a constitutively active engineered G(i)-coupled G protein-coupled receptor (GPCR) to osteoblasts in vivo leads to severe osteopenia. However, little is known about the role of endogenous receptor-mediated G(i) signaling in regulating osteoblast function.

Gs G protein-coupled receptor signaling in osteoblasts elicits age-dependent effects on bone formation.

Age-dependent changes in skeletal growth are important for regulating skeletal expansion and determining peak bone mass. However, how G protein-coupled receptors (GPCRs) regulate these changes is poorly understood. Previously, we described a mouse model expressing Rs1, an engineered receptor with high basal G(s) activity.

Ligand-mediated activation of an engineered gs g protein-coupled receptor in osteoblasts increases trabecular bone formation.

Age-dependent changes in skeletal growth play important roles in regulating skeletal expansion and in the course of many diseases affecting bone. How G protein-coupled receptor (GPCR) signaling affects these changes is poorly understood. Previously, we described a mouse model expressing Rs1, an engineered receptor with constitutive G(s) activity.

Engineering GPCR signaling pathways with RASSLs.

We are creating families of designer G protein-coupled receptors (GPCRs) to allow for precise spatiotemporal control of GPCR signaling in vivo. These engineered GPCRs, called receptors activated solely by synthetic ligands (RASSLs), are unresponsive to endogenous ligands but can be activated by nanomolar concentrations of pharmacologically inert, drug-like small molecules. Currently, RASSLs exist for the three major GPCR signaling pathways (G(s), G(i) and G(q)).

Resolution dependence of the non-metric trabecular structure indices.

Non-metric indices of topological features of trabecular bone structure, such as structure model index (SMI), connectivity density (Conn.D), and degree of anisotropy (DA), provide unique information relevant to bone quality. With recent technological advancement, in vivo assessment of these indices may be possible from images acquired using high-resolution imaging techniques such as high-resolution peripheral quantitative computed tomography (HR-pQCT).

Osteoblast expression of an engineered Gs-coupled receptor dramatically increases bone mass.

Osteoblasts are essential for maintaining bone mass, avoiding osteoporosis, and repairing injured bone. Activation of osteoblast G protein-coupled receptors (GPCRs), such as the parathyroid hormone receptor, can increase bone mass; however, the anabolic mechanisms are poorly understood. Here we use "Rs1," an engineered GPCR with constitutive G(s) signaling, to evaluate the temporal and skeletal effects of G(s) signaling in murine osteoblasts.