Edward Guo

Blocking FSH induces thermogenic adipose tissue and reduces body fat

Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the β-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr. The antibody also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue and enhances thermogenesis. These actions result from the specific binding of the antibody to the β-subunit of Fsh to block its action. Our studies uncover opportunities for simultaneously treating obesity and osteoporosis.

Spine Trabecular Bone Score as an Indicator of Bone Microarchitecture at the Peripheral Skeleton in Kidney Transplant Recipients

BACKGROUND AND OBJECTIVES Studies using high-resolution peripheral quantitative computed tomography showed progressive abnormalities in cortical and trabecular microarchitecture and biomechanical competence over the first year after kidney transplantation. However, high-resolution peripheral computed tomography is a research tool lacking wide availability. In contrast, the trabecular bone score is a novel and widely available tool that uses gray-scale variograms of the spine image from dual-energy x-ray absorptiometry to assess trabecular quality. There are no studies assessing whether trabecular bone score characterizes bone quality in kidney transplant recipients. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS Between 2009 and 2010, we conducted a study to assess changes in peripheral skeletal microarchitecture, measured by high-resolution peripheral computed tomography, during the first year after transplantation in 47 patients managed with early corticosteroid-withdrawal immunosuppression. All adult first-time transplant candidates were eligible. Patients underwent imaging with high-resolution peripheral computed tomography and dual-energy x-ray absorptiometry pretransplantation and 3, 6, and 12 months post-transplantation. We now test if, during the first year after transplantation, trabecular bone score assesses the evolution of bone microarchitecture and biomechanical competence as determined by high-resolution peripheral computed tomography. RESULTS At baseline and follow-up, among the 72% and 78%, respectively, of patients having normal bone mineral density by dual-energy x-ray absorptiometry, 53% and 50%, respectively, were classified by trabecular bone score as having high fracture risk. At baseline, trabecular bone score correlated with spine, hip, and ultradistal radius bone mineral density by dual-energy x-ray absorptiometry and cortical area, density, thickness, and porosity; trabecular density, thickness, separation, and heterogeneity; and stiffness and failure load by high-resolution peripheral computed tomography. Longitudinally, each percentage increase in trabecular bone score was associated with increases in trabecular number (0.35%±1.4%); decreases in trabecular thickness (-0.45%±0.15%), separation (-0.40%±0.15%), and network heterogeneity (-0.48%±0.20%); and increases in failure load (0.22%±0.09%) by high-resolution peripheral computed tomography (all P<0.05). CONCLUSIONS Trabecular bone score may be a useful method to assess and monitor bone quality and strength and classify fracture risk in kidney transplant recipients.

Human bone perivascular niche-on-a-chip for studying metastatic colonization

Significance Improved human preclinical models are needed to better predict patients’ responses to anticancer drugs. Increasing the complexity of models may be a successful strategy only if crucial components of a tumor are identified, replicated, and controlled in vitro. We developed a perivascular niche to study metastatic colonization of the bone. Using a microfluidic chip, we exposed the niche to interstitial flow, oxygen gradients, and external forces, and established a dense vascular network. Cancer cells colonizing the bone resisted targeted therapy by entering a slow proliferative state. We expect that microfluidic niche-on-chip models will facilitate the development of drugs targeting persistent tumor cells into the bone and help manage the risk of metastatic relapse. Eight out of 10 breast cancer patients die within 5 years after the primary tumor has spread to the bones. Tumor cells disseminated from the breast roam the vasculature, colonizing perivascular niches around blood capillaries. Slow flows support the niche maintenance by driving the oxygen, nutrients, and signaling factors from the blood into the interstitial tissue, while extracellular matrix, endothelial cells, and mesenchymal stem cells regulate metastatic homing. Here, we show the feasibility of developing a perfused bone perivascular niche-on-a-chip to investigate the progression and drug resistance of breast cancer cells colonizing the bone. The model is a functional human triculture with stable vascular networks within a 3D native bone matrix cultured on a microfluidic chip. Providing the niche-on-a-chip with controlled flow velocities, shear stresses, and oxygen gradients, we established a long-lasting, self-assembled vascular network without supplementation of angiogenic factors. We further show that human bone marrow-derived mesenchymal stem cells, which have undergone phenotypical transition toward perivascular cell lineages, support the formation of capillary-like structures lining the vascular lumen. Finally, breast cancer cells exposed to interstitial flow within the bone perivascular niche-on-a-chip persist in a slow-proliferative state associated with increased drug resistance. We propose that the bone perivascular niche-on-a-chip with interstitial flow promotes the formation of stable vasculature and mediates cancer cell colonization.

Ectopic implantation of juvenile osteochondral tissues recapitulates endochondral ossification

Subcutaneous implantation in a mouse can be used to investigate tissue maturation in vivo. Here we demonstrate that this simple model can recapitulate endochondral ossification associated with native skeletal development. By histological and micro‐computed tomography analysis we investigated morphological changes of immature bovine osteochondral tissues over the course of subcutaneous implantation in immunocompromised mice for up to 10 weeks. We observed multiple similarities between the ectopic process and native endochondral ossification: (i) permanent cartilage retention in the upper zones; (ii) progressive loss of transient cartilage accompanied by bone formation at the interface; and (iii) remodelling of nascent endochondral bone into mature cancellous bone. Importantly, these processes were mediated by osteoclastogenesis and vascularization. Taken together, these findings advance our understanding of how the simple ectopic model can be used to study phenotypic changes associated with endochondral ossification of native and engineered osteochondral tissues in vivo.