A5080593924- Bone Metabolism and Diseases
- Bone health and osteoporosis research
- Bone health and treatments
- Wnt/β-catenin signaling in development and cancer
- Connective tissue disorders research
- Kruppel-like factors research
- Neurobiology and Insect Physiology Research
- Thyroid and Parathyroid Surgery
- Cellular Mechanics and Interactions
- Osteomyelitis and Bone Disorders Research
- NF-κB Signaling Pathways
- Bone and Dental Protein Studies
- Bone fractures and treatments
- RNA Research and Splicing
- Rheumatoid Arthritis Research and Therapies
- Muscle Physiology and Disorders
- Fibroblast Growth Factor Research
- Photosynthetic Processes and Mechanisms
- Axon Guidance and Neuronal Signaling
- Epigenetics and DNA Methylation
- Cephalopods and Marine Biology
- Cancer-related gene regulation
- Orthopaedic implants and arthroplasty
- Adrenal and Paraganglionic Tumors
- Pituitary Gland Disorders and Treatments
Amgen (United States)
2009-2023
California State University, Northridge
2006
Amgen (Germany)
2004
California Institute of Technology
2001
Sclerosteosis is a rare high bone mass genetic disorder in humans caused by inactivating mutations SOST, the gene encoding sclerostin. Based on these data, sclerostin has emerged as key negative regulator of mass. We generated SOST knockout (KO) mice to gain more detailed understanding effects deficiency bone.Gene targeting was used inactivate and generate line KO mice. Radiography, densitometry, microCT, histomorphometry, mechanical testing were characterize impact male female Comparisons...
Abstract RANKL is a TNF family member that mediates osteoclast formation, activation, and survival by activating RANK. The proresorptive effects of are prevented binding to its soluble inhibitor osteoprotegerin (OPG). Recombinant human OPG-Fc recognizes from multiple species reduced bone resorption increased volume, density, strength in number rodent models disease. clinical development was discontinued favor denosumab, fully monoclonal antibody specifically inhibits primate RANKL. Direct...
Abstract Therapeutic enhancement of fracture healing would help to prevent the occurrence orthopedic complications such as nonunion and revision surgery. Sclerostin is a negative regulator bone formation, treatment with sclerostin monoclonal antibody (Scl-Ab) results in increased formation mass animal models. Our objective was investigate effects systemic administration Scl-Ab two models healing. In both closed femoral model rats fibular osteotomy cynomolgus monkeys, significantly strength...
Abstract Inhibition of the Wnt antagonist sclerostin increases bone mass in patients with osteoporosis and preclinical animal models. Here we show increased levels Dickkopf-1 (DKK-1) animals treated antibody, suggesting a negative feedback mechanism that limits Wnt-driven formation. To test our hypothesis co-inhibition both factors further mass, engineer first-in-class bispecific antibody single residue pair mutations Fab region to promote efficient stable cognate light–heavy chain pairing....
The purpose of this study was to evaluate the effects sclerostin inhibition by treatment with a antibody (Scl-AbII) on bone formation, mass, and strength in an aged, gonad-intact male rat model. Sixteen-month-old Sprague-Dawley rats were injected subcutaneously vehicle or Scl-AbII at 5 25 mg/kg twice per week for weeks (9-10/group). In vivo dual-energy X-ray absorptiometry (DXA) analysis showed that there marked increase areal mineral density lumbar vertebrae (L(1) L(5) ) long bones (femur...
Introduction Inflammation is a major risk factor for systemic bone loss. Proinflammatory cytokines like tumour necrosis (TNF) affect homeostasis and induce It was hypothesised that impaired formation key component in inflammatory loss Dkk-1, Wnt antagonist, strong inhibitor of osteoblast-mediated formation.TNF transgenic (hTNFtg) mice were treated with neutralising antibodies against TNF, Dkk-1 or combination both agents. Systemic architecture analysed by histomorphometry. The expression...
Abstract Type 2 diabetes mellitus results in increased risk of fracture and delayed healing. ZDF fa/fa rats are an established model type with low bone mass We tested whether a sclerostin-neutralizing antibody (Scl-AbVI) would reverse the skeletal deficits diabetic rats. Femoral defects 3 mm were created 11-week-old nondiabetic +/+ stabilized by internal plate. Saline or 25 mg/kg Scl-AbVI was administered subcutaneously (s.c.) twice weekly for 12 weeks (n = 9–10/group). Bone strength...
Densin-180 is a transmembrane protein that tightly associated with the postsynaptic density in CNS neurons and postulated to function as synaptic adhesion molecule. Here we report identification of α-subunit Ca 2+ /calmodulin-dependent kinase II (CaMKII) α-actinin-4 potential binding partners for densin-180 intracellular segment. We demonstrate by yeast two-hybrid biochemical assays portion densin-180, CaMKII (CaMKIIα), α-actinin interact each other at distinct sites can form ternary complex...
Ovariectomy (OVX) results in bone loss caused by increased resorption. RANKL is an essential mediator of We examined whether the inhibitor osteoprotegerin (OPG) would preserve volume, density, and strength OVX rats.Rats were or sham-operated at 3 mo age. Sham controls treated for 6 wk with vehicle (Veh, PBS). rats Veh human OPG-Fc (10 mg/kg, 2/wk). Serum TRACP5b was measured ELISA. BMD lumbar vertebrae (L(1)-L(5)) distal femur DXA. Right femurs processed histomorphometry. Left fifth vertebra...
Abstract The physiological role of Dickkopf-1 (Dkk1) during postnatal bone growth in rodents and adult was examined utilizing an antibody to Dkk1 (Dkk1-Ab) that blocked binding both low density lipoprotein receptor-related protein 6 (LRP6) Kremen2, thereby preventing the Wnt inhibitory activity Dkk1. Treatment growing mice rats with Dkk1-Ab resulted a significant increase mineral because increased formation. In contrast, treatment ovariectomized did not appreciably impact bone, effect...
Clinical studies have revealed a blunting of the bone anabolic effects parathyroid hormone treatment in osteoporotic patients setting pre- or cotreatment with antiresorptive agent alendronate (ALN). Sclerostin monoclonal antibody (Scl-Ab) is currently under clinical investigation as new potential therapy for postmenopausal osteoporosis. The purpose these experiments was to examine influence pretreatment ALN on actions Scl-Ab ovariectomized (OVX) rats. Ten-month-old osteopenic OVX rats were...
ABSTRACT Osteogenesis imperfecta (OI) is characterized by low bone mass, poor quality, and fractures. Standard treatment for OI patients limited to bisphosphonates, which only incompletely correct the phenotype, seem be less effective in adults. Sclerostin-neutralizing antibodies (Scl-Ab) have been shown beneficial animal models of osteoporosis, dominant resulting from mutations genes encoding type I collagen. However, Scl-Ab has not studied recessive OI. Cartilage-associated protein (CRTAP)...
The effects of up to 26 weeks sclerostin antibody (Scl-Ab) treatment were investigated in ovariectomized (OVX) rats. Two months after surgery, 6-month-old osteopenic OVX rats treated with vehicle or Scl-Ab (25 mg/kg, sc, one time per week) for 6, 12, weeks. In vivo dual-energy x-ray absorptiometry analysis demonstrated that the bone mineral density lumbar vertebrae and femur-tibia increased progressively through along progressive increases trabecular cortical mass strength at multiple sites....
RANKL is an essential mediator of bone erosions, but the role in systemic loss had not been studied arthritis. protein was increased rat joint extracts and serum at earliest stages Osteoprotegerin (OPG) treatment reversed local loss, suggesting that both a marker arthritis.RANKL well established as erosions inflammatory arthritis, arthritis studied. We hypothesized could serve novel biomarker for challenged this hypothesis two models sought to determine whether elevated early disease...
Humoral hypercalcemia of malignancy (HHM) is mediated primarily by skeletal and renal responses to tumor-derived PTHrP. PTHrP mobilizes calcium from bone inducing the expression receptor activator for nuclear factor-kappaB ligand (RANKL), a protein that essential osteoclast formation, activation, survival. RANKL does not influence reabsorption, so inhibition rational approach selectively block, thereby reveal, relative contribution HHM. We used inhibitor osteoprotegerin (OPG) evaluate role...
ABSTRACT Results of prior studies suggest that fibroblast growth factor 21 (FGF21) may be involved in bone turnover and the actions peroxisome proliferator-activated receptor (PPAR) α γ mice. We have conducted independent to examine effects FGF21 on homeostasis role PPARα actions. High-fat-diet-induced obesity (DIO) mice were administered vehicle or recombinant human (rhFGF21) intraperitoneally at 0 (vehicle), 0.1, 1, 3 mg/kg daily for 2 weeks. Additional groups DIO received water 10...
Sclerostin antibody (Scl-Ab) restored bone mass and strength in the ovariectomized rat model of postmenopausal osteoporosis. Increased mineral density (BMD) decreased skeletal fragility fracture risk have been reported osteoporotic women receiving Scl-Ab. In males, loss androgen leads to rapid decreases BMD an increased fractures. We hypothesized that Scl-Ab could reverse caused by ablation orchiectomized (ORX) male treated 9-month-old ORX Sprague Dawley rats (3 months after ORX)...
RANKL is an essential mediator of bone resorption, and its activity inhibited by osteoprotegerin (OPG). Transgenic (Tg) rats were engineered to continuously overexpress OPG study the effects continuous long-term inhibition on volume, density, strength. Lumbar vertebrae, femurs, blood obtained from 1-yr-old female OPG-Tg (n = 32) age-matched wildtype (WT) controls 23). had significantly greater serum (up 260-fold) lower TRACP5b osteocalcin compared with WT controls. Vertebral histomorphometry...
Sustained elevation of parathyroid hormone (PTH) is catabolic to cortical bone, as evidenced by deterioration in bone structure (cortical porosity), and a major factor for increased fracture risk chronic kidney disease (CKD). Etelcalcetide (AMG 416), novel peptide agonist the calcium-sensing receptor, reduces PTH levels subtotal nephrectomized (Nx) rats hemodialysis patients with secondary hyperparathyroidism (SHPT) clinical studies; however, effects etelcalcetide on have not been...