Marina Stolina

To explore how preceding treatment with a bisphosphonate (BP) and/or OPG-Fc, a RANKL inhibitor, affects early bone formation (BF) response to sclerostin antibody (Scl-Ab) in vertebral cancellous and cortical bone, we treated ovariectomized rats with various sequences of vehicle (Veh), OPG-Fc, and alendronate (Aln) or zoledronic acid (ZOL) in cycle 1 (0-12 wk) or cycle 2 (12-18 wk) before administering Scl-Ab in cycle 3 (18-24 wk). Treatment sequences included Veh/Veh/Scl-Ab (treatment naïve), OPG-Fc/OPG-Fc/Scl-Ab, OPG-Fc/ZOL/Scl-Ab, Aln/OPG-Fc/Scl-Ab, and OPG-Fc/OPG-Fc_Veh/Scl-Ab (4-wk treatment-free period preceding Scl-Ab). DXA scans and serum bone turnover markers were assessed. Cancellous and endocortical histomorphometric endpoints were quantified at weeks 18, 20, and 24. With Veh/Veh/Scl-Ab, anticipated bone responses to Scl-Ab were observed. From week 18 to week 24, Scl-Ab-mediated bone mass accrual was blunted with preceding antiresorptive sequences. In groups where OPG-Fc immediately preceded Scl-Ab, BF suppression was marked at week 20 with limited modeling-based bone formation (MBBF). In contrast, when ZOL was interposed between OPG-Fc and Scl-Ab, MBBF was modestly reduced at week 20. By week 24, BF surfaces were generally similar in all groups; the contribution of MBBF and remodeling-based bone formation (RBBF) differed. In contrast to other antiresorptive sequences, in OPG-Fc/OPG-Fc_Veh/Scl-Ab, RBBF was also a significant contributor to bone forming surfaces, reflecting a rebound in resorption and remodeling. With the other antiresorptive sequences, MBBF was the major contributor to BF, consistent with prolonged suppression of remodeling at week 24. All prior antiresorptive sequences blunted Scl-Ab effects on early BF. BP exposure (before or after OPG-Fc) improved cumulative effects across all cycles on bone mass compared with OPG-Fc alone. Interposing ZOL between OPG-Fc and Scl-Ab improved the early BF response to Scl-Ab.

Background: Fracture repair involves the reactivation of developmental signaling cascades, including Wnt signaling that stimulates bone formation and bone regeneration. Rodent data indicate that dual inhibition of the Wnt signaling antagonists sclerostin and Dickkopf-1 (DKK1) increases callus bone volume and strength while increasing bone mass systemically. Methods: We evaluated the effects of 16 weeks of subcutaneously administered carrier solution (vehicle, VEH), anti-sclerostin antibody (Scl-Ab), anti-DKK1 antibody (DKK1-Ab), or Scl-Ab plus DKK1-Ab combination therapy (COMBO) on ulnar osteotomy healing in nonhuman primates (cynomolgus monkeys; 20 to 22 per group). Results: Scl-Ab and COMBO therapy increased systemic markers of bone formation versus VEH, with COMBO leading to synergistic increases versus Scl-Ab or DKK1-Ab monotherapies. The COMBO and Scl-Ab groups showed reduced serum markers of bone resorption versus VEH. The COMBO and DKK1-Ab groups exhibited greater callus bone mineral density (BMD), torsional stiffness, and torsional rigidity versus VEH. Lumbar vertebrae from the Scl-Ab and COMBO groups showed greater BMD and bone formation rate versus VEH, and the femoral mid-diaphysis of the Scl-Ab and COMBO groups showed greater periosteal and endocortical bone formation rates versus VEH. Conclusions: DKK1-Ab increased BMD and strength at the ulnar osteotomy site, Scl-Ab increased bone formation and BMD at uninjured skeletal sites, and Scl-Ab plus DKK1-Ab combination therapy induced all of these effects, in some cases to a greater degree versus 1 or both monotherapies. These results in nonhuman primates suggest that DKK1 preferentially regulates bone healing while sclerostin preferentially regulates systemic bone mass. Clinical Relevance: Combination therapy with antibodies against sclerostin and DKK1 may offer a promising therapeutic strategy for both fracture treatment and fracture prevention.

Angiopoietin-2 (Ang-2) is a key prognostic marker and potential mediator of Acute respiratory distress syndrome, yet it is unknown whether inhibiting Ang-2 signaling at its receptor Tie-2 can reduce ...

Heart failure with reduced ejection fraction (HFrEF) constitutes 50% of HF hospitalizations and is characterized by high rates of mortality. To explore the underlying mechanisms of HFrEF etiology and progression, we studied the molecular and cellular differences in four chambers of non-failing (NF, n = 10) and HFrEF (n = 12) human hearts. We identified 333 genes enriched within NF heart subregions and often associated with cardiovascular disease GWAS variants. Expression analysis of HFrEF tissues revealed extensive disease-associated transcriptional and signaling alterations in left atrium (LA) and left ventricle (LV). Common left heart HFrEF pathologies included mitochondrial dysfunction, cardiac hypertrophy and fibrosis. Oxidative stress and cardiac necrosis pathways were prominent within LV, whereas TGF-beta signaling was evident within LA. Cell type composition was estimated by deconvolution and revealed that HFrEF samples had smaller percentage of cardiomyocytes within the left heart, higher representation of fibroblasts within LA and perivascular cells within the left heart relative to NF samples. We identified essential modules associated with HFrEF pathology and linked transcriptome discoveries with human genetics findings. This study contributes to a growing body of knowledge describing chamber-specific transcriptomics and revealed genes and pathways that are associated with heart failure pathophysiology, which may aid in therapeutic target discovery.

Cardiometabolic syndrome has become a global health issue. Heart failure is a common comorbidity of cardiometabolic syndrome. Successful drug development to prevent cardiometabolic syndrome and associated comorbidities requires preclinical models predictive of human conditions. To characterize the heart failure component of cardiometabolic syndrome, cardiometabolic, metabolic, and renal biomarkers were evaluated in obese and lean ZSF1 20-to 22-week-old male rats. Cardiac function, exercise capacity, and left ventricular gene expression were also analyzed. Obese ZSF1 rats exhibited multiple features of human cardiometabolic syndrome by pathological changes in systemic renal, metabolic, and cardiovascular disease circulating biomarkers. Hemodynamic assessment, echocardiography, and decreased exercise capacity confirmed heart failure with preserved ejection fraction. RNA-seq results demonstrated changes in left ventricular gene expression associated with fatty acid and branched chain amino acid metabolism, cardiomyopathy, cardiac hypertrophy, and heart failure. Twelve weeks of growth differentiation factor 15 (GDF15) treatment significantly decreased body weight, food intake, blood glucose, and triglycerides and improved exercise capacity in obese ZSF1 males. Systemic cardiovascular injury markers were significantly lower in GDF15-treated obese ZSF1 rats. Obese ZSF1 male rats represent a preclinical model for human cardiometabolic syndrome with established heart failure with preserved ejection fraction. GDF15 treatment mediated dietary response and demonstrated a cardioprotective effect in obese ZSF1 rats.

Widely distributed osteosclerosis is an unusual radiographic finding with multiple causes. A 42‐year‐old premenopausal Spanish woman gradually acquired dense bone diffusely affecting her axial skeleton and focally affecting her proximal long bones. Systemic lupus erythematosus (SLE) diagnosed in adolescence had been well controlled. She had not fractured or received antiresorptive therapy, and she was hepatitis C virus antibody negative. Family members had low bone mass. Lumbar spine bone mineral density (BMD) measured by dual‐photon absorptiometry (DPA) at age 17 years, while receiving glucocorticoids, was 79% the average value of age‐matched controls. From ages 30 to 37 years, dual‐energy X‐ray absorptiometry (DXA) BMD Z‐scores steadily increased in her lumbar spine from +3.8 to +7.9, and in her femoral neck from –1.4 to –0.7. Serum calcium and phosphorus levels were consistently normal, 25‐hydroxyvitamin D (25OHD) Z‐scores steadily decreased. Skeletal fluorosis, mastocytosis, myelofibrosis, hepatitis C‐associated osteosclerosis, multiple myeloma, and aberrant phosphate homeostasis did not explain her osteosclerosis. Mutation analysis of the LRP5, LRP4, SOST, and osteopetrosis genes was negative. Microarray showed no notable copy number variation. Perhaps her osteosclerosis reflected an interval of autoimmune‐mediated resistance to SOST and/or RANKL. © 2016 American Society for Bone and Mineral Research.

Introduction and Aims: Vascular calcification, a major consequence of secondary hyperparathyroidism (SHPT) due to chronic kidney disease (CKD), likely contributes to the extremely high rates of cardiovascular mortality observed in these patients. Calcimimetic agents effectively decrease parathyroid hormone (PTH) levels and prevent vascular calcification in rodent models of SHPT. In comparison, some studies have shown that low doses of paricalcitol prevented vascular calcification in rodent models of CKD, whereas other reports show that high doses aggravated vascular calcification. AMG 416 is a peptide calcimimetic that substantially lowers PTH levels in CKD patients with SHPT receiving hemodialysis in clinical studies. This study compared the presence and extent of vascular calcification in adenine-induced CKD rats given either AMG 416 or paricalcitol.