bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.02.23.707532

Combination Treatment with Sclerostin and Dkk1 Antibodies Synergizes with Tibial Loading to Stimulate Bone Formation in Aged Mice

Lawson, L.·Chermside-Scabbo, C. J.·Brodt, M. D.·Migotsky, N.·Shuster, J. T.·Buettmann, E. G.·Silva, M. J.
View original source ↗Export metadata ↓

Abstract

Aging is associated with decreased bone formation and bone mass and increased fracture risk. Wnt pathway activation by mechanical loading is a potent strategy to improve bone mass, however, load-induced bone formation is diminished with aging. Neutralizing antibody (Ab) therapies targeting Wnt pathway inhibitors Sclerostin (Scl) and Dickkopf-related protein 1 (Dkk1) have proven successful in preclinical and clinical osteoporotic conditions. We asked whether treatment combining Scl-Ab and Dkk1-Ab can increase load-induced bone formation in a preclinical model of osteoporosis. Aged (22-month) C57BL/6N female mice underwent combination Scl-Ab plus Dkk1-Ab therapy (15 mg/kg each; subcutaneously; 2x/wk; saline control) for 2 weeks, concomitant with a mechanical loading regimen previously shown to induce modest bone formation in tibias of aged mice (-2200 {varepsilon}, 1200 cycles/day, 5 day/wk). Changes in bone morphology and formation were assessed by longitudinal microCT and dynamic histomorphometry, respectively. Molecular indices of bone formation and Wnt pathway activation were assessed by qPCR of cortical bone. Treatment with Scl-Ab plus Dkk1-Ab induced significant improvements in cancellous (BV/TV +50%) and cortical morphology (Ct.Th +25%) in non-loaded limbs of antibody-treated mice vs. vehicle control mice. Importantly, periosteal bone formation rate was 10-fold higher in loaded limbs of antibody versus vehicle treated mice, indicating a synergistic effect. Gene expression analysis showed that antibody treatment and loading synergistically upregulated Wnt1 expression, which may have contributed to the observed synergistic effect on bone formation. These results confirm the potent anabolic effect of combination Scl plus Dkk1 antibody treatment. Moreover, they show that antibody treatment and skeletal loading are more effective at increasing periosteal bone formation in aged mice than either treatment alone. These findings support the concept that combinatorial therapy using dual Scl and Dkk1 antibodies plus weight-bearing exercise may be an effective treatment for age-related osteoporosis.

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Lawson, L., Chermside-Scabbo, C. J., Brodt, M. D., Migotsky, N., Shuster, J. T., Buettmann, E. G., Silva, M. J.. 2026-02-24. Combination Treatment with Sclerostin and Dkk1 Antibodies Synergizes with Tibial Loading to Stimulate Bone Formation in Aged Mice. https://doi.org/10.64898/2026.02.23.707532

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Thoracoabdominal pressure transmission during prone and supine cardiopulmonary resuscitation in fresh-frozen human cadavers

Background: Prone cardiopulmonary resuscitation (CPR) may be necessary when turning a prone patient supine would delay chest compressions. Although prone compressions can generate arterial pressures comparable with or greater than supine CPR, the pathway of pressure transmission is uncertain. We examined synchronized intrathoracic, intra-abdominal, and central arterial pressures in both supine and prone positions. Methods: Two thawed fresh-frozen adult cadavers underwent three, 2-minute mechanical CPR trials per position in a counterbalanced crossover sequence. Solid-state catheters recorded pleural, peritoneal, and central arterial pressures simultaneously. Trial-level outcomes included peak pressure, mean pressure, pressure-time area, and the mean peritoneal-to-pleural pressure gradient. Exploratory fixed-effects models included position, cadaver, and their interaction. Results: Prone CPR increased peak intrathoracic pressure by 7.04 mmHg, peak intra-abdominal pressure by 21.69 mmHg, and peak arterial pressure by 15.40 mmHg. Mean intra-abdominal and arterial pressures increased by 16.22 and 9.90 mmHg, respectively. The mean peritoneal-to-pleural gradient reversed direction from -8.46 mmHg supine to 4.85 mmHg prone. Intrathoracic pressure-time area increased 3.4-fold, from 1.62 to 5.46 mmHg{middle dot}s, and arterial pressure-time area increased 2.2-fold, from 2.96 to 6.42 mmHg{middle dot}s. Conclusions: Compared to supine, prone mechanical CPR generated higher arterial pressures and reversed the pressure relationship across the thoracoabdominal boundary in both cadavers. Higher abdominal pressure coincided with a larger intrathoracic pressure-time area, a pattern compatible with reduced caudal pressure dissipation.

physiology↗
bioRxiv2026

Hypothalamic Farnesoid X Receptor deficiency alters energy balance by modulating hepatic glucose production and adipose tissue metabolism through central insulin signaling.

Objectives: The bile acid nuclear receptor Farnesoid X Receptor (FXR, NR1H4) is a major regulator of metabolism and energy homeostasis in peripheral organs. It modulates bile acid, glucose, and lipid metabolism, as well as fat mass and body weight. However, FXR is also expressed in the brain, particularly in the hypothalamus, a key center for the regulation of energy homeostasis. Although one study has demonstrated a role for brain FXR activation in energy balance, its specific hypothalamic role is still unknown. Here, we examined the role of FXR in the mediobasal hypothalamus in the regulation of energy balance. Methods: We used a genetic approach combined with metabolic phenotyping to determine the effect of FXR invalidation in the mediobasal hypothalamus on metabolic parameters involved in the central regulation of energy homeostasis. Results: Our results demonstrate that hypothalamic FXR deficiency induces a positive energy balance, resulting in a reduction in energy expenditure due to alterations in glucose metabolism accompanied by structural changes in white adipose tissues. Conclusion: This study uncovers a previously unrecognized role for hypothalamic FXR in the central homeostatic control of energy balance, providing new insights into its contribution to peripheral glucose metabolism and adipose tissue structural remodeling.

physiology↗
bioRxiv2026

Rad and Phospholamban are Key Drivers of the Ventricular Adrenergic Response and Stress-Induced Arrhythmia

The adrenergic response is a fundamental mechanism that regulates heart rate (chronotropy), cardiac contractility (inotropy) and relaxation (lusitropy). Adrenergic stress is also a recognized trigger of arrhythmia in disease. Yet, our understanding of the underlying molecular basis remains incomplete. Protein kinase A (PKA) and the calcium/calmodulin-dependent kinase II (CaMKII) phosphorylate multiple targets proposed to participate in the adrenergic response, including the GTP-binding protein Rad, phospholamban (PLB) and ryanodine receptor 2 (RyR2). Here we demonstrate that phosphorylation of both Rad and PLB is necessary for inotropy and lusitropy. We show that changes in cardiac contractility and relaxation are primarily dependent on intracellular calcium handling. Finally, we report that Rad and PLB control stress-induced arrhythmogenesis, despite the phosphorylation of other pro-arrhythmic targets. We have identified the essential molecular components of the adrenergic response, resolving a long-standing debate in cardiac excitation-contraction coupling and refining current models of sympathetic regulation in health and disease.

physiology↗