IU Indianapolis ScholarWorks :: Browsing by Subject "Sclerostin"

Browsing by Subject "Sclerostin"

Now showing 1 - 10 of 13

Combining Sclerostin and DKK1 Inhibitors to Improve Bone Properties in the Aged Skeleton
(Oxford University Press, 2022-12-20) Choi, Roy; Robling, Alexander; Anatomy, Cell Biology and Physiology, School of Medicine
Targeting the secreted Wnt inhibitor sclerostin has been an attractive strategy to improve skeletal health. Sclerostin antibody (romosozumab-aqqg; Evenity) was recently approved by the FDA to treat patients at increased risk of fracture. However, an increased risk of cardiovascular events was reported, resulting in issue a ‘black box warning’ requirement for romosozumab. One potential solution to lower the risk of adverse events is to reduce the medication dose. Previously, we found that dual inhibition of sclerostin and Dkk1 produced extremely potent synergistic bone anabolic effects, in both genetic and pharmacological models. While Dkk1 inhibition alone has no consistent bone-building effects, combining antibodies that target sclerostin (Scl-mAb) and Dkk1 (Dkk1-mAb) at 3:1 ratio resulted in 2-3X more bone gain as Scl-mAb alone. Further, much lower total doses of dual antibody treatment, given at optimized proportions, generated equivalent bone anabolic effects as Scl-mAb alone (at much higher doses), suggesting that a combinational strategy has obvious translational benefits. Finally, we tested whether low-dose combination therapy can maintain the same osteogenic effect as Scl-mAb in adult (6 month) and aged (20 month) mice. Outcome measures derived from radiographic, biomechanical, and histomorphometric assays revealed that a 3:1 ratio of Scl-mAb:Dkk1-mAb at 12.5mg/kg was as efficacious as 25mg/kg of Scl-mAb alone, in both age groups. Moreover, cortical porosity—a significant factor contributing to skeletal fragility in the aged skeleton—was significantly reduced by both Scl-mAb and low-dose combination treatment. In conclusion, our findings suggest that optimized low-dose combinational therapy is viable strategy for improving skeletal fragility.
High-bone-mass causing mutant LRP5 receptors are resistant to endogenous inhibitors in vivo
(Wiley Online Library, 2015-10) Niziolek, Paul J.; MacDonald, Bryan T.; Kedlaya, Rajendra; Zhang, Minjie; Bellido, Teresita; He, Xi; Warman, Matthew L.; Robling, Alexander G.; Department of Anatomy and Cell Biology, IU School of Medicine
Certain missense mutations affecting LRP5 cause high bone mass (HBM) in humans. Based on in vitro evidence, HBM LRP5 receptors are thought to exert their effects by providing resistance to binding/inhibition of secreted LRP5 inhibitors such as sclerostin (SOST) and Dickkopf homolog-1 (DKK1). We previously reported the creation of two Lrp5 HBM knock-in mouse models, in which the human p.A214V or p.G171V missense mutations were knocked into the endogenous Lrp5 locus. To determine whether HBM knock-in mice are resistant to SOST- or DKK1-induced osteopenia, we bred Lrp5 HBM mice with transgenic mice that overexpress human SOST in osteocytes ((8kb) Dmp1-SOST) or mouse DKK1 in osteoblasts and osteocytes ((2.3kb) Col1a1-Dkk1). We observed that the (8kb) Dmp1-SOST transgene significantly lowered whole-body bone mineral density (BMD), bone mineral content (BMC), femoral and vertebral trabecular bone volume fraction (BV/TV), and periosteal bone-formation rate (BFR) in wild-type mice but not in mice with Lrp5 p.G171V and p.A214V alleles. The (2.3kb) Col1a1-Dkk1 transgene significantly lowered whole-body BMD, BMC, and vertebral BV/TV in wild-type mice and affected p.A214V mice more than p.G171V mice. These in vivo data support in vitro studies regarding the mechanism of HBM-causing mutations, and imply that HBM LRP5 receptors differ in their relative sensitivity to inhibition by SOST and DKK1.
Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors
(Elsevier, 2018-12-13) Kim, Hyeonwoo; Wrann, Christiane D.; Jedrychowski, Mark; Vidoni, Sara; Kitase, Yukiko; Nagano, Kenichi; Zhou, Chenhe; Chou, Joshua; Parkman, Virginia-Jeni A.; Novick, Scott J.; Strutzenberg, Timothy S.; Pascal, Bruce D.; Le, Phuong T.; Brooks, Daniel J.; Roche, Alexander M.; Gerber, Kaitlyn K.; Mattheis, Laura; Chen, Wenjing; Tu, Hua; Bouxsein, Mary L.; Griffin, Patrick R.; Baron, Roland; Rosen, Clifford J.; Bonewald, Lynda F.; Spiegelman, Bruce M.; Orthopaedic Surgery, School of Medicine
Irisin is secreted by muscle, increases with exercise, and mediates certain favorable effects of physical activity. In particular, irisin has been shown to have beneficial effects in adipose tissues, brain, and bone. However, the skeletal response to exercise is less clear, and the receptor for irisin has not been identified. Here we show that irisin binds to proteins of the αV class of integrins, and biophysical studies identify interacting surfaces between irisin and αV/β5 integrin. Chemical inhibition of the αV integrins blocks signaling and function by irisin in osteocytes and fat cells. Irisin increases both osteocytic survival and production of sclerostin, a local modulator of bone remodeling. Genetic ablation of FNDC5 (or irisin) completely blocks osteocytic osteolysis induced by ovariectomy, preventing bone loss and supporting an important role of irisin in skeletal remodeling. Identification of the irisin receptor should greatly facilitate our understanding of irisin's function in exercise and human health.
New Insights Into the Local and Systemic Functions of Sclerostin: Regulation of Quiescent Bone Lining Cells and Beige Adipogenesis in Peripheral Fat Depots
(Wiley, 2017-05) Delgado-Calle, Jesus; Bellido, Teresita; Anatomy and Cell Biology, School of Medicine
Nmp4 Suppresses Osteoanabolic Potency
(2023-07) Heim, Crystal Noelle; Bidwell, Joseph; Wek, Ronald; White, Kenneth; Robling, Alexander; Plotkin, Lilian
Treating severe osteoporosis is limited to two strategies: 1. Stimulation of the parathyroid hormone receptor with analogs for parathyroid hormone (PTH) or parathyroid hormone related peptide, and 2. Stimulation of Wnt signaling via neutralization of sclerostin, a natural inhibitor of this pathway, with a monoclonal antibody (romosozumab-aqqg, Scl-mAb). Despite mobilizing distinct molecular and cellular pathways to stimulate bone gain, all their efficacies rapidly diminish. Identifying the barrier to enhancing potency is a clinical priority. We recently reported that mice harboring the conditional loss of the transcription factor Nmp4 (Nuclear Matrix Protein 4) in mesenchymal stem/progenitor cells (MSPCs) exhibited no measurable baseline effect on the skeleton but showed a significantly enhanced increase in bone formation during PTH therapy. Remarkably, (and unexpectedly) skeletal response to PTH therapy was not improved when Nmp4 was conditionally disabled at the osteoblast or osteocyte stages. For the present study, we hypothesized that the potency of any osteoanabolic drug is pre-programmed (and can be re-programmed) in osteoprogenitors. To test this hypothesis, we treated our global Nmp4-/- mice, various conditional knockout mice, and their controls with Scl-mAb. We observed a similar pattern of improved bone response in our mouse models, which we previously observed with the PTH therapy. That is, removal of Nmp4 early in osteoblast differentiation (MSPC) was required for an exaggerated bone-formation response to Scl-mAb therapy. Disabling Nmp4 later in osteogenic differentiation did not increase the potency of Scl-mAb. These data suggest that Nmp4 is part of a common barrier to improving the efficacy of any osteoanabolic. Potential pathways and actors that comprise the re-programming of Nmp4-/- MSPCs to support the exaggerated osteoanabolic effect on the skeleton are discussed.
The Osteocyte: New Insights
(Annual Reviews, 2020-02-10) Robling, Alexander G.; Bonewald, Lynda F.; Anatomy and Cell Biology, School of Medicine
Osteocytes are an ancient cell, appearing in fossilized skeletal remains of early fish and dinosaurs. Despite its relative high abundance, even in the context of nonskeletal cells, the osteocyte is perhaps among the least studied cells in all of vertebrate biology. Osteocytes are cells embedded in bone, able to modify their surrounding extracellular matrix via specialized molecular remodeling mechanisms that are independent of the bone forming osteoblasts and bone-resorbing osteoclasts. Osteocytes communicate with osteoclasts and osteoblasts via distinct signaling molecules that include the RankL/OPG axis and the Sost/Dkk1/Wnt axis, among others. Osteocytes also extend their influence beyond the local bone environment by functioning as an endocrine cell that controls phosphate reabsorption in the kidney, insulin secretion in the pancreas, and skeletal muscle function. These cells are also finely tuned sensors of mechanical stimulation to coordinate with effector cells to adjust bone mass, size, and shape to conform to mechanical demands.
Osteocytes and Their Messengers as Targets for the Treatment of Multiple Myeloma
(Springer, 2017-03) Delgado-Calle, Jesus; Medicine, School of Medicine
Osteocytes, the most abundant cells in the bone, orchestrate the function of osteoblasts and osteocytes to control physiological bone homeostasis. Accumulating evidence demonstrates that alteration of osteocyte function underlies the pathophysiology of several skeletal disorders, and that therapeutic targeting of factors produced by these cells improves skeletal health. Despite the advances in the knowledge of osteocyte biology, the contribution of these cells to the damaging effects of cancer in bone is practically unknown. Multiple myeloma is a plasma cell malignancy characterized by the presence of skeletal lesions and severe bone pain. Recent findings suggest that myeloma cells educate osteocytes to generate a microenvironment that is conducive to tumor progression, skeletal destruction, and bone pain. This review features some of these investigations and discusses the potential of targeting osteocytic pathways and osteocyte messengers for the treatment of multiple myeloma.
The Role of the Osteocyte in Bone and Non-bone Disease
(Elsevier, 2017-03) Bonewald, Lynda F.; Anatomy and Cell Biology, School of Medicine
When normal physiological functions go awry, disorders and disease occurs. This is universal, even for the osteocyte, a cell embedded within the mineralized matrix of bone. It was once thought that this cell was simply a place-holder in bone. However, within the last decade, the number of studies of osteocytes has dramatically increased leading to the discovery of novel functions of these cells. But with the discovery of novel physiological functions came the discoveries of how these cells can also be responsible for not only bone diseases and disorders, but also those of kidney, heart, and potentially muscle.
Sclerostin Directly Stimulates Osteocyte Synthesis of Fibroblast Growth Factor-23
(Springer, 2021) Ito, Nobuaki; Prideaux, Matthew; Wijenayaka, Asiri R.; Yang, Dongqing; Ormsby, Renee T.; Bonewald, Lynda F.; Atkins, Gerald J; Medicine, School of Medicine
Osteocyte produced fibroblast growth factor 23 (FGF23) is the key regulator of serum phosphate (Pi) homeostasis. The interplay between parathyroid hormone (PTH), FGF23 and other proteins that regulate FGF23 production and serum Pi levels is complex and incompletely characterised. Evidence suggests that the protein product of the SOST gene, sclerostin (SCL), also a PTH target and also produced by osteocytes, plays a role in FGF23 expression, however the mechanism for this effect is unclear. Part of the problem of understanding the interplay of these mediators is the complex multi-organ system that achieves Pi homeostasis in vivo. In the current study, we sought to address this using a cell line model of the osteocyte, IDG-SW3, known to express FGF23 at both the mRNA and protein levels. In cultures of differentiated IDG-SW3 cells, both PTH1-34 and recombinant human (rh) SCL remarkably induced Fgf23 mRNA expression dose-dependently within 3 h. Both rhPTH1-34 and rhSCL also strongly induced C-terminal FGF23 protein secretion. Secreted intact FGF23 levels remained unchanged, consistent with constitutive post-translational cleavage of FGF23 in this cell model. Both rhPTH1-34 and rhSCL treatments significantly suppressed mRNA levels of Phex, Dmp1 and Enpp1 mRNA, encoding putative negative regulators of FGF23 levels, and induced Galnt3 mRNA expression, encoding N-acetylgalactosaminyl-transferase 3 (GalNAc-T3), which protects FGF23 from furin-like proprotein convertase-mediated cleavage. The effect of both rhPTH1-34 and rhSCL was antagonised by pre-treatment with the NF-κβ signalling inhibitors, BAY11 and TPCK. RhSCL also stimulated FGF23 mRNA expression in ex vivo cultures of human bone. These findings provide evidence for the direct regulation of FGF23 expression by sclerostin. Locally expressed sclerostin via the induction of FGF23 in osteocytes thus has the potential to contribute to the regulation of Pi homeostasis.
Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation
(Elsevier, 2016-11) Robling, Alexander G.; Kang, Kyung Shin; Bullock, Whitney A.; Foster, William H.; Murugesh, Deepa; Loots, Gabriela G.; Genetos, Damian C.; Anatomy and Cell Biology, School of Medicine
Sclerostin (Sost) is a negative regulator of bone formation that acts upon the Wnt signaling pathway. Sost is mechanically regulated at both mRNA and protein level such that loading represses and unloading enhances Sost expression, in osteocytes and in circulation. The non-coding evolutionarily conserved enhancer ECR5 has been previously reported as a transcriptional regulatory element required for modulating Sost expression in osteocytes. Here we explored the mechanisms by which ECR5, or several other putative transcriptional enhancers regulate Sost expression, in response to mechanical stimulation. We found that in vivo ulna loading is equally osteoanabolic in wildtype and Sost-/- mice, although Sost is required for proper distribution of load-induced bone formation to regions of high strain. Using Luciferase reporters carrying the ECR5 non-coding enhancer and heterologous or homologous hSOST promoters, we found that ECR5 is mechanosensitive in vitro and that ECR5-driven Luciferase activity decreases in osteoblasts exposed to oscillatory fluid flow. Yet, ECR5-/- mice showed similar magnitude of load-induced bone formation and similar periosteal distribution of bone formation to high-strain regions compared to wildtype mice. Further, we found that in contrast to Sost-/- mice, which are resistant to disuse-induced bone loss, ECR5-/- mice lose bone upon unloading to a degree similar to wildtype control mice. ECR5 deletion did not abrogate positive effects of unloading on Sost, suggesting that additional transcriptional regulators and regulatory elements contribute to load-induced regulation of Sost.

Browsing by Subject "Sclerostin"

Results Per Page

Sort Options