Hyperthyroidism-driven bone loss depends on BMP receptor Bmpr1a expression in osteoblasts.

Hyperthyroidism is a well-known trigger of high bone turnover that can lead to the development of secondary osteoporosis. Previously, we have shown that blocking bone morphogenetic protein (BMP) signaling systemically with BMPR1A-Fc can prevent bone loss in hyperthyroid mice. To distinguish between bone cell type-specific effects, conditional knockout mice lacking Bmpr1a in either osteoclast precursors (LysM-Cre) or osteoprogenitors (Osx-Cre) were rendered hyperthyroid and their bone microarchitecture, strength and turnover were analyzed.

Thyroid hormone receptor Thra and Thrb knockout differentially affects osteoblast biology and thyroid hormone responsiveness in vitro.

Thyroid hormones (TH) are important modulators of bone remodeling and thus, thyroid diseases, in particular hyperthyroidism, are able to compromise bone quality and fracture resistance. TH actions on bone are mediated by the thyroid hormone receptors (TR) TRα1 and TRβ1, encoded by Thra and Thrb, respectively. Skeletal phenotypes of mice lacking Thra (Thra ) and Thrb (Thrb ) are well-described and suggest that TRα1 is the predominant mediator of TH actions in bone.

Novel Insights into Osteoclast Energy Metabolism.

Purpose Of Review: Osteoclasts are crucial for the dynamic remodeling of bone as they resorb old and damaged bone, making space for new bone. Metabolic reprogramming in these cells not only supports phenotypic changes, but also provides the necessary energy for their highly energy-consuming activity, bone resorption. In this review, we highlight recent developments in our understanding of the metabolic adaptations that influence osteoclast behavior and the overall remodeling of bone tissue.

Deconstructing cellular senescence in bone and beyond.

Osteocytes are specialized bone cells that orchestrate skeletal remodeling. Senescent osteocytes are characterized by an activation of cyclin-dependent kinase inhibitor p16Ink4a and have been implicated in the pathogenesis of several bone loss disorders. In this issue of the JCI, Farr et al.

Irisin and Bone in Sickness and in Health: A Narrative Review of the Literature.

Irisin is a hormone-like myokine produced by the skeletal muscle in response to exercise. Upon its release into the circulation, it is involved in the browning process and thermogenesis, but recent evidence indicates that this myokine could also regulate the functions of osteoblasts, osteoclasts, and osteocytes. Most human studies have reported that serum irisin levels decrease with age and in conditions involving bone diseases, including both primary and secondary osteoporosis.

Reduced Bone Mass and Increased Osteocyte Tartrate-Resistant Acid Phosphatase (TRAP) Activity, But Not Low Mineralized Matrix Around Osteocyte Lacunae, Are Restored After Recovery From Exogenous Hyperthyroidism in Male Mice.

Hyperthyroidism causes secondary osteoporosis through favoring bone resorption over bone formation, leading to bone loss with elevated bone fragility. Osteocytes that reside within lacunae inside the mineralized bone matrix orchestrate the process of bone remodeling and can themselves actively resorb bone upon certain stimuli. Nevertheless, the interaction between thyroid hormones and osteocytes and the impact of hyperthyroidism on osteocyte cell function are still unknown.

Low Bone Turnover Due to Hypothyroidism or Anti-Resorptive Treatment Does Not Affect Whole-Body Glucose Homeostasis in Male Mice.

Bone is a large and dynamic tissue and its maintenance requires high amounts of energy as old or damaged bone structures need to be replaced during the process of bone remodeling. Glucose homeostasis is an essential prerequisite for a healthy bone and vice versa, the skeleton can act as an endocrine organ on energy metabolism. We recently showed that hypothyroidism in mice leads to an almost complete arrest of bone remodeling.

The Thyroid Hormone Transporter MCT10 Is a Novel Regulator of Trabecular Bone Mass and Bone Turnover in Male Mice.

Thyroid hormones (TH) are essential for skeletal development and adult bone homeostasis. Their bioavailability is determined by specific transporter proteins at the cell surface. The TH-specific transporter monocarboxylate transporter 8 (MCT8) was recently reported as a regulator of bone mass in mice.

The Bone Morphogenetic Protein Pathway: The Osteoclastic Perspective.

Bone health crucially relies on constant bone remodeling and bone regeneration, both tightly controlled processes requiring bone formation and bone resorption. Plenty of evidence identifies bone morphogenetic proteins (BMP) as major players in osteoblast differentiation and thus, bone formation. However, in recent past years, researchers also increasingly reported on the pivotal role of these multi-functional growth factors in osteoclast formation and activity.

Disruption of BMP Signaling Prevents Hyperthyroidism-Induced Bone Loss in Male Mice.

Thyroid hormones (TH) are key regulators of bone health, and TH excess in mice causes high bone turnover-mediated bone loss. However, the underlying molecular mechanisms of TH actions on bone remain poorly defined. Here, we tested the hypothesis whether TH mediate their effects via the pro-osteogenic bone morphogenetic protein (BMP) signaling pathway in vitro and in vivo.

Thyroid Hormone Actions and Bone Remodeling - The Role of the Wnt Signaling Pathway.

Thyroid hormones are indispensable for bone development and growth. Also in adults, bone mass maintenance is under the control of thyroid hormones. Preclinical and clinical studies established untreated hyperthyroidism as a cause for secondary osteoporosis with increased fracture risk.

Lack of the Thyroid Hormone Transporter Mct8 in Osteoblast and Osteoclast Progenitors Increases Trabecular Bone in Male Mice.

Bone is an important target of thyroid hormones (THs), which require transport into target cells to exert their actions. Recently, the TH-specific monocarboxylate transporter 8 (Mct8) was reported as a regulator of bone mass in male mice. However, its global deletion leads to high 3,3',5-L-triiodothyronine (T3) serum concentrations that may mask direct effects of Mct8-deficiency on bone.

The Role of Dickkopf-1 in Thyroid Hormone-Induced Changes of Bone Remodeling in Male Mice.

Thyroid hormones regulate bone homeostasis, and exogenously induced hyperthyroidism and hypothyroidism in mice was recently found to be associated with an altered expression of the Wnt inhibitor Dickkopf-1 (Dkk1), a determinant of bone mass. Here, we assessed the role of Dkk1 in thyroid hormone-induced changes in bone using conditional Dkk1 knockout mice. Male mice with a global (Dkk1fl/fl;Rosa26-CreERT2) or osteocyte-specific (Dkk1fl/fl;Dmp1:Cre) deletion of Dkk1 were pharmacologically rendered hypothyroid or hyperthyroid.

Detection of COPB2 as a KRAS synthetic lethal partner through integration of functional genomics screens.

Mutated KRAS plays an important role in many cancers. Although targeting KRAS directly is difficult, indirect inactivation via synthetic lethal partners (SLPs) is promising. Yet to date, there are no SLPs from high-throughput RNAi screening, which are supported by multiple screens.

The G Protein-Coupled Receptor RAI3 Is an Independent Prognostic Factor for Pancreatic Cancer Survival and Regulates Proliferation via STAT3 Phosphorylation.

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest tumors worldwide. Understanding the function of gene expression alterations is a prerequisite for developing new strategies in diagnostic and therapy. GPRC5A (RAI3), coding for a seven transmembrane G protein-coupled receptor is known to be overexpressed in pancreatic cancer and might be an interesting candidate for therapeutic intervention.

Simultaneous gene silencing of KRAS and anti-apoptotic genes as a multitarget therapy.

Pancreatic cancer is one of the most lethal tumor types worldwide and an effective therapy is still elusive. Targeted therapy focused against a specific alteration is by definition unable to attack broad pathway signaling modification. Tumor heterogeneity will render targeted therapies ineffective based on the regrowth of cancer cell sub-clones.