Depletion of macrophages and osteoclast precursors mitigates iron overload-mediated bone loss.

Iron is an essential element for physiological cellular processes, but is toxic in excess. Iron overload diseases are commonly associated with low bone mass. Increased bone resorption by osteoclasts as well as decreased bone formation by osteoblasts have been implicated in bone loss under iron overload conditions.

Effects of dietary iron deficiency or overload on bone: Dietary details matter.

Purpose: Bone is susceptible to fluctuations in iron homeostasis, as both iron deficiency and overload are linked to poor bone strength in humans. In mice, however, inconsistent results have been reported, likely due to different diet setups or genetic backgrounds. Here, we assessed the effect of different high and low iron diets on bone in six inbred mouse strains (C57BL/6J, A/J, BALB/cJ, AKR/J, C3H/HeJ, and DBA/2J).

Comparison of the effects of high dietary iron levels on bone microarchitecture responses in the mouse strains 129/Sv and C57BL/6J.

Iron is an essential nutrient for all living organisms. Both iron deficiency and excess can be harmful. Bone, a highly metabolic active organ, is particularly sensitive to fluctuations in iron levels.

Transferrin receptor 2 mitigates periodontitis-driven alveolar bone loss.

Periodontitis is associated with significant alveolar bone loss. Patients with iron overload suffer more frequently from periodontitis, however, the underlying mechanisms remain largely elusive. Here, we investigated the role of transferrin receptor 2 (Tfr2), one of the main regulators of iron homeostasis, in the pathogenesis of periodontitis and the dental phenotype under basal conditions in mice.

Prolactin Inhibits or Stimulates the Inflammatory Response of Joint Tissues in a Cytokine-dependent Manner.

The close association between rheumatoid arthritis (RA), sex, reproductive state, and stress has long linked prolactin (PRL) to disease progression. PRL has both proinflammatory and anti-inflammatory outcomes in RA, but responsible mechanisms are not understood. Here, we show that PRL modifies in an opposite manner the proinflammatory actions of IL-1β and TNF-α in mouse synovial fibroblasts in culture.

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.

Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis.

Objective: Rheumatoid arthritis is an inflammatory joint disease in which synovial iron deposition has been described. Transferrin receptor 2 (Tfr2) represents a critical regulator of systemic iron levels. Loss of Tfr2 function in humans and mice results in iron overload.

Dickkopf1 fuels inflammatory cytokine responses.

Many human diseases, including cancer, share an inflammatory component but the molecular underpinnings remain incompletely understood. We report that physiological and pathological Dickkopf1 (DKK1) activity fuels inflammatory cytokine responses in cell models, mice and humans. DKK1 maintains the elevated inflammatory tone of cancer cells and is required for mounting cytokine responses following ligation of toll-like and cytokine receptors.

Dual Roles of Prolactin and Vasoinhibin in Inflammatory Arthritis.

The term inflammatory arthritis defines a family of diseases, including rheumatoid arthritis (RA), caused by an overactive immune system, and influenced by host aspects including sex, reproductive state, and stress. Prolactin (PRL) is a sexually dimorphic, reproductive, stress-related hormone long-linked to RA under the general assumption that it aggravates the disease. However, this conclusion remains controversial since PRL has both negative and positive outcomes in RA that may depend on the hormone circulating levels, synthesis by joint tissues, and complex interactions at the inflammatory milieu.

Vasoinhibin is Generated and Promotes Inflammation in Mild Antigen-induced Arthritis.

Inflammatory arthritis defines a family of diseases influenced by reproductive hormones. Vasoinhibin, a fragment of the hormone prolactin (PRL), has antiangiogenic and proinflammatory properties. We recently showed that vasoinhibin reduces joint inflammation and bone loss in severe antigen-induced arthritis (AIA) by an indirect mechanism involving the inhibition of pannus vascularization.

Shaping the bone through iron and iron-related proteins.

Well-controlled iron levels are indispensable for health. Iron deficiency is the most common cause of anemia, whereas iron overload, either hereditary or secondary due to disorders of ineffective erythropoiesis, causes widespread organ failure. Bone is particularly sensitive to fluctuations in systemic iron levels as both iron deficiency and overload are associated with low bone mineral density and fragility.

Disruption of the hepcidin/ferroportin regulatory circuitry causes low axial bone mass in mice.

Ferroportin (FPN) is the only known iron exporter. Mutations conferring resistance of FPN to hepcidin-mediated degradation cause the iron overload disorder hereditary hemochromatosis type 4. While iron overload is associated with low bone mass, the mechanisms involved are not completely understood.

Vasoinhibin reduces joint inflammation, bone loss, and the angiogenesis and vasopermeability of the pannus in murine antigen-induced arthritis.

Increased permeability and growth (angiogenesis) of blood vessels play a key role in joint swelling and pannus formation in inflammatory arthritis, a family of diseases influenced by reproductive hormones. The hormone prolactin (PRL) protects against joint inflammation, pannus formation, and bone destruction in adjuvant-induced arthritis and these effects may involve its proteolytic conversion to vasoinhibin, a PRL fragment that inhibits angiogenesis and vasopermeability. Here, we show that the intra-articular injection of an adeno-associated virus type-2 (AAV2) vector encoding vasoinhibin reduced joint inflammation, the hyperplasia, vascular density, and vasopermeability of the pannus, and the loss of bone in mice subjected to antigen-induced arthritis.

Vasoinhibin Suppresses Nerve Growth Factor-Induced Differentiation and Survival of PC12 Pheochromocytoma Cells.

Background: Vasoinhibin, a protein derived from prolactin, regulates various vascular functions including endothelial cell survival. Of note, vasoinhibin is present in the central nervous system, where it triggers neuroendocrine and behavioral responses to stress. Moreover, vasoinhibin compromises nerve growth factor (NGF)-induced neurite outgrowth in primary sensory neurons of the peripheral nervous system.

Prolactin regulates liver growth during postnatal development in mice.

The liver grows during the early postnatal period first at slower and then at faster rates than the body to achieve the adult liver-to-body weight ratio (LBW), a constant reflecting liver health. The hormone prolactin (PRL) stimulates adult liver growth and regeneration, and its levels are high in the circulation of newborn infants, but whether PRL plays a role in neonatal liver growth is unknown. Here, we show that the liver produces PRL and upregulates the PRL receptor in mice during the first 2 wk after birth, when liver growth lags behind body growth.

Prolactin blocks the expression of receptor activator of nuclear factor κB ligand and reduces osteoclastogenesis and bone loss in murine inflammatory arthritis.

Background: Prolactin (PRL) reduces joint inflammation, pannus formation, and bone destruction in rats with polyarticular adjuvant-induced arthritis (AIA). Here, we investigate the mechanism of PRL protection against bone loss in AIA and in monoarticular AIA (MAIA).

Methods: Joint inflammation, trabecular bone loss, and osteoclastogenesis were evaluated in rats with AIA treated with PRL (via osmotic minipumps) and in mice with MAIA that were null (Prlr-/-) or not (Prlr+/+) for the PRL receptor.

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1.

Adeno-associated virus (AAV) vector-mediated delivery of inhibitors of blood-retinal barrier breakdown (BRBB) offers promise for the treatment of diabetic macular edema. Here, we demonstrated a reversal of blood-retinal barrier pathology mediated by AAV type 2 (AAV2) vectors encoding vasoinhibin or soluble VEGF receptor 1 (sFlt-1) when administered intravitreally to diabetic rats. Efficacy and safety of the AAV2 vasoinhibin vector were tested by monitoring its effect on diabetes-induced changes in the retinal vascular bed and thickness, and in the electroretinogram (ERG).

Prolactin anterior pituitary expression and circulating levels are reduced in obese and diabetic rats: role of TGF-β and TNF-α.

The levels of the hormone prolactin (PRL) are reduced in the circulation of patients with Type 2 diabetes and in obese children, and lower systemic PRL levels correlate with an increased prevalence of diabetes and a higher risk of metabolic syndrome. The secretion of anterior pituitary (AP) PRL in metabolic diseases may be influenced by the interplay between transforming growth factor β (TGF-β) and tumor necrosis factor α (TNF-α), which inhibit and can stimulate AP PRL synthesis, respectively, and are known contributors to insulin resistance and metabolic complications. Here, we show that TGF-β and TNF-α antagonize the effect of each other on the expression and release of PRL by the GH4C1 lactotrope cell line.

Vasoinhibins regulate the inner and outer blood-retinal barrier and limit retinal oxidative stress.

Vasoinhibins are prolactin fragments present in the retina, where they have been shown to prevent the hypervasopermeability associated with diabetes. Enhanced bradykinin (BK) production contributes to the increased transport through the blood-retina barrier (BRB) in diabetes. Here, we studied if vasoinhibins regulate BRB permeability by targeting the vascular endothelium and retinal pigment epithelium (RPE) components of this barrier.

Prolactin-derived vasoinhibins increase anxiety- and depression-related behaviors.

The hormone prolactin (PRL) regulates neuroendocrine and emotional stress responses. It is found in the hypothalamus, where the protein is partially cleaved to vasoinhibins, a family of N-terminal antiangiogenic PRL fragments ranging from 14 to 18kDa molecular masses, with unknown effects on the stress response. Here, we show that the intracerebroventricular administration of a recombinant vasoinhibin, containing the first 123 amino acids of human PRL that correspond to a 14kDa PRL, exerts anxiogenic and depressive-like effects detected in the elevated plus-maze, the open field, and the forced swimming tests.

Arthritis and prolactin: a phylogenetic viewpoint.

Arthritic disorders are family of diseases that have existed since vertebrate life began. Their etiology is multifactorial with genetic, environmental, and gender factors driving chronic joint inflammation. Prolactin is a sexually dimorphic hormone in mammals that can act to both promote and ameliorate rheumatic diseases.

Prolactin promotes cartilage survival and attenuates inflammation in inflammatory arthritis.

Chondrocytes are the only cells in cartilage, and their death by apoptosis contributes to cartilage loss in inflammatory joint diseases, such as rheumatoid arthritis (RA). A putative therapeutic intervention for RA is the inhibition of apoptosis-mediated cartilage degradation. The hormone prolactin (PRL) frequently increases in the circulation of patients with RA, but the role of hyperprolactinemia in disease activity is unclear.