6475 Prevents Bone Loss in a Clinically Relevant Oral Model of Glucocorticoid-Induced Osteoporosis in Male CD-1 Mice.

Glucocorticoids (GCs) are commonly used anti-inflammatory medications with significant side effects, including glucocorticoid-induced osteoporosis (GIO). We have previously demonstrated that chronic subcutaneous GC treatment in mice leads to gut barrier dysfunction and trabecular bone loss. We further showed that treating with probiotics or barrier enhancers improves gut barrier function and prevents GIO.

Periosteal Bone Formation Varies with Age in Periostin Null Mice.

Periostin, also known as osteoblast-specific factor 2, is a matricellular protein predominantly expressed at the periosteum of bone. During growth and development, periostin contributes to periosteal expansion by facilitating osteoblast differentiation and mineralization. Later in life, periosteal expansion provides an adaptive strategy to increase tissue strength without requiring substantial increase in bone mass.

The mechanotransduction of MLO-Y4 cells is disrupted by the senescence-associated secretory phenotype of neighboring cells.

Age-related bone loss is attributed to the accumulation of senescent cells and their increasing production of inflammatory cytokines as part of the senescence-associated secretory phenotype (SASP). In otherwise healthy individuals, osteocytes play a key role in maintaining bone mass through their primary function of responding to skeletal loading. Given that osteocytes' response to loading is known to steadily decline with age, we hypothesized that the increasing presence of senescent cells and their SASP inhibit osteocytes' response to loading.

Insulin-like growth factor-1 regulates the mechanosensitivity of chondrocytes by modulating TRPV4.

Both mechanical and biochemical stimulation are required for maintaining the integrity of articular cartilage. However, chondrocytes respond differently to mechanical stimuli in osteoarthritic cartilage when biochemical signaling pathways, such as Insulin-like Growth Factor-1 (IGF-1), are altered. The Transient Receptor Potential Vanilloid 4 (TRPV4) channel is central to chondrocyte mechanotransduction and regulation of cartilage homeostasis.

The Diminishing Returns of Mechanical Loading and Potential Mechanisms that Desensitize Osteocytes.

Adaptation to mechanical loading is critical to maintaining bone mass and offers therapeutic potential to preventing age-related bone loss and osteoporosis. However, increasing the duration of loading is met with "diminishing returns" as the anabolic response quickly becomes saturated. As a result, the anabolic response to daily activities and repetitive bouts of loading is limited by the underlying mechanisms that desensitize and render bone unresponsive at the cellular level.

Osteocytes' expression of the PTH/PTHrP receptor has differing effects on endocortical and periosteal bone formation during adenine-induced CKD.

Osteocytes play a key role in the pathophysiology of chronic kidney disease (CKD). However, the extent to which osteocytes contribute to abnormalities in bone turnover due to excessive levels of parathyroid hormone (PTH) remains poorly understood. The purpose of this study was to determine the extent to which bone formation and tissue strength during the progression of CKD is modified through osteocytes' response to PTH.

Involvement of the Gut Microbiota and Barrier Function in Glucocorticoid-Induced Osteoporosis.

Glucocorticoids (GCs) are potent immune-modulating drugs with significant side effects, including glucocorticoid-induced osteoporosis (GIO). GCs directly induce osteoblast and osteocyte apoptosis but also alter intestinal microbiota composition. Although the gut microbiota is known to contribute to the regulation of bone density, its role in GIO has never been examined.

Probiotic Lactobacillus reuteri Prevents Postantibiotic Bone Loss by Reducing Intestinal Dysbiosis and Preventing Barrier Disruption.

Antibiotic treatment, commonly prescribed for bacterial infections, depletes and subsequently causes long-term alterations in intestinal microbiota composition. Knowing the importance of the microbiome in the regulation of bone density, we investigated the effect of postantibiotic treatment on gut and bone health. Intestinal microbiome repopulation at 4-weeks postantibiotic treatment resulted in an increase in the Firmicutes:Bacteroidetes ratio, increased intestinal permeability, and notably reduced femoral trabecular bone volume (approximately 30%, p < 0.

Loss of the PTH/PTHrP receptor along the osteoblast lineage limits the anabolic response to exercise.

Exercise and physical activity are critical to maintain bone mass and strength throughout life. Both exercise and physical activity subject bone to a unique combination of stimuli in the forms of dynamic loading and a systemic increase in parathyroid hormone (PTH). Although dynamic loading is considered to be the primary osteogenic stimuli, the influence of increasing PTH levels remains unclear.

Examining the influence of PTH(1-34) on tissue strength and composition.

The lacunar-canaliculi system is a network of channels that is created and maintained by osteocytes as they are embedded throughout cortical bone. As osteocytes modify their lacuna space, the local tissue composition and tissue strength are subject to change. Although continual exposure to parathyroid hormone (PTH) can induce adaptation at the lacunar wall, the impact of intermittent PTH treatment on perilacunar adaptation remains unclear.

Bone adaptation in response to treadmill exercise in young and adult mice.

Exercise is a key determinate of fracture risk and provides a clinical means to promote bone formation. However, the efficacy of exercise to increase bone mass declines with age. The purpose of this study was to identify age-related differences in the anabolic response to exercise at the cellular and tissue level.

PTH signaling mediates perilacunar remodeling during exercise.

Mechanical loading and release of endogenous parathyroid hormone (PTH) during exercise facilitate the adaptation of bone. However, it remains unclear how exercise and PTH influence the composition of bone and how exercise and PTH-mediated compositional changes influence the mechanical properties of bone. Thus, the primary purpose of this study was to establish compositional changes within osteocytes' perilacunar region of cortical bone following exercise, and evaluate the influence of endogenous PTH signaling on this perilacunar adaptation.

Exercise increases pyridinoline cross-linking and counters the mechanical effects of concurrent lathyrogenic treatment.

The collagen cross-link profile of bone, associated with bone strength and fracture toughness, is tightly regulated (affecting cross-link quantity, type, lysine hydroxylation and maturity) and may contribute to the improvements in bone quality during exercise. We hypothesized that 1) exercise promotes mature cross-link formation, 2) increased mature cross-linking is accompanied by shifts in lysine hydroxylation, and 3) these changes in collagen cross-link profile have positive effects on mechanical properties. Growing male C57Bl6 mice were treated with 30 min/day of running exercise, 350 mg/kg/day β-aminopropionitrile (BAPN) injected subcutaneously to inhibit enzymatic collagen cross-linking, or both exercise and BAPN, from 5 to 8 weeks of age.

PTH Signaling During Exercise Contributes to Bone Adaptation.

Improving the structural integrity of bone reduces fracture risk and development of osteoporosis later in life. Exercise can increase the mechanical properties of bone, and this increase is often attributed to the dynamic loading created during exercise. However, the increase in systemic parathyroid hormone (PTH) levels during exercise gives reason to hypothesize that PTH signaling also regulates bone adaptation in response to exercise.

Hydraulic Pressure during Fluid Flow Regulates Purinergic Signaling and Cytoskeleton Organization of Osteoblasts.

During physiological activities, osteoblasts experience a variety of mechanical forces that stimulate anabolic responses at the cellular level necessary for the formation of new bone. Previous studies have primarily investigated the osteoblastic response to individual forms of mechanical stimuli. However in this study, we evaluated the response of osteoblasts to two simultaneous, but independently controlled stimuli; fluid flow-induced shear stress (FSS) and static or cyclic hydrostatic pressure (SHP or CHP, respectively).

Does blood pressure enhance solute transport in the bone lacunar-canalicular system?

Solute transport through bone plays an important role in tissue metabolism and cellular mechanotransduction. Due to limited diffusion within the mineralized bone matrix, both mechanical loading and vascular pressure have been proposed to drive interstitial fluid flow within the lacunar-canalicular system (LCS); thereby augmenting solute diffusion in bone. Although blood supply is critical for bone nutrition, growth, and fracture healing, whether physiological blood pressures can drive significant fluid and solute convection remains controversial within the literature.

Cyclic Hydraulic Pressure and Fluid Flow Differentially Modulate Cytoskeleton Re-Organization in MC3T3 Osteoblasts.

Mechanical loads are essential towards maintaining bone mass and skeletal integrity. Such loads generate various stimuli at the cellular level, including cyclic hydraulic pressure (CHP) and fluid shear stress (FSS). To gain insight into the anabolic responses of osteoblasts to CHP and FSS, we subjected MC3T3-E1 preosteoblasts to either FSS (12 dynes/cm(2)) or CHP varying from 0 to 68 kPa at 0.

In situ permeability measurement of the mammalian lacunar-canalicular system.

Bone is capable of adapting its mass and structure under mechanical cues. Bone cells respond to various mechanical stimuli including substrate strain, fluid pressure, and fluid flow (shear stress) in vitro. Although tissue-level strains are well documented experimentally, microfluidic parameters around bone cells are quantified mainly through theoretical modeling.