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Enhanced Osteocyte Differentiation: Cathepsin D and L Secretion by Human Adipose-Derived Mesenchymal Stem Cells.

Adipose-derived mesenchymal stem cells (ASCs) have the potential to differentiate into bone, cartilage, fat, and neural cells and promote tissue regeneration and healing. It is known that they can have variable responses to hypoxic conditions. In the present study, we aimed to explore diverse changes in the cells and secretome of ASCs under a hypoxic environment over time and to present the possibility of ASCs as therapeutic agents from a different perspective. The expression differences of proteins between normoxic and hypoxic conditions (6, 12, or 24 h) were specifically investigated in huma

Abnormal Bone Tissue Organization and Osteocyte Lacunocanalicular Network in Early-Onset Osteoporosis Due to SGMS2 Mutations.

Pathological variants in SGMS2, encoding sphingomyelin synthase 2 (SMS2), result in a rare autosomal dominant skeletal disorder with cranial doughnut lesions. The disease manifests as early-onset osteoporosis or a more severe skeletal dysplasia with low bone mineral density, frequent fractures, long-bone deformities, and multiple sclerotic cranial lesions. The exact underlying molecular features and skeletal consequences, however, remain elusive. This study investigated bone tissue characteristics in two adult males with a heterozygous SGMS2 mutation p.Arg50* and significant bone fragility. Tr

Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin.

Although the control of bone-resorbing osteoclasts through osteocyte-derived RANKL is well defined, little is known about the regulation of osteoclasts by osteocyte death. Indeed, several skeletal diseases, such as bone fracture, osteonecrosis, and inflammation are characterized by excessive osteocyte death. Herein we show that osteoclasts sense damage-associated molecular patterns (DAMPs) released by necrotic osteocytes via macrophage-inducible C-type lectin (Mincle), which induced their differentiation and triggered bone loss. Osteoclasts showed robust Mincle expression upon exposure to necr…

Botox-induced muscle paralysis alters intracortical porosity and osteocyte lacunar density in skeletally mature rats.

Reduced mechanical loading can lead to disuse osteoporosis, resulting in bone fragility. Disuse models report macroscopic bone loss due to m … nterstitial fluid flow, affecting molecular transport and the transmission of mechanical signals to osteocytes. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Microfluidic co-culture platform for investigating osteocyte-osteoclast signalling during fluid shear stress mechanostimulation.

Bone cells exist in a complex environment where they are constantly exposed to numerous dynamic biochemical and mechanical stimuli. These st … last differentiation towards nOCY. We also used this system to show an increased mechanoresponse of osteocytes when in co-culture with osteoclasts. We envision broad applicability of the presented approach for microfluidic perfusion co-culture of multiple cell types in the presence of fluid flow stimulation, and as a tool to investigate osteocyte mechanotran …

A Role for the Calcitonin Receptor to Limit Bone Loss During Lactation in Female Mice by Inhibiting Osteocytic Osteolysis.

During lactation, the large transfer of calcium from the mother to the milk is primarily sourced from the maternal skeleton. To determine wh … e bone of lactating global CTRKO females. Because these genes have been shown to be up-regulated in osteocytes during lactation when osteocytes resorb their surrounding bone matrix, together with their reported expression of the CTR, we determined the osteocyte lacunar area in cortical bone. After lactation, the top 20% of osteocyte lacunar area in global CT …

Osteocyte morphology in human tibiae of different bone pathologies with different bone mineral density--is there a role for mechanosensing?

Matrix strains due to external loading are different in bones of different pathologies with different bone mineral density (BMD), and are likely sensed by the osteocytes, the putative bone mechanosensors. The mechanosensitivity of osteocytes appears to be strongly influenced by their morphology. In this study, we explored the possibility that osteocyte morphology might play a role in various bone pathologies with different BMD. Confocal laser scanning microscopy and nano-CT were used to quantitatively determine 3D morphology and alignment of osteocytes and osteocyte lacunae in human proximal t…

Correlation between the structure of the wall of the bone lacuna and the localization of the osteocyte within this lacuna. Electron-microscopic studies.

A correlation between the structure of the wall of the bone lacuna and the localization of the osteocyte within this lacuna was the object of investigation under light and electron microscopes. On the basis of the structural divergences detected, the author distinguished zones A and B in the osteocyte situated in the lacuna. Zone B is characterized by a parallel, compact system of collagen fibrils which form a characteristic ridge in the lacunar wall, a continuous demarcating line bordering this wall, the osteocyte cytoplasm in this part lying far from the lacuna wall and surrounding the nucle

Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling.

Fibroblastic growth factor 23 (FGF23) is a circulating phosphaturic hormone. Inactivating mutations of the endopeptidase PHEX or the SIBLING protein DMP1 result in equivalent intrinsic bone mineralization defects and increased Fgf23 expression in osteocytes. The mechanisms whereby PHEX and DMP1 regulate Fgf23 expression are unknown. We examined the possibility that PHEX and DMP1 regulate Fgf23 through a common pathway by analyzing the phenotype of compound Phex and Dmp1 mutant mice (Hyp/Dmp1(-/-)). Compared to single-mutant littermates, compound-mutant Hyp/Dmp1(-/-) mice displayed nonadditive …

Xenograft of Human Umbilical Mesenchymal Stem Cells from Wharton's Jelly Differentiating into Osteocytes and Reducing Osteoclast Activity Reverses Osteoporosis in Ovariectomized Rats.

We examined the effects of human umbilical cord-derived mesenchymal stem cells (HUMSCs) in Wharton's jelly on ovariectomy (OVX)-induced osteoporosis by using in vitro and in vivo experiments. Two months after OVX, the rats gained weight and had a decreased serum estradiol level . Both micro-computed tomography (micro-CT) and histochemical analyses revealed a marked decrease in the bone volume (BV) and collagen content within the head, neck, and distal condyle of the femur, indicating that the osteoporosis animal model was successfully established 2 mo after bilateral OVX. Subsequently, 2.5 × 1

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… In Vitro Coculture System Indicates that HUMSCs Do Not Trigger Osteoblasts to Differentiate into Mature Osteocytes To investigate whether HUMSCs promote the differentiation of osteoblasts into mature osteocytes, osteoblasts were cultured alone in vitro or with HUMSCs. … In Vitro Coculture System Revealed that Osteoblasts Promoted Differentiation of HUMSCs into Mature Osteocytes To examine whether osteoblasts induce differentiation of HUMSCs into mature osteocytes, HUMSCs were cultured alone or with osteoblasts in vitro for 2 wk. …

Transcriptomic comparison of osteocyte cell lines - determining their utility as models to study sex hormone regulation of skeletal function.

Osteocytes are critical for bone development, and tightly regulate bone (re)modelling by directing the differentiation and activity of osteoblast and osteoclasts. Primary osteocyte isolation is challenging, therefore MLO-A5 and MLO-Y4 osteocyte-like cell lines have been instrumental in dissecting osteocytogenesis and bone mineralisation. Limited comparative analysis of these closely related in vitro models has been undertaken, therefore we used transcriptomic analysis to dissect their transcriptional similarities. Principal component analysis showed MLO-A5 and MLO-Y4 cells form distinct cluste…

New knock-in mouse lines Dmp1em1(CreERT2) and Dmp1em2(ZsGreen) enable precise osteocyte-specific targeting and visualization.

Bone in adult mammals plays critical structural and endocrine functions, both largely rely on osteocytes-the most abundant bone cells and principal source of bone-derived hormones, such as fibroblast growth factor 23 and sclerostin. The widely used 10-kb promoter-driven transgenic Tg(Dmp1-Cre) and Tg(Dmp1-CreERT2) lines, while widely used and helpful, utilize transgenic approaches with transgene expression driven by the Dmp1 promoter. The transgene expression suffers from positional effects with off-target expression in muscle, brain, and other tissues, limiting their applications, causing a m…

The talin1-p53 axis inhibits osteocyte senescence to promote bone mass and mediate skeletal adaptation to mechanical stimulation.

Background: Osteoporosis is a major public health concern worldwide. As the predominant and long-lived bone cells, osteocytes serve as key regulators of bone remodeling and mechanotransduction. However, the molecular mechanisms underlying their regulatory roles remain poorly understood. The roles of talin1, a key focal adhesion protein linking integrins to the cytoskeleton, in regulation of osteocyte function and skeletal homeostasis remain unclear. Methods: Osteocyte-specific talin1 conditional knockout (cKO) mice were established, and their skeletal phenotypes were assessed through micro-CT,…

Fibroblast growth factor receptor signaling in maturing osteoblasts controls cell-matrix interactions critical for osteocyte survival.

The terminal differentiation of osteoblasts into osteocytes, the most abundant cell type in cortical bone, is critical for skeletal homeostasis. Osteocyte loss is a hallmark of bone aging and fragility, yet the mechanisms regulating osteocyte formation and survival are poorly understood. We show that inactivation of fibroblast growth factor receptor 1 (Fgfr1) in the mature osteoblast lineage results in extensive osteocyte death, identifying FGFR1 signaling as essential for osteocyte viability and bone integrity. Lineage tracing and analysis of endogenous and induced appositional bone formation…

Immune escape of Staphylococcus aureus mediated by osteocyte lacuna-canalicular network leads to persistent and uncured bone infection.

Bone infections, specifically chronic osteomyelitis, are characterized by recurrent episodes. They are considered intractable clinical diseases as they require protracted and difficult-to-cure courses. Staphylococcus aureus (S. aureus) is the most common pathogen responsible for bone infections and has high destruction rates. Previous literature has indicated that during S. aureus osteomyelitis, immune evasion mainly involves three mechanisms: biofilm formation, intracellular infection, and abscess formation. However, recently, it was observed that S. aureus can enter and persist for a long ti

Titanium Particles Activate Osteocytic Connexin 43 to Induce Oxidative Stress and Osteoclastogenesis Through the JAK-STAT Pathway.

Aims: Periprosthetic osteolysis (PPO), a leading cause of aseptic loosening in joint replacement, arose from complex interactions among osteoblasts, osteoclasts, and osteocytes. Given the pivotal role of connexin 43 (Cx43) in osteocyte communication and bone remodeling, investigating its function was essential for understanding the mechanisms of osteolysis. Our previous studies showed that titanium (Ti) particles increased Cx43 expression in osteocytes. However, the role of Cx43 in osteolysis remained unclear. This study investigated the role of Cx43-mediated regulation of osteocytes on osteoc…

Articular cartilage degeneration and aberrant osteocyte perilacunar/canalicular remodeling in subchondral bone of patients with developmental dysplasia of the hip.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a congenital musculoskeletal disease that impairs the hip joint and exacerbates hip … is. Histological and immunohistochemical staining was used to observe chondrocytes in cartilage and osteocytes in subchondral bone. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining was used to investigate the apoptotic osteocytes in subchondral bone. Ploton silver staining was used to visualize lacunocanalicular network and picrosirius r …

Reactive oxygen species-mediated endoplasmic reticulum stress contributes to osteocyte death induced by orthodontic compressive force.

During orthodontic tooth movement (OTM), osteocytes, the most mechanosensitive cells in alveolar bone, suffer the heavy orthodontic force and initiate alveolar bone resorption on the compression side. However, the inherent mechanisms of compressive force-induced osteocyte death are not fully understood. In this study, we established an OTM model on Sprague-Dawley rats by inserting coil springs to investigate osteocyte damage on the compression side of alveolar bone. We then applied compressive force on the MLO-Y4 osteocyte-like cell line in vitro to explore whether the reactive oxygen species …

Irisin inhibits osteocyte apoptosis by activating the Erk signaling pathway in vitro and attenuates ALCT-induced osteoarthritis in mice.

Moderate exercise can alleviate symptoms of osteoarthritis (OA) such as pain, stiffness, and joint deformities that are associated with prog … atase showed a decreased number of osteoclasts. Irisin significantly increased the proliferation of osteocytes, protected them from apoptosis, and maintained cellular activity by regulating the expression of Bax, Bcl-2, and osteoprotegerin/receptor activator of nuclear factor (NF)-kB-ligand (OPG/Rankl). Irisin activated serine/threonine-selective protein kin …

The role of connectivity and stochastic osteocyte behavior in the distribution of perilabyrinthine bone degeneration. A Monte Carlo based simulation study.

Previous studies of undecalcified temporal bones labeled with fluorescent tissue time markers and basic fuchsine have documented the unique spatial and temporal patterns underlying inner ear bone development, morphology and degeneration, and has led to the identification of inner ear OPG as the candidate inhibiter of perilabyrinthine bone resorption. Resulting age related excessive matrix microdamage, osteocyte death and degeneration of the OPG signaling pathway is expected to trigger bone remodeling in the otic capsule, but when this happens the morphology of the remodeling bone is abnormal a