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Current Osteoporosis Reports Dec 2022The purpose of this review is to discuss the molecular mechanisms involved in osteocyte dendrite formation, summarize the similarities between osteocytic and neuronal... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to discuss the molecular mechanisms involved in osteocyte dendrite formation, summarize the similarities between osteocytic and neuronal projections, and highlight the importance of osteocyte dendrite maintenance in human skeletal disease.
RECENT FINDINGS
It is suggested that there is a causal relationship between the loss of osteocyte dendrites and the increased osteocyte apoptosis during conditions including aging, microdamage, and skeletal disease. A few mechanisms are proposed to control dendrite formation and outgrowth, such as via the regulation of actin polymerization dynamics. This review addresses the impact of osteocyte dendrites in bone health and disease. Recent advances in multi-omics, in vivo and in vitro models, and microscopy-based imaging have provided novel approaches to reveal the underlying mechanisms that regulate dendrite development. Future therapeutic approaches are needed to target the process of osteocyte dendrite formation.
Topics: Humans; Osteocytes; Bone and Bones; Aging; Dendrites
PubMed: 36087214
DOI: 10.1007/s11914-022-00753-8 -
Current Osteoporosis Reports Apr 2015There is considerable variation in the shape of osteocyte lacunae, which is likely to influence the function of osteocytes as the professional mechanosensors of bone. In... (Review)
Review
There is considerable variation in the shape of osteocyte lacunae, which is likely to influence the function of osteocytes as the professional mechanosensors of bone. In this review, we first discussed how mechanical loading could affect the shape of osteocyte lacunae. Recent studies show that osteocyte lacunae are aligned to collagen. Since collagen fiber orientation is affected by loading mode, this alignment may help to understand how mechanical loading shapes the osteocyte lacuna. Secondly, we discussed how the shape of osteocytes could influence their mechanosensation. In vitro, round osteocytes are more mechanosensitive than flat osteocytes. Altered lacunar morphology has been associated with bone pathology. It is important to know whether osteocyte shape is part of the etiology.
Topics: Animals; Cell Shape; Collagen; Humans; In Vitro Techniques; Mechanotransduction, Cellular; Osteocytes; Stress, Mechanical; Weight-Bearing
PubMed: 25663071
DOI: 10.1007/s11914-015-0256-1 -
Nature Communications May 2021Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes...
Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10) and osteoarthritis (P = 1.6 × 10). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.
Topics: Age Factors; Animals; Bone Diseases; Bone and Bones; Computational Biology; Female; Homeostasis; Humans; Male; Mice; Mice, Knockout; Osteocytes; Osteoporosis; Sequence Analysis, RNA; Sex Factors; Transcriptome
PubMed: 33953184
DOI: 10.1038/s41467-021-22517-1 -
Calcified Tissue International May 2022Disuse osteoporosis describes a state of bone loss due to local skeletal unloading or systemic immobilization. This review will discuss advances in the field that have... (Review)
Review
Disuse osteoporosis describes a state of bone loss due to local skeletal unloading or systemic immobilization. This review will discuss advances in the field that have shed light on clinical observations, mechanistic insights and options for the treatment of disuse osteoporosis. Clinical settings of disuse osteoporosis include spinal cord injury, other neurological and neuromuscular disorders, immobilization after fractures and bed rest (real or modeled). Furthermore, spaceflight-induced bone loss represents a well-known adaptive process to microgravity. Clinical studies have outlined that immobilization leads to immediate bone loss in both the trabecular and cortical compartments accompanied by relatively increased bone resorption and decreased bone formation. The fact that the low bone formation state has been linked to high levels of the osteocyte-secreted protein sclerostin is one of the many findings that has brought matrix-embedded, mechanosensitive osteocytes into focus in the search for mechanistic principles. Previous basic research has primarily involved rodent models based on tail suspension, spaceflight and other immobilization methods, which have underlined the importance of osteocytes in the pathogenesis of disuse osteoporosis. Furthermore, molecular-based in vitro and in vivo approaches have revealed that osteocytes sense mechanical loading through mechanosensors that translate extracellular mechanical signals to intracellular biochemical signals and regulate gene expression. Osteocytic mechanosensors include the osteocyte cytoskeleton and dendritic processes within the lacuno-canalicular system (LCS), ion channels (e.g., Piezo1), extracellular matrix, primary cilia, focal adhesions (integrin-based) and hemichannels and gap junctions (connexin-based). Overall, disuse represents one of the major factors contributing to immediate bone loss and osteoporosis, and alterations in osteocytic pathways appear crucial to the bone loss associated with unloading.
Topics: Gap Junctions; Hindlimb Suspension; Humans; Ion Channels; Osteocytes; Osteogenesis; Osteoporosis
PubMed: 33738515
DOI: 10.1007/s00223-021-00836-1 -
Frontiers in Endocrinology 2020Bone is the most frequent site of breast cancer and prostate cancer metastasis, and one of the most common sites of metastasis for many solid tumors. Once cancer cells... (Review)
Review
Bone is the most frequent site of breast cancer and prostate cancer metastasis, and one of the most common sites of metastasis for many solid tumors. Once cancer cells colonize in the bone, it imposes a major clinical challenge for the treatment of the disease, and fatality rates increase drastically. Bone, the largest organ in the body, provides a fertile microenvironment enriched with nutrients, growth factors and hormones, a generous reward for cancer cells. Dependent on cancer type, cancer cells can cause osteoblastic (bone forming) or osteolytic lesions to promote the net resorption and/or release of growth factors from the bone extracellular matrix. These processes activate a "vicious cycle", leading to disruption of bone integrity and promoting cancer cell growth and migration. Cancer cells influence the bone microenvironment favoring their colonization and growth. In order to metastasize to the bone, cancer cells must first migrate from the site of origin, and once established within the bone, they must overcome the dormant inducing effects of resident cells. If successful, cancer cells can then colonize and continually disrupt bone homeostasis that is primarily maintained by osteocytes, the most abundant bone cell type. For example, it has been shown that exercise induces osteocytes to release anabolic factors that inhibit osteoclast resorptive activity, promote dormancy and the release of anti-cancer factors that inhibit breast cancer cell metastasis. In this review, we will summarize recent research findings and provide mechanistic insights related to the role of osteocytes in osteolytic metastasis.
Topics: Bone Neoplasms; Breast Neoplasms; Female; Humans; Male; Osteocytes; Prostatic Neoplasms; Tumor Microenvironment
PubMed: 33162934
DOI: 10.3389/fendo.2020.567844 -
Current Osteoporosis Reports Aug 2019In perilacunar/canalicular remodeling (PLR), osteocytes dynamically resorb, and then replace, the organic and mineral components of the pericellular extracellular... (Review)
Review
PURPOSE OF REVIEW
In perilacunar/canalicular remodeling (PLR), osteocytes dynamically resorb, and then replace, the organic and mineral components of the pericellular extracellular matrix. Given the enormous surface area of the osteocyte lacuna-canalicular network (LCN), PLR is important for maintaining homeostasis of the skeleton. The goal of this review is to examine the motivations and critical considerations for the analysis of PLR, in both in vitro and in vivo systems.
RECENT FINDINGS
Morphological approaches alone are insufficient to elucidate the complex mechanisms regulating PLR in the healthy skeleton and in disease. Understanding the role and regulation of PLR will require the incorporation of standardized PLR outcomes as a routine part of skeletal phenotyping, as well as the development of improved molecular and cellular outcomes. Current PLR outcomes assess PLR enzyme expression, the LCN, and bone matrix composition and organization, among others. Here, we discuss current PLR outcomes and how they have been applied to study PLR induction and suppression in vitro and in vivo. Given the role of PLR in skeletal health and disease, integrated analysis of PLR has potential to elucidate new mechanisms by which osteocytes participate in skeletal health and disease.
Topics: Bone Matrix; Bone Remodeling; Carbonic Anhydrases; Cathepsin K; Cell Line; Homeostasis; Humans; Hydrogen-Ion Concentration; Imaging, Three-Dimensional; Matrix Metalloproteinases; Microscopy, Confocal; Microscopy, Electron, Scanning; Osteocytes; Proton-Translocating ATPases; X-Ray Microtomography
PubMed: 31227998
DOI: 10.1007/s11914-019-00514-0 -
JCI Insight Oct 2023Osteocytes express parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptors and respond to the PTHrP analog abaloparatide (ABL) and to the PTH 1-34 fragment...
Osteocytes express parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptors and respond to the PTHrP analog abaloparatide (ABL) and to the PTH 1-34 fragment teriparatide (TPTD), which are used to treat osteoporosis. Several studies indicate overlapping but distinct skeletal responses to ABL or TPTD, but their effects on cortical bone may differ. Little is known about their differential effects on osteocytes. We compared cortical osteocyte and skeletal responses to ABL and TPTD in sham-operated and ovariectomized mice. Administered 7 weeks after ovariectomy for 4 weeks at a dose of 40 μg/kg/d, TPTD and ABL had similar effects on trabecular bone, but ABL showed stronger effects in cortical bone. In cortical osteocytes, both treatments decreased lacunar area, reflecting altered peri-lacunar remodeling favoring matrix accumulation. Osteocyte RNA-Seq revealed that several genes and pathways were altered by ovariectomy and affected similarly by TPTD and ABL. Notwithstanding, several signaling pathways were uniquely regulated by ABL. Thus, in mice, TPTD and ABL induced a positive osteocyte peri-lacunar remodeling balance, but ABL induced stronger cortical responses and affected the osteocyte transcriptome differently. We concluded that ABL affected the cortical osteocyte transcriptome in a manner subtly different from TPTD, resulting in more beneficial remodeling/modeling changes and homeostasis of the cortex.
Topics: Female; Mice; Animals; Teriparatide; Parathyroid Hormone-Related Protein; Osteocytes; Transcriptome; Estrogens
PubMed: 37870958
DOI: 10.1172/jci.insight.161932 -
Bone Jun 2013Glucocorticoids are used for the treatment of inflammatory and autoimmune diseases. While they are effective therapy, bone loss and incident fracture risk are high.... (Review)
Review
Glucocorticoids are used for the treatment of inflammatory and autoimmune diseases. While they are effective therapy, bone loss and incident fracture risk are high. While previous studies have found GC effects on both osteoclasts and osteoblasts, our work has focused on the effects of GCs on osteocytes. Osteocytes exposed to low dose GCs undergo autophagy while osteocytes exposed to high doses of GCs or for a prolonged period of time undergo apoptosis.
Topics: Animals; Autophagy; Bone Resorption; Glucocorticoids; Humans; Minerals; Osteocytes
PubMed: 23356984
DOI: 10.1016/j.bone.2013.01.034 -
Bone Jun 2013Apoptotic death of osteocytes was recognized over 15 years ago, but its significance for bone homeostasis has remained elusive. A new paradigm has emerged that invokes... (Review)
Review
Apoptotic death of osteocytes was recognized over 15 years ago, but its significance for bone homeostasis has remained elusive. A new paradigm has emerged that invokes osteocyte apoptosis as a critical event in the recruitment of osteoclasts to a specific site in response to skeletal unloading, fatigue damage, estrogen deficiency and perhaps in other states where bone must be removed. This is accomplished by yet to be defined signals emanating from dying osteocytes, which stimulate neighboring viable osteocytes to produce osteoclastogenic cytokines. The osteocyte apoptosis caused by chronic glucocorticoid administration does not increase osteoclasts; however, it does negatively impact maintenance of bone hydration, vascularity, and strength.
Topics: Animals; Apoptosis; Bone Remodeling; Humans; Osteocytes; RANK Ligand; Signal Transduction; Weight-Bearing
PubMed: 23238124
DOI: 10.1016/j.bone.2012.11.038 -
Acta Biomaterialia May 2023Bone fragility is a profound complication of type 1 diabetes mellitus (T1DM), increasing patient morbidity. Within the mineralized bone matrix, osteocytes build a...
Bone fragility is a profound complication of type 1 diabetes mellitus (T1DM), increasing patient morbidity. Within the mineralized bone matrix, osteocytes build a mechanosensitive network that orchestrates bone remodeling; thus, osteocyte viability is crucial for maintaining bone homeostasis. In human cortical bone specimens from individuals with T1DM, we found signs of accelerated osteocyte apoptosis and local mineralization of osteocyte lacunae (micropetrosis) compared with samples from age-matched controls. Such morphological changes were seen in the relatively young osteonal bone matrix on the periosteal side, and micropetrosis coincided with microdamage accumulation, implying that T1DM drives local skeletal aging and thereby impairs the biomechanical competence of the bone tissue. The consequent dysfunction of the osteocyte network hampers bone remodeling and decreases bone repair mechanisms, potentially contributing to the enhanced fracture risk seen in individuals with T1DM. STATEMENT OF SIGNIFICANCE: Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease that causes hyperglycemia. Increased bone fragility is one of the complications associated with T1DM. Our latest study on T1DM-affected human cortical bone identified the viability of osteocytes, the primary bone cells, as a potentially critical factor in T1DM-bone disease. We linked T1DM with increased osteocyte apoptosis and local accumulation of mineralized lacunar spaces and microdamage. Such structural changes in bone tissue suggest that T1DM speeds up the adverse effects of aging, leading to the premature death of osteocytes and potentially contributing to diabetes-related bone fragility.
Topics: Humans; Osteocytes; Diabetes Mellitus, Type 1; Aging; Bone and Bones; Apoptosis
PubMed: 36878337
DOI: 10.1016/j.actbio.2023.02.037