Degenerative Bone Disease Research Articles

The Role of BMP Signaling in Osteoclast Regulation.

The osteogenic effects of Bone Morphogenetic Proteins (BMPs) were delineated in 1965 when Urist et al. showed that BMPs could induce ectopic bone formation. In subsequent decades, the effects of BMPs on bone formation and maintenance were established. BMPs induce proliferation in osteoprogenitor cells and increase mineralization activity in osteoblasts. The role of BMPs in bone homeostasis and repair led to the approval of BMP2 by the Federal Drug Administration (FDA) for anterior lumbar interbody fusion (ALIF) to increase the bone formation in the treated area. However, the use of BMP2 for treatment of degenerative bone diseases such as osteoporosis is still uncertain as patients treated with BMP2 results in the stimulation of not only osteoblast mineralization, but also osteoclast absorption, leading to early bone graft subsidence. The increase in absorption activity is the result of direct stimulation of osteoclasts by BMP2 working synergistically with the RANK signaling pathway. The dual effect of BMPs on bone resorption and mineralization highlights the essential role of BMP-signaling in bone homeostasis, making it a putative therapeutic target for diseases like osteoporosis. Before the BMP pathway can be utilized in the treatment of osteoporosis a better understanding of how BMP-signaling regulates osteoclasts must be established.

Investigation into the Hybrid Production of a Superelastic Shape Memory Alloy with Additively Manufactured Structures for Medical Implants.

The demographic change in and the higher incidence of degenerative bone disease have resulted in an increase in the number of patients with osteoporotic bone tissue causing. amongst other issues, implant loosening. Revision surgery to treat and correct the loosenings should be avoided, because of the additional patient stress and high treatment costs. Shape memory alloys (SMA) can help to increase the anchorage stability of implants due to their superelastic behavior. The present study investigates the potential of hybridizing NiTi SMA sheets with additively manufactured Ti6Al4V anchoring structures using laser powder bed fusion (LPBF) technology to functionalize a pedicle screw. Different scanning strategies are evaluated, aiming for minimized warpage of the NiTi SMA sheet. For biomechanical tests, functional samples were manufactured. A good connection between the additively manufactured Ti6Al4V anchoring structures and NiTi SMA substrate could be observed though crack formation occurring at the transition area between the two materials. These cracks do not propagate during biomechanical testing, nor do they lead to flaking structures. In summary, the hybrid manufacturing of a NiTi SMA substrate with additively manufactured Ti6Al4V structures is suitable for medical implants.

The JAK inhibitor Tofacitinib inhibits structural damage in osteoarthritis by modulating JAK1/TNF-alpha/IL-6 signaling through Mir-149-5p.

Osteoarthritis (OA), a common articular bone degenerative disease, is exacerbated by proinflammatory cytokine signaling. Mounting evidence suggests that epigenetic modifiers, namely microRNAs (miRs), are dysregulated in articular chondrocytes (ACs) during OA. An initial database search led to the identification of miR-149-5p, which was downregulated in clinical OA samples and contributed to chronic inflammation, by increasing TNF-α/IL-6 signaling within the synovium, and OA progression. We overexpressed miR-149-5p in the human chondrocyte cell lines C20A4 and C28/I2 to examine its role in chondrocyte hypertrophy and osteoclastogenesis and found a significant decrease in IL-6 expression, an increase in SOX9 expression, and a reduction in chondrocyte hypertrophy. We evaluated the therapeutic effects of tofacitinib (JAK inhibitor) by suppressing inflammation and restoring miR-149-5p expression. Tofacitinib-treated C20A4 and C28/I2 cells had a significantly lower expression of JAK/IL-6/TNF-α and an increased level of miR-149-5p. Notably, tofacitinib treatment reduced AC hypertrophy and secretion of RANKL and IL-6. Finally, an OA mouse model was used to evaluate the therapeutic potential of tofacitinib. Intra-articular injection of tofacitinib significantly lowered arthritis scores and bone degradation in treated mice compared with their control counterparts. We show for the first time that tofacitinib suppresses the expression level of JAK1/TNF-α/IL-6 by upregulating miR-149-5p level. Our findings revealed the functional association between proinflammatory JAK1/TNF-α/IL-6 signaling and ACs development and highlight the therapeutic potential of tofacitinib in OA.

Osteogenic Regulation by Graphene Nanoparticles in Human Mesenchymal Stem Cells

Background Degenerative bone diseases caused by trauma, cancer, or aging imposes a global health care burden every year. Treatment strategies include directing stem cell differentiation through osteogenesis, thereby creating new bone material for repairment. We previously identified that adult mesenchymal stem cells (MSCs) cultured on graphene nanoparticles spontaneously supports osteoblast development in vitro. However, the osteo-genetic signaling of MSCs in the presence of graphene is largely unknown. Therefore, this study sought to measure genetic expressions of MSCs cultured on graphene using focused PCR arrays. Methods MSCs were extracted from human adipose tissue (hAD-MSCs) and human bone marrow (hBM-MSCs) and expanded in growth media. For experimental conditions, hAD-MSCs and hBM-MSCs were seeded on a graphene surface and cultured for either 7 or 21 days. At each time point, cells were extracted for total RNA and reverse transcribed to cDNA before loading onto RT2 Profiler PCR Human Osteogenesis Array (Qiagen, Hilden, Germany). Gene expressions of both cell lines were compared either over time (day 7 as the control to day 21 as the treated group) or between both cell lines at each time point (hAD-MSCs to hBM-MSCs at day 7 or day 21). Results were analyzed using Qiagen Gene Globe software to determine the relative fold change in comparison to the control. Fold changes were considered statistically significant at p < 0.05. Results We examined expression of four transcriptional genes known to control stem cell fate: DLX5, RUNX2, SOX9, and SP7. In hAD-MSCs, RUNX2 was up-regulated while SOX9 and SP7 were down-regulated, suggesting RUNX2 to be a master regulator in hAD-MSCs. In contrast, all genes were down-regulated in hBM-MSCs. However, when hBM-MSCs were compared to hAD-MSCs, all genes were up-regulated at both time points. Interestingly, the fold changes at day 7 were more robust compared to that observed at day 21, suggesting transcriptional regulation of osteogenesis in hBM-MSCs occurs at an earlier time point. Secondly, we examined common markers of osteogenesis including ALPL, BGLAP, PHEX, and SPP1. In hAD-MSCs, ALPL, BGLAP, and PHEX were upregulated, while SPP1 was down-regulated.In hBM-MSCs, ALP, PHEX, and SPP1 were up-regulated, overall suggesting osteo-genetic signaling by graphene occurs in both cell types. Conclusion hAD-MSCs and hBM-MSCs cultured on graphene showed significant changes in osteogenic gene expressions. These cells were cultured in absence of any chemical inducers, suggesting graphene nanoparticles alone commits osteo-genetic signaling of MSCs. We also observed that osteogenesis of hBM-MSCs may occur at an earlier time point than hAD-MSCs. Lastly, we identified DLX5 as a novel osteogenic regulator supported by graphene. Overall, we show that MSCs isolated from two independent tissue sources spontaneously express osteogenic genes in the presence of graphene.

Bone targeting nanocarrier-assisted delivery of adenosine to combat osteoporotic bone loss

Extracellular adenosine has been shown to play a key role in maintaining bone health and could potentially be used to treat bone loss. However, systemic administration of exogenous adenosine to treat bone disorders remains a challenge due to the ubiquitous presence of adenosine receptors in different organs and the short half-life of adenosine in circulation. Towards this, we have developed a bone-targeting nanocarrier and determined its potential for systemic administration of adenosine. The nanocarrier, synthesized via emulsion suspension photopolymerization, is comprised of hyaluronic acid (HA) copolymerized with phenylboronic acid (PBA), a moiety that can form reversible bonds with adenosine. The bone binding affinity of the nanocarrier was achieved by alendronate (Aln) conjugation. Nanocarriers functionalized with the alendronate (Aln-NC) showed a 45% higher accumulation in the mice vertebrae in vivo compared to those lacking alendronate molecules (NCs). Systemic administration of adenosine via bone-targeting nanocarriers (Aln-NC) attenuated bone loss in ovariectomized (OVX) mice. Furthermore, bone tissue of mice treated with adenosine-loaded Aln-NC displayed trabecular bone characteristics comparable to healthy controls as shown by microcomputed tomography, histochemical staining, bone labeling, and mechanical strength. Overall, our results demonstrate the use of a bone-targeting nanocarrier towards systemic administration of adenosine and its application in treating bone degenerative diseases such as osteoporosis.

Deficiency of optineurin enhances osteoclast differentiation by attenuating the NRF2-mediated antioxidant response

Abnormally increased resorption contributes to bone degenerative diseases such as Paget’s disease of bone (PDB) through unclear mechanisms. Recently, the optineurin (OPTN) gene has been implicated in PDB, and global OPTN knockout mice (Optn−/−) were shown to exhibit increased formation of osteoclasts (osteoclastogenesis). Growing evidence, including our own, has demonstrated that intracellular reactive oxygen species (ROS) stimulated by receptor activator of nuclear factor kappa-B ligand (RANKL) can act as signaling molecules to promote osteoclastogenesis. Here, we report that OPTN interacts with nuclear factor erythroid-derived factor 2-related factor 2 (NRF2), the master regulator of the antioxidant response, defining a pathway through which RANKL-induced ROS could be regulated for osteoclastogenesis. In this study, monocytes from Optn−/− and wild-type (Optn+/+) mice were utilized to differentiate into osteoclasts, and both qRT-PCR and tartrate-resistant acid phosphatase (TRAP) staining showed that the Optn−/− monocytes exhibited enhanced osteoclastogenesis compared to the Optn+/+ cells. CellROX® staining, qRT-PCR, and Western blotting indicated that OPTN deficiency reduced the basal expression of Nrf2, inhibited the expression of NRF2-responsive antioxidants, and increased basal and RANKL-induced intracellular ROS levels, leading to enhanced osteoclastogenesis. Coimmunoprecipitation (co-IP) showed direct interaction, and immunofluorescence staining showed perinuclear colocalization of the OPTN-NRF2 granular structures during differentiation. Finally, curcumin and the other NRF2 activators attenuated the hyperactive osteoclastogenesis induced by OPTN deficiency. Collectively, our findings reveal a novel OPTN-mediated mechanism for regulating the NRF2-mediated antioxidant response in osteoclasts and extend the therapeutic potential of OPTN in the aging process resulting from ROS-triggered oxidative stress, which is associated with PDB and many other degenerative diseases.

How miR-31-5p and miR-33a-5p Regulates SP1/CX43 Expression in Osteoarthritis Disease: Preliminary Insights.

Osteoarthritis (OA) is a degenerative bone disease that involved micro and macro-environment of joints. To date, there are no radical curative treatments for OA and novel therapies are mandatory. Recent evidence suggests the role of miRNAs in OA progression. In our previous studies, we demonstrated the role of miR-31-5p and miR-33a families in different bone regeneration signaling. Here, we investigated the role of miR-31-5p and miR-33a-5p in OA progression. A different expression of miR-31-5p and miR-33a-5p into osteoblasts and chondrocytes isolated from joint tissues of OA patients classified in based on different Kellgren and Lawrence (KL) grading was highlighted; and through a bioinformatic approach the common miRNAs target Specificity proteins (Sp1) were identified. Sp1 regulates the expression of gap junction protein Connexin43 (Cx43), which in OA drives the modification of (i) osteoblasts and chondrocytes genes expression, (ii) joint inflammation cytokines releases and (iii) cell functions. Concerning this, thanks to gain and loss of function studies, the possible role of Sp1 as a modulator of CX43 expression through miR-31-5p and miR-33a-5p action was also evaluated. Finally, we hypothesize that both miRNAs cooperate to modulate the expression of SP1 in osteoblasts and chondrocytes and interfering, consequently, with CX43 expression, and they might be further investigated as new possible biomarkers for OA.

Craniomandibular Osteopathy in Mixed Breed Dogs

Background: Craniomandibular osteopathy (CMO) is a degenerative, osteopetrotic, and self-limiting bone disease that is rare in the canine species. The most affected bones and joints are the branches of the mandible, tympanic bulla, and temporomandibular joint (TMJ) with generalized thickening of the bone trabeculae, increased lines of bone cementation, and bone proliferation. The aim of the present study was to evaluate 2 cases of CMO in mixed-breed dogs belonging to the same litter sent to the Laboratório Regional de Diagnóstico, Faculdade de Veterinária, Universidade Federal de Pelotas (LRD / FV / UFPel).Cases: Three canines (mixed-breed, 2 female and 1 male) belonging to the same litter presented at eight months of age with increases in volume and pain in the face, difficulties in moving the jaw, anorexia, and sialorrhea. The 2 female dogs were euthanized and sent to LRD / FV / UFPel for necropsy. The animals underwent radiography of the left and right lateral and dorsoventral lateral projections in the imaging sector of the Hospital de Clínicas Veterinária (HCV) at UFPel. During the necropsy, fragments of organs from the abdominal and thoracic cavities, as well as the central nervous system and head bones, were collected and fixed in 10% buffered formalin. The tissue samples were cleaved, processed routinely, embedded in paraffin, cut into sections of 3 µm thickness, and stained using hematoxylin and eosin (HE). The bone fragments were decalcified in a 50/50 solution of 8% hydrochloric acid and 8% formic acid and subsequently cleaved and stained with HE. The head and jaw of one of the animals was dissected and subjected to maceration in water at room temperature. Radiographic examination of the two remaining animals showed irregular and exuberant bone proliferation in the mandible and temporomandibular region. In the tympanic bullae, occipital bone, and zygomatic process, thickening of the structures was observed with increased opacity. On necropsy, the animals were cachectic with marked muscle atrophy and increased volume of the mandibular branches and head bones, in addition to marked edema in the adjacent subcutaneous tissue. The regional lymph nodes were enlarged, and in one of the animals, bilateral lesions in the femurs were also observed. In the head subjected to biological maceration, areas of bone proliferation and rarefaction were observed, with increased volume and destruction of the TMJ. On histopathological evaluation of the ventral portion of the mandibular bodies, a network of bony trabeculae was observed, composed of a chondroid matrix with different degrees of mineralization. The cortical portion of the bones exhibited loss of lamellar compactness, with greater spread of the bone trabeculae. The bone trabeculae were perpendicular to the long axis of the cortical of the mandible and were distributed in the medullary spaces, presenting some dense foci of inflammatory infiltrates composed predominantly of neutrophils, lymphocytes, and plasma cells.Discussion: The breeds most predisposed to developing CMO are the West Highland White Terrier and Scottish Terrier; however, the disease has also been described in other non-Terriers. Nevertheless, there are no descriptions in the literature of mixed-breed animals (SRD), with this report being the first of CMO in SRD dogs. The bones most frequently affected in CMO are those of the head. In Terrier dogs, the TMJ is also affected. In the cases of this study, severe CMO occurred, affecting both the head bones and TMJ, and in 1 of the animals, it also affected the femurs. Although CMO has not previously been reported in SRD dogs, the condition can seriously affect these animals, and differential diagnosis should always be made.Keywords: degenerative bone disease, bone proliferation, lion jaw, TMJ.Título: Osteopatia craniomandibular em cães sem raça definidaDescritores: doença óssea degenerativa, proliferação óssea, mandíbula de leão, ATM.

Lower Limb Design for a Child Test Dummy, based on Osteogenesis Imperfecta characteristics

Active and passive safety have played an essential role in solidifying ground transportation. However, safety-focused on children with some rare diseases is little attacked. This article shows the design of a diseased leg prototype into a crash test dummy Q3, the novelty of this work is based on the morphology and biocompatibility of the lower limbs, which principal characteristics of this prototype replicate the shape of a child with bone-degenerative diseases. In this work, it shows the essential features that a child dummy of this type must contain in order to generate a homologation and approval under the strictest passive safety standards used in the automotive industry. Results show the important kinematics parameters and CAD bones development necessary to conform a new numerical crash test dummy prototype.

In vivo characterization of carbon dots–bone interactions: toward the development of bone-specific nanocarriers for drug delivery

Current treatments for osteoporosis and other bone degenerative diseases predominately rely on preventing further bone erosion rather than restoring bone mass, as the latter treatments can unintentionally trigger cancer development by undiscriminatingly promoting cell proliferation. One approach to circumvent this problem is through the development of novel chemical carriers to deliver drug agents specifically to bones. We have recently shown that carbon nanodots (C-dots) synthesized from carbon nanopowder can bind with high affinity and specificity to developing bones in the larval zebrafish. Larval bones, however, are physiologically different from adult bones in their growth, repair, and regeneration properties. Here we report that C-dots can bind to adult zebrafish bones and that this binding is highly specific to areas of appositional growth. C-dots deposition occurred within 30 minutes after delivery and was highly selective, with bones undergoing regeneration and repair showing higher levels of C-dots deposition than bones undergoing normal homeostatic turnover. Importantly, C-dots deposition did not interfere with bone regeneration or the animal’s health. Together, our results establish C-dots as a potential novel vehicle for the targeted delivery of drugs to treat adult bone disease.

Analgesic and Anti-Inflammatory Effects of Aucklandia lappa Root Extracts on Acetic Acid-Induced Writhing in Mice and Monosodium Iodoacetate-Induced Osteoarthritis in Rats.

Osteoarthritis (OA) is an age-related joint disease and one of the most common degenerative bone diseases among elderly people. The currently used therapeutic strategies relying on nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids for OA are often associated with gastrointestinal, cardiovascular, and kidney disorders, despite being proven effective. Aucklandia lappa is a well-known traditional medicine. The root of A. lappa root has several bioactive compounds and has been in use as a natural remedy for bone diseases and other health conditions. We evaluated the A. lappa root extracts on OA progression as a natural therapeutic agent. A. lappa substantially reduced writhing numbers in mice induced with acetic acid. Monosodium iodoacetate (MIA) was injected into the rats through their knee joints of rats to induce experimental OA, which shows similar pathological characteristics to OA in human. A. lappa substantially reduced the MIA-induced weight-bearing of hind limb and reversed the cartilage erosion in MIA rats. IL-1β, a representative inflammatory mediator in OA, was also markedly decreased by A. lappa in the serum of MIA rats. In vitro, A. lappa lowered the secretion of NO and suppressed the IL-1β, COX-2, IL-6, and iNOS production in RAW264.7 macrophages activated with LPS. Based on its analgesic and anti-inflammatory effects, A. lappa could be a potential remedial agent against OA.

Instrumented Hip Implant: A Review

About 20% of people older than forty years old face more bone degenerative diseases. The older population is increasing quite rapidly than before which increases the need for knee or hip implants tremendously. One of the major problems of the current implants is their short lifetime and their impact on the surrounding human tissue. The short life can be attributed to implant wear, loosening, and misalignment, which often cause pain and discomfort to the patient. Functional failure of the implant may be followed by a revision surgery, which is often painful and has a relatively low success rate. Moreover, to avoid unexpected failure and unnoticed deterioration of the implant, it is important to make provision for monitoring implants' performance. Instrumented implants can provide accurate monitoring of the loosening state of the implant, which can delay the revision surgeries and its consequences. This study provides a comprehensive review of the technological development of instrumented hip implants to monitor the status of the implants. The main requirements for the implants are highlighted by reviewing different aspects of the instrumented hip implant systems. In-vivo studies reported in the literature were summarized. Vibration and Acoustic Emission (AE) measurement based loosening detection were found to be the most common methods for in-vitro studies. A comprehensive review of power supply and communication modules was presented. Despite the advancement in this field, current systems are not yet able to provide effective monitoring of the implant's status during the daily activities of patients.

Effect of Low-Intensity Vibration on Bone Strength, Microstructure, and Adiposity in Pre-Osteoporotic Postmenopausal Women: A Randomized Placebo-Controlled Trial

ABSTRACT There has been evidence that cyclical mechanical stimulation may be osteogenic, thus providing opportunities for nonpharmacological treatment of degenerative bone disease. Here, we applied this technology to a cohort of postmenopausal women with varying bone mineral density (BMD) T-scores at the total hip (−0.524 ± 0.843) and spine (−0.795 ± 1.03) to examine the response to intervention after 1 year of daily treatment with 10 minutes of vibration therapy in a randomized double-blinded trial. The device operates either in an active mode (30 Hz and 0.3 g) or placebo. Primary endpoints were changes in bone stiffness at the distal tibia and marrow adiposity of the vertebrae, based on 3 Tesla high-resolution MRI and spectroscopic imaging, respectively. Secondary outcome variables included distal tibial trabecular microstructural parameters and vertebral deformity determined by MRI, volumetric and areal bone densities derived using peripheral quantitative computed tomography (pQCT) of the tibia, and dual-energy X-ray absorptiometry (DXA)-based BMD of the hip and spine. Device adherence was 83% in the active group (n = 42) and 86% in the placebo group (n = 38) and did not differ between groups (p = .7). The mean 12-month changes in tibial stiffness in the treatment group and placebo group were +1.31 ± 6.05% and −2.55 ± 3.90%, respectively (group difference 3.86%, p = .0096). In the active group, marrow fat fraction significantly decreased after 12 months of intervention (p = .0003), whereas no significant change was observed in the placebo group (p = .7; group difference −1.59%, p = .029). Mean differences of the changes in trabecular bone volume fraction (p = .048) and erosion index (p = .044) were also significant, as was pQCT-derived trabecular volumetric BMD (vBMD; p = .016) at the tibia. The data are commensurate with the hypothesis that vibration therapy is protective against loss in mechanical strength and, further, that the intervention minimizes the shift from the osteoblastic to the adipocytic lineage of mesenchymal stem cells. © 2020 American Society for Bone and Mineral Research (ASBMR).

Fgf9 Negatively Regulates Bone Mass by Inhibiting Osteogenesis and Promoting Osteoclastogenesis Via MAPK and PI3K/AKT Signaling.

Fibroblast growth factor 9 (Fgf9) is a well-known factor that regulates bone development; however, its function in bone homeostasis is still unknown. Previously, we identified a point mutation in the FGF9 gene (p.Ser99Asn, S99N) and generated an isogeneic knock-in mouse model, which revealed that this loss-of-function mutation impaired early joint formation and was responsible for human multiple synostosis syndrome 3 (SYNS3). Moreover, newborn and adult S99N mutant mice exhibited significantly increased bone mass, suggesting that Fgf9 also participated in bone homeostasis. Histomorphology, tomography, and serological analysis of homozygous newborns and heterozygous adults showed that the Fgf9S99N mutation immensely increased bone mass and bone formation in perinatal and adult bones and decreased osteoclastogenesis in adult bone. An in vitro differentiation assay further revealed that the S99N mutation enhanced bone formation by promoting osteogenesis and mineralization of bone marrow mesenchymal stem cells (BMSCs) and attenuating osteoclastogenesis of bone marrow monocytes (BMMs). Considering the loss-of-function effect of the S99N mutation, we hypothesized that Fgf9 itself inhibits osteogenesis and promotes osteoclastogenesis. An in vitro differentiation assay revealed that Fgf9 prominently inhibited BMSC osteogenic differentiation and mineralization and showed for the first time that Fgf9 promoted osteoclastogenesis by enhancing preosteoclast aggregation and cell-cell fusion. Furthermore, specific inhibitors and in vitro differentiation assays were used and showed that Fgf9 inhibited BMSC osteogenesis mainly via the MEK/ERK pathway and partially via the PI3K/AKT pathway. Fgf9 also promoted osteoclastogenesis as a potential costimulatory factor with macrophage colony-stimating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) by coactivating the MAPK and PI3K/AKT signaling pathways. Taken together, our study demonstrated that Fgf9 is a negative regulator of bone homeostasis by regulating osteogenesis and osteoclastogenesis and provides a potential therapeutic target for bone degenerative diseases. © 2020 American Society for Bone and Mineral Research (ASBMR).

The Development of Maillard Reaction, and Advanced Glycation End Product (AGE)-Receptor for AGE (RAGE) Signaling Inhibitors as Novel Therapeutic Strategies for Patients with AGE-Related Diseases.

Advanced glycation end products (AGEs) are generated by nonenzymatic modifications of macromolecules (proteins, lipids, and nucleic acids) by saccharides (glucose, fructose, and pentose) via Maillard reaction. The formed AGE molecules can be catabolized and cleared by glyoxalase I and II in renal proximal tubular cells. AGE-related diseases include physiological aging, neurodegenerative/neuroinflammatory diseases, diabetes mellitus (DM) and its complications, autoimmune/rheumatic inflammatory diseases, bone-degenerative diseases, and chronic renal diseases. AGEs, by binding to receptors for AGE (RAGEs), alter innate and adaptive immune responses to induce inflammation and immunosuppression via the generation of proinflammatory cytokines, reactive oxygen species (ROS), and reactive nitrogen intermediates (RNI). These pathological molecules cause vascular endothelial/smooth muscular/connective tissue-cell and renal mesangial/endothelial/podocytic-cell damage in AGE-related diseases. In the present review, we first focus on the cellular and molecular bases of AGE–RAGE axis signaling pathways in AGE-related diseases. Then, we discuss in detail the modes of action of newly discovered novel biomolecules and phytochemical compounds, such as Maillard reaction and AGE–RAGE signaling inhibitors. These molecules are expected to become the new therapeutic strategies for patients with AGE-related diseases in addition to the traditional hypoglycemic and anti-hypertensive agents. We particularly emphasize the importance of “metabolic memory”, the “French paradox”, and the pharmacokinetics and therapeutic dosing of the effective natural compounds associated with pharmacogenetics in the treatment of AGE-related diseases. Lastly, we propose prospective investigations for solving the enigmas in AGE-mediated pathological effects.

Insights into the In Vitro Formation of Apatite from Mg‐Stabilized Amorphous Calcium Carbonate

AbstractA protein‐free formation of bone‐like apatite from amorphous precursors through ball‐milling is reported. Mg2+ ions are crucial to achieve full amorphization of CaCO3. Mg2+ incorporation generates defects which strongly retard a recrystallization of ball‐milled Mg‐doped amorphous calcium carbonate (BM‐aMCC), which promotes the growth of osteoblastic and endothelial cells in simulated body fluid and has no effect on endothelial cell gene expression. Ex situ snapshots of the processes revealed the reaction mechanisms. For low Mg contents (&lt;30%) a two phase system consisting of Mg‐doped amorphous calcium carbonate (ACC) and calcite “impurities” was formed. For high (&gt;40%) Mg2+ contents, BM‐aMCC follows a different crystallization path via magnesian calcite and monohydrocalcite to aragonite. While pure ACC crystallizes rapidly to calcite in aqueous media, Mg‐doped ACC forms in the presence of phosphate ions bone‐like hydroxycarbonate apatite (dahllite), a carbonate apatite with carbonate substitution in both type A (OH−) and type B (PO43−) sites, which grows on calcite “impurities” via heterogeneous nucleation. This process produces an endotoxin‐free material and makes BM‐aMCC an excellent “ion storage buffer” that promotes cell growth by stimulating cell viability and metabolism with promising applications in the treatment of bone defects and bone degenerative diseases.

Ultrasonic measurements of the femoral neck in human volunteers using the backscatter amplitude decay constant

Osteoporosis is a degenerative bone disease that affects millions of people worldwide. The goal of this study was to test a new ultrasonic technique developed for clinical bone assessment called the backscatter amplitude decay constant (BADC). Ultrasonic backscatter measurements were performed on 97 volunteers at the left and right femoral necks using an ultrasonic imaging system (Terason T3000) equipped with a 3.5 MHz convex array transducer. The backscatter signals were analyzed to determine the backscatter amplitude decay constant (BADC), a parameter that measures the exponential decay in the amplitude of the backscatter signal. For comparison, additional ultrasonic measurements were performed at the left and right heels using an ultrasonometer (GE Achilles EXPII) to measure the stiffness index of the calcaneus. BADC demonstrated weak but statistically significant correlations with stiffness index (R &amp;lt; 0.25, p &amp;lt; 0.05). With further refinement of the measurement technique, BADC may be a useful parameter for ultrasonic bone assessment.

Autophagy in fate determination of mesenchymal stem cells and bone remodeling.

Mesenchymal stem cells (MSCs) have been widely exploited as promising candidates in clinical settings for bone repair and regeneration in view of their self-renewal capacity and multipotentiality. However, little is known about the mechanisms underlying their fate determination, which would illustrate their effectiveness in regenerative medicine. Recent evidence has shed light on a fundamental biological role of autophagy in the maintenance of the regenerative capability of MSCs and bone homeostasis. Autophagy has been implicated in provoking an immediately available cytoprotective mechanism in MSCs against stress, while dysfunction of autophagy impairs the function of MSCs, leading to imbalances of bone remodeling and a wide range of aging and degenerative bone diseases. This review aims to summarize the up-to-date knowledge about the effects of autophagy on MSC fate determination and its role as a stress adaptation response. Meanwhile, we highlight autophagy as a dynamic process and a double-edged sword to account for some discrepancies in the current research. We also discuss the contribution of autophagy to the regulation of bone cells and bone remodeling and emphasize its potential involvement in bone disease.

Adverse Impact of Heavy Metals on Bone Cells and Bone Metabolism Dependently and Independently through Anemia.

Mounting evidence is revealing that heavy metals can incur disordered bone homeostasis, leading to the development of degenerative bone diseases, including osteoporosis, osteoarthritis, degenerative disk disease, and osteomalacia. Meanwhile, heavy metal‐induced anemia has been found to be intertwined with degenerative bone diseases. However, the relationship and interplay among these adverse outcomes remain elusive. Thus, it is of importance to shed light on the modes of action (MOAs) and adverse outcome pathways (AOPs) responsible for degenerative bone diseases and anemia under exposure to heavy metals. In the current Review, the epidemiological and experimental findings are recapitulated to interrogate the contributions of heavy metals to degenerative bone disease development which may be attributable dependently and independently to anemia. A few likely mechanisms are postulated for anemia‐independent degenerative bone diseases, including dysregulated osteogenesis and osteoblastogenesis, imbalanced bone formation and resorption, and disturbed homeostasis of essential trace elements. By contrast, remodeled bone microarchitecture, inhibited erythropoietin production, and disordered iron homeostasis are speculated to account for anemia‐associated degenerative bone disorders upon heavy metal exposure. Together, this Review aims to elaborate available literature to fill in the knowledge gaps in understanding the detrimental effects of heavy metals on bone cells and bone homeostasis through different perspectives.

The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases.

Osteocytes are the most abundant (~95%) cells in bone with the longest half-life (~25 years) in humans. In the past osteocytes have been regarded as vestigial cells in bone, since they are buried inside the tough bone matrix. However, during the last 30 years it has become clear that osteocytes are as important as bone forming osteoblasts and bone resorbing osteoclasts in maintaining bone homeostasis. The osteocyte cell body and dendritic processes reside in bone in a complex lacuno-canalicular system, which allows the direct networking of osteocytes to their neighboring osteocytes, osteoblasts, osteoclasts, bone marrow, blood vessels, and nerves. Mechanosensing of osteocytes translates the applied mechanical force on bone to cellular signaling and regulation of bone adaptation. The osteocyte lacuno-canalicular system is highly efficient in transferring external mechanical force on bone to the osteocyte cell body and dendritic processes via displacement of fluid in the lacuno-canalicular space. Osteocyte mechanotransduction regulates the formation and function of the osteoblasts and osteoclasts to maintain bone homeostasis. Osteocytes produce a variety of proteins and signaling molecules such as sclerostin, cathepsin K, Wnts, DKK1, DMP1, IGF1, and RANKL/OPG to regulate osteoblast and osteoclast activity. Various genetic abnormality-associated rare bone diseases are related to disrupted osteocyte functions, including sclerosteosis, van Buchem disease, hypophosphatemic rickets, and WNT1 and plastin3 mutation-related disorders. Meticulous studies during the last 15 years on disrupted osteocyte function in rare bone diseases guided for the development of various novel therapeutic agents to treat bone diseases. Studies on genetic, molecular, and cellular mechanisms of sclerosteosis and van Buchem disease revealed a role for sclerostin in bone homeostasis, which led to the development of the sclerostin antibody to treat osteoporosis and other bone degenerative diseases. The mechanism of many other rare bone diseases and the role of the osteocyte in the development of such conditions still needs to be investigated. In this review, we mainly discuss the knowledge obtained during the last 30 years on the role of the osteocyte in rare bone diseases. We speculate about future research directions to develop novel therapeutic drugs targeting osteocyte functions to treat both common and rare bone diseases.