Revista de Osteoporosis y Metabolismo Mineral

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Category: Original Articles

The Wnt/β-catenin pathway decreases the amount of osteoclasts in the bone and promotes its apoptosis

The accumulated evidence over the past few years has established that the Wnt/β-catenin pathway is crucial for bone formation and the maintenance of skeletal homeostasis [1,2]. Wnt proteins exert their cellular functions by activating different signaling pathways, commonly called canonical pathway and non-canonical pathways [3]. The former acts by controlling the amount of β-catenin not associated with cadherin, while the other routes do not require the presence of β-catenin [4]. At present, the signaling pathway mediated by β-catenin is the best studied and understood. Activation of the Wnt/β-catenin pathway begins at the cell membrane with the binding of certain Wnt ligands, such as Wnt3a, to the transmembrane receptors of the Frizzled family. This binding recruits the LRP5/6 co-receptor (low-density-lipoprotein receptor-related protein 5/6), to form a ternary complex that destabilizes a cytoplasmic conglomerate of proteins that would otherwise phosphorylate the β-catenin of the cytoplasm for its destruction in the proteasome [5-7]. So, after ligand binding to the receptor, β-catenin is not phosphorylated or destroyed, and, therefore, can accumulate in the cytoplasm, from where it will be transferred to the nucleus. There it joins the transcription factor TCF/LEF (T-cell factor/lymphoid enhancer factor) and induces target gene expression [8].

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A novel therapeutic target for osteoarthritis: control of cellular plasticity and senescence using connexin43

Osteoarthritis (OA) is a chronic disease that is characterized by a progressive degradation of the articular cartilage that covers the surface of the synovial joints, which allow the movement of the skeleton without causing pain. Chondrocytes from patients with osteoarthritis undergo changes in the phenotype associated with an increase in catabolic and inflammatory activity [1,2], along with an increase in cellular senescence and senescence-associated secretory phenotype (SASP) [2,3]. Our research group has previously shown that chondrocytes in the articular cartilage have long cytoplasmic projections that cross the extracellular matrix (ECM) [4], which form connections and gap junctions (GJs) through connexin-43 channels (Cx43) [4,5]. In 2013, our research group published relevant results associated with alterations in the activity of Cx43 in osteoarthritis, indicating that from the disease’s early stages there is an increase and changes in the localization of the protein in the cartilage of patients with arthrosis [6]. Subsequently, using animal models, we observed that the C-terminal domain of Cx43 plays a fundamental role in the structure and composition of articular cartilage [7].

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Qualitative and quantitative status of general bone in osteonecrosis of the jaws. Effect of bisphosphonates

Osteonecrosis of the jaw (ONJ) is a disease described fairly recently. After the reported findings by Marx [1], bisphosphonates were considered the etiological agent responsible for the disease, even being called osteonecrosis due to bisphosphonates [2-5], which is wrong since many factors in addition to these drugs may be implicated in the etiopathogenesis of ONJ [1,6,7].
One of the hypothesis about ONJ’s development would be the existence of an excess suppression of bone remodeling, which can be produced by bisphosphonates or by other potent anti-resorptives, such as denosumab, a drug that is also involved in ONJ [8,9]. Since these drugs act on the entire skeleton, if there is such an excess of oversupression of bone remodelling, one could expect the existence of alterations in both the amount of BMD and bone quality in other locations. Although there are many descriptions of isolated cases or series of this disease in the literature, outlining its clinical characteristics and possible association with different diseases and risk factors [1,3-7,10], we have not found publications that analyze the possible quantitative alterations and/or qualitative bone in patients with ONJ.

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Osteogenic cells affected by soluble tumor factors contribute to bone pre-metastatic niche formation

The appearance of metastatic disease seriously threatens the survival rate of patients who develop a tumor. Certain types of tumors have been found to present a high tendency to colonize specific organs. From the hypothesis formulated by Paget (“seed-and-soil”) [1], few studies have deciphered the regulatory mechanisms of metastatic organotropism. Initial studies focused on the function of the intrinsic properties of the tumor cell, such as gene expression and colonization regulation pathways, in the direction of organotropism [2-4].
Bone is an organ frequently infiltrated by the metastatic spread of solid tumors [5,6]. The appearance of metastatic disease is a serious threat in the survival rate of patients who develop a tumor. From 65-80% of subjects with prostate cancer or metastatic breast present skeletal complications [5]. The study of bone metastases has mainly focused on the interaction of the tumor cell with the bone, once the metastasis has been established, ignoring the subclinical stages of the process that occurs previously. The establishment of tumor cells in the bone microenvironment alters the balance of the bone remodeling process between bone formation, induced by osteoblasts, and osteoclast-mediated resorption. Consequently, the survival and proliferation pathways of tumor cells are favored, inducing the formation of “a vicious cycle of bone metastases” [7].
Though not exclusive, tumors cause two different types of skeletal lesions. The most common form, represented by breast cancer is the osteolytic lesion associated with an alteration of bone remodeling with an increase in osteoclastic activity and subsequent osteolysis [8-11].

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Calcidiol levels and muscle function maintenance, functional capacity and bone mineral bone density in non-selected Spanish population

The aging process is associated with a loss of muscle mass and strength, as well as a decrease in bone mineral density (BMD), which can lead to reduced mobility, greater risk of falls and the appearance of fractures [1,2]. In recent years, special emphasis has been placed on maintaining an adequate vitamin D status to optimize muscle strength and BMD in order to reduce falls and fractures [3-5]. Although a recent meta-analysis questions the usefulness of vitamin D supplements to reduce the risk of falls, BMD decrease and fractures [6], there are sufficient arguments that demonstrate the importance of vitamin D on muscle and bone health. Vitamin D stimulates the absorption of calcium from the intestine and maintains the serum calcium levels that are required for normal bone mineralization and for the maintenance of muscle function [7]. Several in vivo studies suggest vitamin D’s role in regulating muscle mass and its function. Observational studies show that vitamin D deficiency in the elderly is associated with reduced muscle mass and strength [8-10], lower physical performance [8,11], and increased risk of falls [12].

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Effects of mechanical stimulation on communication between bone cells

Mechanical force is one of the most important stimuli that the bone receives to regulate bone mass, shape and microarchitecture. The endoskeleton reacts to an increase in load by forming more bone or decreasing its mass in the absence of mechanical stress [1]. This is because the stimulation triggers the mechanotransduction process in which osteocytes, considered bone’s key mechanosensory cells, when stimulated, send chemical signals that affect the paracrine regulation of osteoblast and osteoclast behavior [2,3]. It also has been found to have an anti-apoptotic effect on osteocytes [4].
With mechanical loading, the expression of sclerostin, which is an inhibitor of the protein signaling pathway Wnt/β-catenin constitutively secreted by osteocytes, decreases thus causing an increase in osteoblastogenesis [5,6]. On the other hand, apoptotic osteocytes induce the secretion of the receptor activator for nuclear factor κ B ligand (RANKL), indirectly stimulating osteoclastogenesis [7]. In addition, some chemokines, a family of chemotactic cytokines, could be involved in bone remodeling when expressed by bone cells and provide key signals to recruit different cellular subpopulations [8].

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The determining role of a resorption marker, carboxyterminal telopeptide of collagen I, in assessing therapeutic compliance in patients treated with oral bisphosphonates

Osteoporosis is a metabolic disease characterized by low bone mass and microstructural deterioration of the bone tissue that leads to increased bone fragility. The main complication involves the appearance of fragility fractures [1]. Osteoporotic fractures are an important health problem [2] associated with high healthcare costs [3]. To prevent the appearance of fractures, different drugs are available that act on bone metabolism and are associated with reduced fracture risk [4]. The most commonly used in Spain are bisphosphonates [5]. However, in order to observe this protective effect, adequate therapeutic compliance is required [6]. In osteoporosis, as in all chronic diseases, compliance is low. In a recent study conducted in Spain, the overall persistence per year after commencing osteoporosis drug is 47%, and at two years, close to 27% [7].

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Different development of serum sclerostin compared to other bone remodeling markers in the first year after a liver transplant

Solid organ transplantation is an effective alternative in the final stage of multiple chronic diseases, increasing patients’ survival. However, this improvement is associated with certain complications, such as a higher incidence of osteoporosis and an increased risk of fractures [1]. Numerous studies have concluded that there is a loss of bone mass after transplantation, more marked between the first three and six months, which lasts up to a year after the same. Subsequently there is a stabilization and even recovery of bone mass in the two subsequent years [2-4].
Liver transplantation is considered an independent risk factor in the development of osteoporosis [1-3]. In the case of patients with a liver graft, the incidence of fracture is estimated at 10-43% [1], with the spine location being the most frequent [2-4]. Among the factors that contribute to the increased risk of osteoporosis and fractures in these patients are: prolonged treatment with immunosuppressants (mainly calcineurin inhibitors) [2,5-8] and glucocorticoids [9,10], vitamin D deficiency (very common due to malnutrition) and alterations in liver function found in most patients with cirrhosis [1-3].

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Genetic study of atypical femoral fractures using exome sequencing in three affected sisters and three unrelated patients

Osteoporosis and its associated fractures are the most common postmenopausal bone problems, affecting women and men of all ethnic groups. Nitrogen-containing bisphosphonates (N-BPs), including alendronate, risendronate, ibandronate and zolendronate figure as the most widely used osteoporosis treatments in millions of patients worldwide. Despite the significant anti-fracture efficacy of BPs, which has been widely demonstrated in several clinical trials and systematic reviews, some infrequent adverse effects associated with prolonged use have been described, including atypical femur fractures (AFFs). These fractures are non-traumatic and characterized by their subtrochanteric location or in the diaphysis of the femur, and are frequently bilateral.
AFFs’ pathogenic mechanisms are not completely known and much has been speculated about their causes. An excessive suppression of bone resorption by N-BPs could trigger an AFF but its pathophysiology is complex and other important factors are reportedly involved. Some proposed risk factors are cortical thickness and pelvic geometry. In addition, cases of AFF have been described in patients affected by other monogenic bone diseases, such as hypophosphatasia, osteogenesis imperfecta or the syndrome of osteoporosis pseudoglioma.

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Functional studies of DKK1 variants present in the general population

The Wnt pathway’s role in regulating bone remodeling has been demonstrated in multiple studies. On the one hand, polymorphisms have been described in several genes of the Wnt pathway that show an association with bone mineral density (BMD) and the risk of fracture. Rare or infrequent mutations have also been described in various genes of the Wnt pathway, which cause more rare bone phenotypes, such as osteoporosis-pseudoglioma (OPPG, OMIM 259770), autosomal recessive osteogenesis imperfecta of type XV (OMIM 615220)8, and osteosclerosis (OMIM 144750). The Wnt pathway begins with the formation of a heterotrimeric complex between the Frizzled receptor, the LRP5 co-receptor and the Wnt ligand. Once this complex is formed, β-catenin accumulates in the cytoplasm and translocates to the nucleus where it can activate the transcription of numerous target genes. In osteoblasts, the Wnt pathway has been shown to activate the transcription of genes that clearly contribute to bone formation. In addition, this pathway is finely regulated by a series of extracellular inhibitors, including the protein sclerostin, encoded by the SOST gene, and the DKK1 protein, encoded by a gene with the same name. These two proteins perform their function, preventing the formation of the heterotrimeric complex. The proteins sclerostin and DKK1 thus form other heterotrimeric complexes, together with LRP5 and LRP4 (in the case of sclerostin) and together with LRP5 and Kremen (in the case of DKK1).

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Bone tissue mechanical strength is independent of age in healthy individuals

Osteoporotic fractures pose a serious public health problem given their high prevalence and enormous impact in terms of morbidity, mortality and economic cost. Hence there is considerable interest in understanding the underlying pathophysiology of bone fragility, which, from a mechanical standpoint, is determined by bone strength. Bone resistance, in turn, comes from the integration of bone mineral quantity, bone architecture, and the material properties of bone.
The mineral quantity of the bone is usually measured by bone densitometry (DXA), the most commonly used, standardized method for assessing bone mass and fracture risk. Bone architecture, both at the micro- and macroscopic level, is examined using different imaging techniques, including high-resolution peripheral quantitative tomography, bone magnetic resonance and the more accessible Trabecular Bone Score. However, the material properties of bone are difficult to assess due to its high complexity, reflected in its multiple constituents including non-collagenous proteins, crystallinity, hydration of bone tissue, and the characteristics of mineralization and collagen, among others. Furthermore, as researchers need bone tissue samples for analysis, the study of these properties has traditionally been restricted to a few centers specialized in bio-mechanics.

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Factors secreted by bone cells induce intracellular calcium accumulation and cyclic AMP and activation of ERK 1/2 in prostate cancer cells; evaluation by fluorescence techniques in living cells

Bone metastasis is a frequent complication in advanced stages of patients with prostate cancer, one of the cancers with greater mortality and morbidity in developed countries. Avoiding the different stages necessary for the tumor cell to abandon the primary tumor, migrate and establish itself in the bone microenvironment is one of the main strategies to prevent bone metastases. The invasion of primary tumor cells into skeletal niches is associated with the activation of bone cells that release growth factors and cytokines, which in turn promote tumor growth in metastases. As a result, the so-called “vicious cycle” of bone metastases is generated, which varies the physiology of bone and alters bone remodeling. In the case of bone metastases caused by prostate cancer, osteolytic and osteoblastic lesions are produced as a result of the activation of osteoclasts and osteoblasts respectively. In bone metastasis processes, it has been observed that tumor cells are able to secrete factors such as tumor necrosis factor alpha (TNF-α), interleukin 11 (IL-11), matrix metalloprotease 1 (MMP1), Jagged1 and protein related to parathormone (PTHrP), which directly or indirectly activate osteoclasts, giving rise to osteoclast metastases. Matrix degradation by osteoclasts releases transforming growth factor β (TGF-β) and insulin-like growth factor (IGF-1) that promote the survival of tumor cells. In contrast, the secretion by tumor cells of other factors such as fibroblast growth factor (FGF) and bone morphogenetic proteins (BMPs) can stimulate osteoblast differentiation resulting in osteoblastic lesions.

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