Treatment Of Metabolic Bone Diseases Research Articles

Omega-3 PUFAs prevent bone impairment and bone marrow adiposity in mouse model of obesity

Obesity adversely affects bone and fat metabolism in mice and humans. Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) have been shown to improve glucose metabolism and bone homeostasis in obesity. However, the impact of omega-3 PUFAs on bone marrow adipose tissue (BMAT) and bone marrow stromal cell (BMSC) metabolism has not been intensively studied yet. In the present study we demonstrated that omega-3 PUFA supplementation in high fat diet (HFD + F) improved bone parameters, mechanical properties along with decreased BMAT in obese mice when compared to the HFD group. Primary BMSCs isolated from HFD + F mice showed decreased adipocyte and higher osteoblast differentiation with lower senescent phenotype along with decreased osteoclast formation suggesting improved bone marrow microenvironment promoting bone formation in mice. Thus, our study highlights the beneficial effects of omega-3 PUFA-enriched diet on bone and cellular metabolism and its potential use in the treatment of metabolic bone diseases.

Bone health in children undergoing solid organ transplantation.

Pediatric solid organ transplant recipients are a unique and growing patient population who are at risk for metabolic bone disease both before and after transplantation. The odds of sustaining a fracture in adulthood are significantly higher if an individual has sustained at least one childhood fracture, therefore, close monitoring before and after transplant is essential. Emerging data in patients with chronic kidney disease mineral and bone disorder (CKD-MBD) and hepatic osteodystrophy highlights the role of fibroblast growth factor 23 in the pathogenesis of metabolic bone disease in these conditions. While dual X-ray absorptiometry (DXA) is the most widely used imaging modality for assessment of bone mass in children, quantitative computer tomography (QCT) is an emerging modality, especially for patients with glucocorticoid-induced osteoporosis. Solid organ transplantation improves organ function and quality of life; however, bone mineral density can decline following transplantation, particularly during the first three to six months. Immunosuppressive medications, including glucocorticoids, are a major contributing factor. Following transplant, treatment should be tailored to achieve mineral homeostasis, correct nutritional deficiencies, and improve physical conditioning. In summary, early identification and treatment of metabolic bone disease can improve the bone health status of pediatric transplant recipients as they enter adulthood. http://links.lww.com/MOP/A71.

The role of lactoferrin in bone remodeling: evaluation of its potential in targeted delivery and treatment of metabolic bone diseases and orthopedic conditions.

Lactoferrin (Lf) is a multifunctional protein that is synthesized endogenously and has various biological roles including immunological regulation, antibacterial, antiviral, and anticancer properties. Recently, research has uncovered Lf's critical functions in bone remodeling, where it regulates the function of osteoblasts, chondrocytes, osteoclasts, and mesenchymal stem cells. The signaling pathways involved in Lf's signaling in osteoblasts include (low density lipoprotein receptor-related protein - 1 (LRP-1), transforming growth factor β (TGF-β), and insulin-like growth factor - 1 (IGF-1), which activate downstream pathways such as ERK, PI3K/Akt, and NF-κB. These pathways collectively stimulate osteoblast proliferation, differentiation, and mineralization while inhibiting osteoclast differentiation and activity. Additionally, Lf's inhibitory effect on nuclear factor kappa B (NF-κB) suppresses the formation and activity of osteoclasts directly. Lf also promotes chondroprogenitor proliferation and differentiation to chondrocytes by activating the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphoinositide 3-kinase/protein kinase B(PI3K/Akt)signaling pathways while inhibiting the expression of matrix-degrading enzymes through the suppression of the NF-κB pathway. Lf's ability to stimulate osteoblast and chondrocyte activity and inhibit osteoclast function accelerates fracture repair, as demonstrated by its effectiveness in animal models of critical-sized long bone defects. Moreover, studies have indicated that Lf can rescue dysregulated bone remodeling in osteoporotic conditions by stimulating bone formation and suppressing bone resorption. These beneficial effects of Lf on bone health have led to its exploration in nutraceutical and pharmaceutical applications. However, due to the large size of Lf, small bioactive peptides are preferred for pharmaceutical applications. These peptides have been shown to promote bone fracture repair and reverse osteoporosis in animal studies, indicating their potential as therapeutic agents for bone-related diseases. Nonetheless, the active concentration of Lf in serum may not be sufficient at the site requiring bone regeneration, necessitating the development of various delivery strategies to enhance Lf's bioavailability and target its active concentration to the site requiring bone regeneration. This review provides a critical discussion of the issues mentioned above, providing insight into the roles of Lf in bone remodeling and the potential use of Lf as a therapeutic target for bone disorders.

HSPB7 oppositely regulates human mesenchymal stromal cell-derived osteogenesis and adipogenesis

BackgroundRecent evidence suggests that accumulation of marrow adipose tissue induced by aberrant lineage allocation of bone marrow-derived mesenchymal stromal cells (BMSCs) contributes to the pathophysiologic processes of osteoporosis. Although master regulators of lineage commitment have been well documented, molecular switches between osteogenesis and adipogenesis are largely unknown.MethodsHSPB7 gene expression during osteogenic and adipogenic differentiation of BMSCs was evaluated by qPCR and Western blot analyses. Lentiviral-mediated knockdown or overexpression of HSPB7 and its deletion constructs were used to assess its function. The organization of cytoskeleton was examined by immunofluorescent staining. ALP activity, calcium assay, Alizarin Red S staining and Oil Red O staining were performed in vitro during osteoblast or adipocyte differentiation. SB431542 and Activin A antibody were used to identify the mechanism of Activin A in the regulation of osteogenic differentiation in BMSCs.ResultsIn this study, we identified HSPB7 capable of oppositely regulating osteogenic and adipogenic differentiation of BMSCs. HSPB7 silencing promoted adipogenesis while reducing osteogenic differentiation and mineralization. Conversely, overexpression of HSPB7 strongly enhanced osteogenesis, but no effect was observed on adipogenic differentiation. Deletion of the N-terminal or C-terminal domain of HSPB7 led to decreased osteoblastic potency and mineralization. Mechanistically, our data showed that Activin A is a downstream target participating in HSPB7 knockdown-mediated osteogenic inhibition.ConclusionsOur findings suggest that HSPB7 plays a positive role in driving osteoblastic differentiation, and with the capability in maintaining the osteo-adipogenesis balance. It holds great promise as a potential therapeutic target in the treatment of bone metabolic diseases.

Paracrine and endocrine functions of osteocytes

Osteocytes are dendritic-shaped cells embedded in the bone matrix and are terminally differentiated from osteoblasts. Inaccessibility due to their location has hindered the understanding of the molecular functions of osteocytes. However, scientific advances in the past few decades have revealed that osteocytes play critical roles in bone and mineral metabolism through their paracrine and endocrine functions. Sclerostin produced by osteocytes regulates bone formation and resorption by inhibiting Wnt/β-catenin signaling in osteoblast-lineage cells. Receptor activator of nuclear factor κ B ligand (RANKL) derived from osteocytes is essential for osteoclastogenesis and osteoclast activation during postnatal life. Osteocytes also secrete fibroblast growth factor 23 (FGF23), an endocrine FGF that regulates phosphate metabolism mainly by increasing phosphate excretion and decreasing 1, 25-dihydroxyvitamin D production in the kidneys. The regulation of FGF23 production in osteocytes is complex and multifactorial, involving many local and systemic regulators. Antibodies against sclerostin, RANKL, and FGF23 have emerged as new strategies for the treatment of metabolic bone diseases. Improved undrstanding of the paracrine and endocrine functions of osteocytes will provide insight into future therapeutic options.

Strategies of Macrophages to Maintain Bone Homeostasis and Promote Bone Repair: A Narrative Review

Bone homeostasis (a healthy bone mass) is regulated by maintaining a delicate balance between bone resorption and bone formation. The regulation of physiological bone remodeling by a complex system that involves multiple cells in the skeleton is closely related to bone homeostasis. Loss of bone mass or repair of bone is always accompanied by changes in bone homeostasis. However, due to the complexity of bone homeostasis, we are currently unable to identify all the mechanisms that affect bone homeostasis. To date, bone macrophages have been considered a third cellular component in addition to osteogenic spectrum cells and osteoclasts. As confirmed by co-culture models or in vivo experiments, polarized or unpolarized macrophages interact with multiple components within the bone to ensure bone homeostasis. Different macrophage phenotypes are prone to resorption and formation of bone differently. This review comprehensively summarizes the mechanisms by which macrophages regulate bone homeostasis and concludes that macrophages can control bone homeostasis from osteoclasts, mesenchymal cells, osteoblasts, osteocytes, and the blood/vasculature system. The elaboration of these mechanisms in this narrative review facilitates the development of macrophage-based strategies for the treatment of bone metabolic diseases and bone defects.

VITAMIN D AND OPHTHALMOPATHIAS. A REVIEW.

The importance of vitamin D3 (hydroxycholecalciferol) as one of the liposoluble vitamins is known in the prevention and treatment of metabolic bone diseases (rickets, osteomalacia, osteoporosis). In recent years, however, information has increased on the importance of vitamin D3 in numerous organ systems and in the pathogenesis of various diseases, e. g. ophthalmopathies. The immunological functions of vitamin D3 are the subject of studies dealing with autoimmune optic nerve disorders and their results appear to have a positive effect on demyelinating diseases. It also plays an important role in maintaining the thickness of the retinal nerve fiber layer, but its additional administration has not been successful. Optical neuritis may be the first sign of multiple sclerosis. It appears that sufficient serum vitamin D3 levels may protect patients from deterioration in the form of a further attack of demyelination. The course of diabetic retinopathy is probably also influenced by vitamin D3, inter alia, by correlating the fact that its receptor and the enzymes of its metabolism are expressed on the retina. Low serum levels of vitamin D3 may even trigger age-related macular degeneration. Conversely, higher dietary intake of vitamin D3 may positively affect neovascularization. The optimal level of hydroxycholecalciferol is between 60 and 200 nmol /l, the severe deficit represents a decrease below 25 nmol/l. The body can normally produce up to 10,000 IU of this vitamin after exposure to sunlight. However, the demonstration of its protective character in connection with the mentioned diseases of the retina and optic nerve will require a sufficient number of studies to confirm the facts found so far about this rediscovered vitamin.

Autophagy: An important target for natural products in the treatment of bone metabolic diseases.

Bone homeostasis depends on a precise dynamic balance between bone resorption and bone formation, involving a series of complex and highly regulated steps. Any imbalance in this process can cause disturbances in bone metabolism and lead to the development of many associated bone diseases. Autophagy, one of the fundamental pathways for the degradation and recycling of proteins and organelles, is a fundamental process that regulates cellular and organismal homeostasis. Importantly, basic levels of autophagy are present in all types of bone-associated cells. Due to the cyclic nature of autophagy and the ongoing bone metabolism processes, autophagy is considered a new participant in bone maintenance. Novel therapeutic targets have emerged as a result of new mechanisms, and bone metabolism can be controlled by interfering with autophagy by focusing on certain regulatory molecules in autophagy. In parallel, several studies have reported that various natural products exhibit a good potential to mediate autophagy for the treatment of metabolic bone diseases. Therefore, we briefly described the process of autophagy, emphasizing its function in different cell types involved in bone development and metabolism (including bone marrow mesenchymal stem cells, osteoblasts, osteocytes, chondrocytes, and osteoclasts), and also summarized research advances in natural product-mediated autophagy for the treatment of metabolic bone disease caused by dysfunction of these cells (including osteoporosis, rheumatoid joints, osteoarthritis, fracture nonunion/delayed union). The objective of the study was to identify the function that autophagy serves in metabolic bone disease and the effects, potential, and challenges of natural products for the treatment of these diseases by targeting autophagy.

Celiac disease and bone.

Celiac disease (CD) is an autoimmune disorder characterized by small intestinal inflammation triggered by gluten ingestion in genetically-predisposed individuals. A frequent extra-intestinal manifestation of CD is metabolic bone disease which contributes to an increased risk of fracture. The mechanisms underlying bone disease in CD remain incompletely understood, but multiple processes have been proposed including (1) malabsorption of calcium and vitamin D leading to secondary hyperparathyroidism and increased skeletal resorption, (2) pro-inflammatory cytokines altering the osteoprotegerin and receptor activator of nuclear kappa-B ligand ratio favoring osteoclastogenesis, (3) hypogonadism, and (4) low weight and malnutrition. Most studies show reduced bone mineral density in patients with CD. Bone microarchitecture is also deteriorated leading to reduced whole bone stiffness. Many, but not all investigations, have shown an increased risk of fracture associated with CD. The main stay of therapy for CD is maintaining a gluten-free diet. Improvement in bone mineral density with adherence to a gluten-free diet has been well-established. Bone mineral density remains lower, however, compared to controls and increased fracture risk can persist. There is no consensus on the timing of dual-energy x-ray absorptiometry for bone mineral density assessment in patients with CD. Routine screening for CD in patients with osteoporosis is not recommended. Little data are available on the use or efficacy of prescription osteoporosis therapeutics in patients with CD. Studies are needed to develop standardized guidelines for screening and treatment of metabolic bone disease in patients with CD to identify those who may need early intervention with prescription osteoporosis therapy.

The role of the Wnt signalling pathway in the energy metabolism of bone remodelling

Bone remodelling is necessary to repair old and impaired bone caused by aging and its effects. Injury in the process of bone remodelling generally leads to the development of various bone diseases. Energy metabolism plays crucial roles in bone cell formation and function, the disorder of which will disrupt the balance between bone formation and bone resorption. Here, we review the intrinsic interactions between bone remodelling and energy metabolism and the role of the Wnt signalling pathway. We found a close interplay between metabolic pathways and bone homeostasis, demonstrating that bone plays an important role in the regulation of energy balance. We also discovered that Wnt signalling is associated with multiple biological processes regulating energy metabolism in bone cells. Thus, targeted regulation of Wnt signalling and the recovery of the energy metabolism function of bone cells are key means for the treatment of metabolic bone diseases.

Effects of BMSC-Derived EVs on Bone Metabolism.

Extracellular vesicles (EVs) are small membrane vesicles that can be secreted by most cells. EVs can be released into the extracellular environment through exocytosis, transporting endogenous cargo (proteins, lipids, RNAs, etc.) to target cells and thereby triggering the release of these biomolecules and participating in various physiological and pathological processes. Among them, EVs derived from bone marrow mesenchymal stem cells (BMSC-EVs) have similar therapeutic effects to BMSCs, including repairing damaged tissues, inhibiting macrophage polarization and promoting angiogenesis. In addition, BMSC-EVs, as efficient and feasible natural nanocarriers for drug delivery, have the advantages of low immunogenicity, no ethical controversy, good stability and easy storage, thus providing a promising therapeutic strategy for many diseases. In particular, BMSC-EVs show great potential in the treatment of bone metabolic diseases. This article reviews the mechanism of BMSC-EVs in bone formation and bone resorption, which provides new insights for future research on therapeutic strategies for bone metabolic diseases.

Metabolic Bone Disease of Prematurity.

Metabolic Bone Disease of Prematurity.

Total Joint Arthroplasty and Osteoporosis: Looking Beyond the Joint to Bone Health

BackgroundMetabolic bone diseases in the total joint arthroplasty (TJA) population are undertested and undertreated, leading to increased risk of adverse outcomes such as periprosthetic fractures. This study aims to better characterize the current state of bone care in TJA patients using Fracture Risk Assessment Tool (FRAX) score risk stratifications. MethodsIn total, 505 consecutive TJA patients who meet the Endocrine Society guidelines for osteoporosis screening were included for review. They were divided into a high risk or low risk group depending on FRAX scores and were compared based on screening, diagnosis, and treatment of metabolic bone disease. Logistic regression models were used to analyze factors influencing screening and treatment. A population analysis involving 2,000 TJA patients, and a complication analysis involving 40 periprosthetic fracture patients were conducted. ResultsAmong high risk patients undergoing TJA, 90% did not receive any pharmacological treatment for osteoporosis, 45% were not treated with vitamin D or calcium, and 88% did not receive bone density testing in the routine care period. Among patients with pre-existing osteoporosis undergoing TJA, 80% were not treated with any osteoporosis medications and 33% of these patients were not taking vitamin D or calcium. Female gender and past fracture history contributed to whether patients received screening and treatment. Patients with periprosthetic hip fractures have significantly higher FRAX scores compared to control THA patients. ConclusionThere are significant gaps in metabolic bone care of the geriatric TJA population regarding both screening and treatment. Metabolic bone care and risk identification with FRAX should be highly considered for TJA patients.

Metabolic Bone Diseases and New Drug Developments

Metabolic bone diseases are serious health issues worldwide, since several million individuals over the age of 50 are at risk of bone damage and should be worried about their bone health. One in every two women and one in every four men will break a bone during their lifetime due to a metabolic bone disease. Early detection, raising bone health awareness, and maintaining a balanced healthy diet may reduce the risk of skeletal fractures caused by metabolic bone diseases. This review compiles information on the most common metabolic bone diseases (osteoporosis, primary hyperparathyroidism, osteomalacia, and fluorosis disease) seen in the global population, including their symptoms, mechanisms, and causes, as well as discussing their prevention and the development of new drugs for treatment. A large amount of research literature suggests that balanced nutrition and balanced periodic supplementation of calcium, phosphate, and vitamin D can improve re-absorption and the regrowth of bones, and inhibit the formation of skeletal fractures, except in the case of hereditary bone diseases. Meanwhile, new and improved drug formulations, such as raloxifene, teriparatide, sclerostin, denosumab, and abaloparatide, have been successfully developed and administered as treatments for metabolic bone diseases, while others (romososumab and odanacatib) are in various stages of clinical trials.

Tyrosine 12 of human calcitonin modulates its amyloid formation, membrane binding, and bioactivity

Irreversible aggregation greatly limits the bioavailability and therapeutic activity of peptide-based drugs, so preventing protein or peptide aggregation is a common issue in drug formulation. Human calcitonin (hCT), a peptide hormone secreted by thyroidal parafollicular cells, can regulate blood calcium levels and maintain bone structure. Hence, it can be used as a treatment for metabolic bone diseases, such as osteoporosis and Paget's disease. However, hCT has a relatively high propensity to form amyloid fibrils that hinder its biological function and limit its pharmaceutical potential. In previous studies, we demonstrated, along with other research groups, that modifying specific residues of hCT is sufficient to prevent hCT aggregation. We proceeded to find the key residues that regulate the aggregation of hCT for a better understanding of the mechanism of hCT aggregation. In this work, we used amyloid propensity prediction software and found that Tyr12 may play a key role in regulating hCT aggregation. Thus, we propose three human calcitonin variants (Y12E, Y12P, Y12R) for hCT non-amyloidogenic substituents and examined the aggregation characteristics of variants using multiple biophysical techniques. Y12E showed the best anti-aggregation propensity and can work as inhibitor of hCT aggregation. We also found this residue is crucial for membrane binding and receptor binding. The data presented herein provides an overview of Tyr12 that should be carefully considered in peptide design.

Membrane Transport Proteins in Osteoclasts: The Ins and Outs.

During bone resorption, the osteoclast must sustain an extraordinarily low pH environment, withstand immense ionic pressures, and coordinate nutrient and waste exchange across its membrane to sustain its unique structural and functional polarity. To achieve this, osteoclasts are equipped with an elaborate set of membrane transport proteins (pumps, transporters and channels) that serve as molecular ‘gatekeepers’ to regulate the bilateral exchange of ions, amino acids, metabolites and macromolecules across the ruffled border and basolateral domains. Whereas the importance of the vacuolar-ATPase proton pump and chloride voltage-gated channel 7 in osteoclasts has long been established, comparatively little is known about the contributions of other membrane transport proteins, including those categorized as secondary active transporters. In this Special Issue review, we provide a contemporary update on the ‘ins and outs’ of membrane transport proteins implicated in osteoclast differentiation, function and bone homeostasis and discuss their therapeutic potential for the treatment of metabolic bone diseases.

Daily oral supplementation of Hochu-Ekki-To prevents osteoclastic activation and bone loss in ovariectomized mice

Bone remodeling is sophisticatedly regulated by two different cell types: bone-resorbing osteoclasts and bone-forming osteoblasts. Hochu-Ekki-To, a Japanese traditional herbal medicine, is commonly used for the treatment of chronic diseases or frailty after an illness; however, its effects on metabolic bone diseases such as osteoporosis are not well known. We herein report that daily oral Hochu-Ekki-To administration significantly inhibits osteoclast activation as well as the reduction in bone volume in ovariectomized mice. Our results suggest that supplementation with Hochu-Ekki-To might be beneficial for the prophylaxis and treatment of metabolic bone diseases associated with abnormal osteoclast activation.

3D Bioprinted Osteogenic Tissue Models for In Vitro Drug Screening.

Metabolic bone disease affects hundreds of millions of people worldwide, and as a result, in vitro models of bone tissue have become essential tools to help analyze bone pathogenesis, develop drug screening, and test potential therapeutic strategies. Drugs that either promote or impair bone formation are in high demand for the treatment of metabolic bone diseases. These drugs work by targeting numerous signaling pathways responsible for regulating osteogenesis such as Hedgehog, Wnt/β-catenin, and PI3K-AKT. In this study, differentiated bone marrow-derived mesenchymal stem cell (BM-MSC) scaffold-free 3D bioprinted constructs and 2D monolayer cultures were utilized to screen four drugs predicted to either promote (Icariin and Purmorphamine) or impair osteogenesis (PD98059 and U0126). Osteogenic differentiation capacity was analyzed over a four week culture period by evaluating mineralization, alkaline phosphatase (ALP) activity, and osteogenesis related gene expression. Responses to drug treatment were observed in both 3D differentiated constructs and 2D monolayer cultures. After four weeks in culture, 3D differentiated constructs and 2D monolayer cultures treated with Icariin or Purmorphamine showed increased mineralization, ALP activity, and the gene expression of bone formation markers (BGLAP, SSP1, and COL1A1), signaling molecules (MAPK1, WNT1, and AKT1), and transcription factors (RUNX2 and GLI1) that regulate osteogenic differentiation relative to untreated. 3D differentiated constructs and 2D monolayer cultures treated with PD98059 or U0126 showed decreased mineralization, ALP activity, and the expression of the aforementioned genes BGLAP, SPP1, COL1A1, MAPK1, AKT1, RUNX2, and GLI1 relative to untreated. Differences in ALP activity and osteogenesis related gene expression relative to untreated cells cultured in a 2D monolayer were greater in 3D constructs compared to 2D monolayer cultures. These findings suggest that our bioprinted bone model system offers a more sensitive, biologically relevant drug screening platform than traditional 2D monolayer in vitro testing platforms.

In silico tools predict effects of drugs on bone remodelling.

Researchers have developed an in silico (computer) platform that couples tissue adaptation with cellular and molecular interactions to simulate bone adaptation to mechanical loading and progress and treatment of metabolic bone diseases. What is the benefit of such in silico tools, and how can credibility of the simulation outcomes be established?

Irisin deficiency disturbs bone metabolism.

Balancing the process of bone formation and resorption is important in the maintenance of healthy bone. Therefore, the discovery of novel factors that can regulate bone metabolism remains needed. Irisin is a newly identified hormone-like peptide. Recent studies have reported the involvement of irisin in many physiological and pathological conditions with bone mineral density changes, including osteopenia and osteoporotic fractures. In this study, we generated the first line of Osx-Cre:FNDC5/irisin KO mice, in which FNDC5/irisin was specifically deleted in the osteoblast lineage. Gene and protein expressions of irisin were remarkably decreased in bones but no significant differences in other tissues were observed in knockout mice. FNDC5/irisin deficient mice showed a lower bone density and significantly delayed bone development and mineralization from early-stage to adulthood. Ourphenotypical analysis exhibited decreased osteoblast-related gene expression and increased osteoclast-related gene expression in bone tissues, and reduced adipose tissue browning due to bone-born irisin deletion. By harvesting and culturing MSCs from the knockout mice, we found that osteoblastogenesis was inhibited and osteoclastogenesis was increased. By using irisin stimulated wildtype primary cells as a gain-of-function model, we further revealed the effects and mechanisms of irisin on promoting osteogenesis and inhibiting osteoclastogenesis in vitro. In addition, positive effects of exercise, including bone strength enhancement and body weight loss were remarkably weakened due to irisin deficiency. Interestingly, these changes can be rescued by supplemental administration of recombinant irisin during exercise. Our study indicates that irisin plays an important role in bone metabolism and the crosstalk between bone and adipose tissue. Irisin represents a potential molecule for the prevention and treatment of bone metabolic diseases.