scholarly journals Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

2013 ◽  
Vol 169 (2) ◽  
pp. R39-R57 ◽  
Author(s):  
Jens Bollerslev ◽  
Kim Henriksen ◽  
Morten Frost Nielsen ◽  
Kim Brixen ◽  
Wim Van Hul
Keyword(s):  
Bone Formation ◽  
Bone Metabolism ◽  
Energy Homeostasis ◽  
Autosomal Dominant ◽  
Chloride Transport ◽  
Ex Vivo ◽  
Whole Body ◽  
High Bone Mass ◽  
Treatment Of Osteoporosis ◽  
Autosomal Dominant Osteopetrosis

Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller ofLRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis).Ex vivostudies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

scholarly journals Cellular Distribution, Regulated Expression, and Functional Role of the Anorexigenic Peptide, NUCB2/Nesfatin-1, in the Testis

Endocrinology ◽  
2012 ◽  
Vol 153 (4) ◽  
pp. 1959-1971 ◽  
Author(s):  
D. García-Galiano ◽  
R. Pineda ◽  
T. Ilhan ◽  
J. M. Castellano ◽  
F. Ruiz-Pino ◽  
...  
Keyword(s):  
Leydig Cell ◽  
Functional Role ◽  
Energy Homeostasis ◽  
Ex Vivo ◽  
Whole Body ◽  
Mrna Levels ◽  
Gonadal Function ◽  
Human Choriogonadotropin ◽  
Puberty Onset

Nesfatin-1, product of the precursor NEFA/nucleobindin2 (NUCB2), was initially identified as anorectic hypothalamic neuropeptide, acting in a leptin-independent manner. In addition to its central role in the control of energy homeostasis, evidence has mounted recently that nesfatin-1 is also produced in peripheral metabolic tissues, such as pancreas, adipose, and gut. Moreover, nesfatin-1 has been shown to participate in the control of body functions gated by whole-body energy homeostasis, including puberty onset. Yet, whether, as is the case for other metabolic neuropeptides, NUCB2/nesfatin-1 participates in the direct control of gonadal function remains unexplored. We document here for the first time the expression of NUCB2 mRNA in rat, mouse, and human testes, where NUCB2/nesfatin-1 protein was identified in interstitial mature Leydig cells. Yet in rats, NUCB2/nesfatin-1 became expressed in Sertoli cells upon Leydig cell elimination and was also detected in Leydig cell progenitors. Although NUCB2 mRNA levels did not overtly change in rat testis during pubertal maturation and after short-term fasting, NUCB2/nesfatin-1 content significantly increased along the puberty-to-adult transition and was markedly suppressed after fasting. In addition, testicular NUCB2/nesfatin-1 expression was up-regulated by pituitary LH, because hypophysectomy decreased, whereas human choriogonadotropin (super-agonist of LH receptors) replacement enhanced, NUCB2/nesfatin-1 mRNA and peptide levels. Finally, nesfatin-1 increased human choriogonadotropin-stimulated testosterone secretion by rat testicular explants ex vivo. Our data are the first to disclose the presence and functional role of NUCB2/nesfatin-1 in the testis, where its expression is regulated by developmental, metabolic, and hormonal cues as well as by Leydig cell-derived factors. Our observations expand the reproductive dimension of nesfatin-1, which may operate directly at the testicular level to link energy homeostasis, puberty onset, and gonadal function.

scholarly journals A case of autosomal dominant osteopetrosis type II with a severe bone phenotype but no amino acid converting mutation in the CLCN7 gene

2021 ◽  
Author(s):  
Jochen Hofstaetter ◽  
Gerald James Atkins ◽  
Masakazu Kogawa ◽  
Stephane Blouin ◽  
Barbara Misof ◽  
...  
Keyword(s):  
Amino Acid ◽  
Bone Repair ◽  
Mineral Content ◽  
Autosomal Dominant ◽  
Bone Matrix ◽  
Type Ii ◽  
High Bone Mass ◽  
T Score ◽  
Osteocyte Lacunae ◽  
Autosomal Dominant Osteopetrosis

Autosomal Dominant Osteopetrosis type II (ADOII), also known as Albers-Schonberg disease, is caused by mutation of the CLCN7 chloride channel gene and is characterized by reduced bone resorption. Here we report on an individual with the classic features of ADOII, who had a history of fractures from childhood, displayed high bone mass and characteristic sandwich vertebrae on x-ray. Our genetic analyses showed no amino acid converting mutation in the patients DNA but we did find evidence of haploinsufficiency of CLCN7 mRNA. An iliac crest bone sample from the patient revealed bone tissue and material abnormalities relative to normal controls based on quantitative backscattered electron imaging and histomorphometric analyses. Additionally to lamellar bone, we observed significant amounts of woven bone and mineralised cartilage, as well as an increased frequency and thickness (up to 15 microns) of cement lines. Giant osteoclasts with numerous nuclei were present. The bone mineralisation density distribution (BMDD) of the entire bone area revealed markedly increased average mineral content of the dense bone (CaMean T-score +10.1) and frequency of bone with highest mineral content (CaHigh T-score +19.6), suggesting continued mineral accumulation and lack of bone remodelling. Osteocyte lacunae sections (OLS) characteristics were unremarkable except the OLS shape which was unusually circular. Together, our findings suggest that the reduced expression of CLCN7 mRNA in osteoclasts, and possibly also osteocytes, causes poorly remodelled bone with abnormal bone matrix with high mineral content. This together with the lack of adequate bone repair mechanisms makes the material brittle and prone to fracture.

scholarly journals Periodontal profile and radiographic characterization of the jaws in a patient with autosomal dominant osteopetrosis

2017 ◽  
Vol 2017 ◽  
Author(s):  
Davi da Silva Barbirato ◽  
Mariana Fampa Fogacci ◽  
Mariana Arruda ◽  
Monique Oliveira Rodrigues ◽  
Leonardo Vieira Neto
Keyword(s):  
Bone Metabolism ◽  
Autosomal Dominant ◽  
Osteoclast Differentiation ◽  
Dental Service ◽  
List Type ◽  
First Case ◽  
Dental Management ◽  
Tooth Extractions ◽  
Systemic Component ◽  
Autosomal Dominant Osteopetrosis

Summary Osteopetrosis (OP) comprehends a rare group of conditions, presenting on radiographs increased bone density, deriving from irregularities in osteoclast differentiation or function. In the autosomal dominant osteopetrosis (ADO), some patients stay asymptomatic for some time, or only develop mild symptoms. The dental surgeon is often the first to presuppose the disease during routine imaging examinations, referring the patient to a specialized medical group. Furthermore, osteomyelitis is one of the major OP complications, and should be refrained through frequent dental monitoring. Signals of cortical interruption, sclerotic sequestra or periosteal new bone formation, should be looked for in these patients. Their dental management is complex and procedures encompassing bone tissue, such as implant procedures, tissue regenerations, tooth extractions, maxillofacial surgeries and orthodontic treatments, when elected, should be avoided. This case report describes a case of ADO with a diagnosis of moderate generalized chronic periodontitis, not statistically related to plaque index. This is the first case to describe such a condition, in which the systemic component and the altered bone metabolism seem to be related to the loss of periodontal apparatus, independent of the biofilm. Concerning prevention, we can reinforce the need for frequent dental monitoring to avoid further interventions in those cases. Learning points: This paper reports a case in which the systemic component and the altered bone metabolism seem to have been related to the loss of periodontal attachment apparatus, independent of the biofilm. The periodontal damage observed in the OP patient was not related to the dental plaque, which leads us to suggest that the cases of periodontitis in OP patients should be diagnosed as periodontitis as a manifestation of systemic diseases. The periodontitis prevention should be longed for in OP patients thus, we propose that doctors responsible for patients with OP refer them to a dental service as soon as possible and that dentists should be aware of the preventive dentistry value as well as the most appropriate dental management for those cases.

scholarly journals Role of Biomolecules in Osteoclasts and Their Therapeutic Potential for Osteoporosis

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 747
Author(s):  
Xin Zhao ◽  
Suryaji Patil ◽  
Fang Xu ◽  
Xiao Lin ◽  
Airong Qian
Keyword(s):  
Transcription Factors ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Metabolism ◽  
Therapeutic Potential ◽  
Bone Microarchitecture ◽  
Treatment Of Osteoporosis ◽  
Non Coding Rnas ◽  
And Function

Osteoclasts (OCs) are important cells that are involved in the regulation of bone metabolism and are mainly responsible for coordinating bone resorption with bone formation to regulate bone remodeling. The imbalance between bone resorption and formation significantly affects bone metabolism. When the activity of osteoclasts exceeds the osteoblasts, it results in a condition called osteoporosis, which is characterized by reduced bone microarchitecture, decreased bone mass, and increased occurrences of fracture. Molecules, including transcription factors, proteins, hormones, nucleic acids, such as non-coding RNAs, play an important role in osteoclast proliferation, differentiation, and function. In this review, we have highlighted the role of these molecules in osteoclasts regulation and osteoporosis. The developed therapeutics targeting these molecules for the treatment of osteoporosis in recent years have also been discussed with challenges faced in clinical application.

Results of study of biochemical markers of bone metabolism in men with coronary heart disease

2020 ◽  
pp. 39-43
Author(s):  
A. V. Voronkina ◽  
T. A. Raskina ◽  
M. V. Letaeva ◽  
Yu. V. Averkieva ◽  
O. S. Malyshenko ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Bone Formation ◽  
Bone Metabolism ◽  
Biochemical Markers ◽  
Coronary Atherosclerosis ◽  
Cathepsin K ◽  
Arterial Calcification ◽  
Mineral Density ◽  
Bone Remodeling Markers

The development of atherosclerosis is closely related to the calcification of the vessel intima and fibrous plaques, being a complex and multifactorial process, in which the markers of bone formation and resorption play an important role. Objective. To study the biochemical markers of bone metabolism in men with stable coronary heart disease (CHD). Material and methods. The study included 102 men with verified CHD. Data were evaluated by densitometry, coronary angiography, multispiral computed tomography, color duplex scanning of brachiocephalic arteries, serum lipids (total cholesterol, triglycerides [TG], high-density [LHD] and low-density lipoprotein cholesterol), concentrationsin the blood of osteocalcin (OC), bone alkaline phosphatase (BAP), cathepsin K and C-telopeptides (CTx). Results. Concentrations of BAP, cathepsin K and CTx in patients with CHD were significantly higher than in men without CHD. The concentration of OC in men with normal bone mineral density was significantly lower than in patients with osteopenic syndrome. There was a direct correlation between OC and antiatherogenic HDL cholesterol and the inverse correlation between OC and TG, CTx and TG. There was no correlation between the level of bone remodeling markers and coronary artery (CA) lesion variant and the severity of coronary atherosclerosis on SYNTAX scale. The correlation analysis did not reveal the connection of biochemical markers of bone metabolism with the severity of coronary atherosclerosis and calcification and thickness of intima-media complex of carotid arteries. Absolute values of bone formation indices (BAP, OC) were significantly higher in patients with severe СA calcification than in patients without signs of calcification. Summary. Increased rates of osteogenesis and osteoresorption characterize the accelerated process of bone metabolism and indicate in favor of high rates of bone loss in men with CHD, which confirms the likelihood of common pathophysiological mechanisms of bone resorption and arterial calcification.

Changes in bone metabolism associated with exposure to industrial vibration

2020 ◽  
pp. 766-766
Author(s):  
A. V. Sukhova ◽  
E. N. Kryuchkova
Keyword(s):  
Bone Mineral Density ◽  
Alkaline Phosphatase ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Metabolism ◽  
Biochemical Markers ◽  
Mineral Density ◽  
Local Vibration ◽  
Markers Of Bone Formation

The influence of general and local vibration on bone remodeling processes is investigated. The interrelations between the long - term exposure of industrial vibration and indicators of bone mineral density (T-and Z-criteria), biochemical markers of bone formation (osteocalcin, alkaline phosphatase) and bone resorption (ionized calcium, calcium/creatinine) were established.

scholarly journals DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Haiyan Zhou ◽  
Xinyi Peng ◽  
Jie Hu ◽  
Liwen Wang ◽  
Hairong Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Adipose Tissue ◽  
T Cell ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Whole Body ◽  
Brown Adipose ◽  
Ifn Γ ◽  
Diet Induced Thermogenesis

AbstractAdipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.

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