The role of genetic and metabolic disorders in osteoporosis

Osteoporosis is a progressive multifactorial systemic disease of the skeletal system characterized by the damage of the microarchitectonics of the bone tissue, which leads to the occurrence of low-energy fractures and impairment of the quality of life of individuals. The risk factors for the development of osteoporosis include smoking, which inhibits calcium absorption in the intestine and not only contributes to the reduction of bone density but also acts as a predictor of bronchopulmonary pathology. The systemic inflammation that develops in patients with chronic obstructive pulmonary disease, associated with the production of interleukins (IL)-6, IL-1, IL-8, and tumor necrosis factor – α, stimulates osteoclast-mediated bone resorption and a low level of osteoprotegerin closes the circle. In clinical practice, the determination of markers of bone resorption is required. This is a tartrate-resistant acid phosphatase, the 5β fraction of which signals the end of the resorption process; these are hydroxypyridine crosslinks – pyridoline (PYD) and deoxypyridoline, that stabilize the bone collagen molecule. Genetic factors also play an important role in the development of osteoporosis. The presence of the GG genotype or the G allele of the 283 A> G polymorphism (Bsml) of the VDR gene is a predictor of osteoporosis of the lumbar vertebrae L1-L4. The substitution of cytosine for thymine (C> T) in exon 17 of the calcitonin gene (CALCR) at position 1340 leads to the substitution of the amino acid proline (CCG) for leucine (CTG) at position 463 of the receptor protein molecule and affects bone density. But the most phylogenetically ancient mechanism for regulating the development and maintenance of tissue homeostasis by controlling cell proliferation, differentiation, migration, and apoptosis is the Wnt signaling pathway (SP-Wnt). Alterations in Wnt signaling observed in cases of genetic mutations cause various diseases of the human skeleton. A systematic literature search was carried out using the Scopus, PubMed, Web of Science databases.

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BIOCHEMICAL MARKERS OF BONE RESORPTION, REGULATION OF OSTEOCLASTOGENESIS AND BONE LOSS FOLLOWING LIVER TRANSPLANTATION

Osteoporosis and Bone Diseases ◽

10.14341/osteo2013118-23 ◽

2013 ◽

Vol 16 (1) ◽

pp. 18-23

Author(s):

V P Buzulina ◽

I A Pronchenko ◽

I P Ermakova ◽

N P Shmerko ◽

A A Andrianova ◽

...

Keyword(s):

Liver Transplantation ◽

Bone Density ◽

Bone Resorption ◽

Vitamin D3 ◽

Tartrate Resistant Acid Phosphatase ◽

Specific Marker ◽

Neck Of Femur ◽

Early Date ◽

Trap 5B ◽

Markers Of Bone Resorption

Methods and results: bone densitometry of L2-L4 and neck of femur, the level in serum of blood some hormones (PTH, vitamin D3, estradiol, testosterone) and cytokines (OPG, IL-6, FNO-a) regulating osteoclastogenesis as well as comparative analyses of two bone resorption markers β-crosslaps and tartrate-resistant acid phosphatase type 5b (TRAP-5b) were fulfilled at different periods following orthotopic liver transplantation. At the early date after operation there were the bone density decrease of L2-L4, the lowering of vitamin D3, estradiol in women, testosterone in men and the elevation of cytokines and of resorption markers. In 1 and 2 years following liver transplantation there were revealed the rise of bone density, the level of PTH, estradiol, testosterone, which were associated with the lowering of IL-6, FNO-a and β-crosslaps while the level of vitamin D3 and TRAP-5b remained stable. Conclusion: at the early date TRAP-5b was more specific marker of bone resorption which did not depend on collagen metabolism in liver. In 1 and 2 years following liver transplantation bone resorbtion was association with level of PTH, FNO-a and OPG.

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Myeloma Cells Suppress Osteoblast Differentiation by Secreting a Soluble Wnt Inhibitor, sFRP-2.

Blood ◽

10.1182/blood.v104.11.2356.2356 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2356-2356 ◽

Cited By ~ 2

Author(s):

Takashi Oshima ◽

Masahiro Abe ◽

Jin Asano ◽

Tomoko Hara ◽

Kenichi Kitazoe ◽

...

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Wnt Signaling ◽

Signaling Pathway ◽

Cell Lines ◽

Osteoblast Differentiation ◽

Wnt Signaling Pathway ◽

Bone Destruction ◽

Nodule Formation ◽

Mrna Levels

Abstract Multiple myeloma (MM), a malignancy of plasma cells, develops in the bone marrow, and generates devastating bone destruction. Along with enhanced bone resorption, clinical evidence has also suggested suppression of bone formation as a contributing factor to the bone loss in MM. In contrast to recent understanding on mechanisms of osteolysis enahnced in MM, little is known about factors responsible for impaired bone formation. A canonical Wingless-type (Wnt) signaling pathway has recently been shown to play a critical role in osteoblast differentiation. Therefore, in the present study, we aimed to clarify mechanisms of suppression of osteoblast differentiation by MM cells with a particular focus on a canonical Wnt signaling pathway. Because several secreted Frizzled related protein (sFRP) and DKK family members are known as soluble Wnt antagonists, we first examined the expression of sFRP-1, 2 and 3 and DKK-1 in MM cell lines including U266, RPMI8226 and ARH77. All cell lines expressed sFRP-2 and sFRP-3 mRNA observed by RT-PCR. However, sFRP-1 was not expressed in any cell line, and Dkk-1 was expressed only in U266 cells at mRNA levels. We next conducted Western blot analyses for these factors and detected only sFRP-2 in immunoprecipitants of conditioned media as well as cell lysates of all these cell lines. However, no other factors were found at protein levels. Furthermore, sFRP-2 mRNA and protein expression was detected in most MM cells from patients with advanced or terminal stages of MM with bone destruction including plasma cell leukemia (3/4 and 8/10, respectively). In order to examine a biological role for sFRP-2, we added recombinant sFRP-2 to MC3T3-E1 cell culture together with BMP-2. Exogenous sFRP-2 partially suppressed alkaline phosphatase activity but almost completely mineralized nodule formation enhanced by BMP-2. Furthermore, sFRP-2 immunodepletion significantly restored mineralized nodule formation in MC3T3-E1 cells suppressed by RPMI8226 and ARH77 CM. These results suggest that sFRP-2 alone is able to suppress osteoblast differentiation induced by BMP-2 and that MM cell-derived sFRP-2 is among predominant factors responsible for defective bone formation in MM. Because MM cell-derived factors such as DKK-1, IGF-BP4 and IL-3 other than sFRP-2 have been implicated as an inhibitor of osteoblast differentiation, sFRP-2 may act alone or in combination with such other factors to potently suppress bone formation in MM. Taken together, MM cells may cause an imbalance of bone turnover with enhanced osteoclastic bone resorption and concomitantly suppressed bone formation, which leads to devastating destruction and a rapid loss of bone.

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Thyroid Hormone Actions and Bone Remodeling – The Role of the Wnt Signaling Pathway

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1088-1215 ◽

2020 ◽

Vol 128 (06/07) ◽

pp. 450-454

Author(s):

Franziska Lademann ◽

Elena Tsourdi ◽

Lorenz C. Hofbauer ◽

Martina Rauner

Keyword(s):

Thyroid Hormone ◽

Bone Resorption ◽

Bone Mass ◽

Thyroid Hormones ◽

Wnt Signaling ◽

Signaling Pathway ◽

Bone Development ◽

Wnt Signaling Pathway ◽

Bone Homeostasis ◽

Normal Thyroid Function

AbstractThyroid hormones are indispensable for bone development and growth. Also in adults, bone mass maintenance is under the control of thyroid hormones. Preclinical and clinical studies established untreated hyperthyroidism as a cause for secondary osteoporosis with increased fracture risk. Thus, normal thyroid function is essential for bone health. Mechanistically, thyroid hormone excess accelerates bone turnover with predominant bone resorption. How thyroid hormones affect osteoblast and osteoclast functions, however, still remains ill-defined. The Wnt signaling pathway is a major determinant of bone mass and strength as it promotes osteoblastogenesis and bone formation, while inhibiting bone resorption. So far, only few studies investigated a possible link between thyroid hormones, bone metabolism and the Wnt pathway. In this review, we summarize the literature linking thyroid hormones to bone homeostasis through Wnt signaling and discuss its potential as a therapeutic approach to treat hyperthyroidism-induced bone loss.

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