β-alanyl-l-histidinato zinc and bone resorption

• 1.1.β-Alanyl-l-histidinato zinc (AHZ), in which zinc is chelated to β-alanyl-l-histidine, is a new zinc compound. β-Alanyl-l-histidine can uniquely chelated zinc ion in various essential trace metals. More recently, it has been demonstrated that this compound has more intensive effect than zinc sulfate on bone metabolism, suggesting a role as pharmacological tool in osteoporosis. This review describes mainly the action of AHZ on bone resorption as summarized in the following.
• 2.2. The prolonged oral administration of AHZ (10–100 mg/kg/day) can completely prevent bone loss in the femur of ovariectomized rats, indicating the preventive effect of AHZ on bone resorption in vivo.
• 3.3. The decrease in bone calcium content induced by various bone resorbing factors was completely inhibited by the presence of AHZ (10⁻⁶-10⁻⁴ M) in bone tissue culture system in vitro.
• 4.4. Many bone resorbing agents can stimulate the formation (differentiation) of osteoclasts from marrow cells. AHZ (10⁻⁶-10⁻⁴ M) clearly inhibited osteoclast-like cell formation in mouse marrow culture in vitro.
• 5.5. AHZ may act on the process of parathyroid hormone-induced protein kinase C activation which is involved in Ca²⁺-signaling in osteoclastic cells.

     

Association of vitamin D receptor and estrogen receptor-α gene polymorphismwith peak bone mass and bone size in Chinese women

AIM: To investigate if vitamin D receptor (VDR) gene Apa I polymorphism and estrogen receptor-alpha (ER-alpha) gene Pvu II, Xba I polymorphisms are related to bone mineral density (BMD), bone mineral content (BMC) and bone size in premenopausal Chinese women. METHODS: The VDR Apa I genotype and ER-alpha Pvu II, Xba I genotype were determined by PCR-restriction fragment length polymorphism (RFLP) in 493 unrelated healthy women aged 20-40 years of Han nationality in Shanghai city. BMD (g/cm(2)), BMC (g), and bone areal size (BAS, cm(2) ) at lumbar spine 1-4 (L(1-4)) and proximal femur (femoral neck, trochanter and Ward's triangle) were measured by duel-energy X-ray absorptionmetry. RESULTS: All allele frequencies did not deviate from Hardy-Weinberg equilibrium. After phenotypes were adjusted for age, height, and weight, a significant association was found between VDR Apa I genotype and BMC variation at L(1-4) and Ward's triangle (P<0.05), but not in BMD or BAS at lumbar spine and proximal femur. ER-a Pvu II, Xba I genotype was not related to BMC, BMD, and BAS at all sites. CONCLUSION: The study suggested that Apa I polymorphism in VDR gene may influence on attainment and maintenance of peak bone mass in premenopausal Chinese women.     

Repair and formation of cartilage and bone: are they possible?

Osteoporosis and osteoarthritis cause serious problems to the mobility, and therefore to the quality of life, of aged people. This is due to the fact that both diseases result from irreversible loss of quality or function of the tissues; i.e., bone and articular cartilage. Recent progress in molecular biology and developmental biology, however, have contributed a great deal to our understanding of the mechanisms regulating growth and differentiation of osteoblasts and chondrocytes, the cells responsible for producing bone and cartilage, respectively. In vivo studies using animals including humans also shed light on the mechanism underlying these biological events as well as diseases and provide ideas for possible interventions for treating these disease states. This review will deal with these new developments in the field and discuss possibility to develop new potential strategies for treating patients with those disorders.     

Association of vitamin D receptor and estrogen receptor-αgene polymorphism with peak bone mass and bone size in Chinese women

AIM: To investigate if vitamin D receptor (VDR) gene Apa I polymorphism and estrogen receptor-α (ER-α) gene Pvu II, Xba I polymorphisms are related to bone mineral density (BMD), bone mineral content (BMC) and bone size in premenopausal Chinese women. METHODS: The VDR Apa I genotype and ER-α Pvu II, Xba I genotype were determined by PCR-restriction fragment length polymorphism (RFLP) in 493 unrelated healthy women aged 20-40 years of Han nationality in Shanghai city.…     

How useful are measures of BMD and bone turnover?

Measurements of bone mineral density (BMD) and biochemical markers of bone turnover are useful in the diagnosis and management of osteoporosis, as well as in research relating to the pathogenesis and treatment of the disease. Recent challenges to the utility of these measures have resulted in some confusion among both researchers and clinicians. BMD accounts for the great majority of bone strength and is the current gold standard for the diagnosis of osteoporosis, as well as for prediction of fracture risk. Although bone turnover increases sharply after menopause, biochemical markers of bone turnover have limited usefulness in fracture risk prediction. Persistently elevated bone turnover throughout the menopause is associated with structural decrements, cannot be measured routinely and non-invasively. In research applications, both BMD and markers of bone turnover are used to identify candidate agents in preclinical and clinical studies. In addition, head-to-head comparisons of treatments utilize these measures, because fracture endpoint trials would need to be extraordinarily large and complex. Analyses that have suggested that change in BMD or bone turnover 'explains' little of change in fracture risk with treatment appear to be flawed. Although neither can perfectly predict fracture, they are our current best alternatives.     

The effect of semelil (angipars?) on bone resorption and bone formation markers in type 2 diabetic patients

Background and purpose of the study

Diabetes mellitus has been recognized as a major risk factor for osteoporosis in which bone turnover is affected by different mechanisms. As the morbidity, mortality and financial cost related to osteoporosis are expected to rise in Iran in coming years, and considering the efficacy of Angipars® for improvement of different ulcers which made it a new herbal drug in diabetic foot ulcer, there is a need to evaluate the effect of this new drug on different organs including bone resorption and bone formation markers.

Methods

In this randomized, double- blind clinical trial, 61 diabetic patients were included. The subjects were randomly divided into intervention and control groups. Subjects of intervention group received 100 mg of Angipars® twice a day. Laboratory tests including bone resorption and bone formation markers were performed at baseline and after 3 months.

Result

31 patients in study group and 30 patients in control group finished the study. The mean age of the study population and the mean disease duration was respectively 51.8 ± 6.2 and 7.5 ± 4.7 years with no significant differences between intervention and control patients. No statistically significant differences between patients and controls were observed in pyridinoline, osteocalcin, urine calcium, bone alkaline phosphatase and tumor necrosis factor (TNF-α). Only urine creatinine level significantly changed between two groups after 3 month of treatment (p-value: 0.029)

Conclusion

In conclusion, the findings of this study indicate that Semelil (Angipars®) had no beneficial or harmful effects on bone. It might be other effects of this new component on bone turnover process which need more studies and more time to be discovered.     

SSRIs,bone mineral density,and risk of fractures — a review

A possibility for selective serotonin reuptake inhibitors (SSRIs) to increase the risk of bone fracture has been debated during recent years. Proposed causes include an ability for the drugs to reduce bone mineral density (BMD). Experimental data have identified a functional 5-HT system in bone, although its role is unclear. Results from numerous epidemiological studies are heterogeneous and several different associations have been suggested; between depression and low BMD, SSRIs and low BMD, depression and falls, SSRIs and falls, depression and fractures, and SSRIs and fractures. In this paper, we review the available data and discuss the various study results. Based on the current available data, we conclude that it is not possible to determine whether SSRIs may negatively influence bone regulation or are innocent bystanders. It is likely that only a large, prospective, long-term study designed to investigate changes in BMD will be able to answer the question.     

Harmine, a β-carboline alkaloid, inhibits osteoclast differentiation and bone resorption in vitro and in vivo

Bone homeostasis is controlled by the balance between osteoblastic bone formation and osteoclastic bone resorption. Excessive bone resorption is involved in the pathogenesis of bone-related disorders such as osteoporosis, arthritis and periodontitis. To obtain new antiresorptive agents, we searched for natural compounds that can inhibit osteoclast differentiation and function. We found that harmine, a β-carboline alkaloid, inhibited multinucleated osteoclast formation induced by receptor activator of nuclear factor-κB ligand (RANKL) in RAW264.7 cells. Similar results were obtained in cultures of bone marrow macrophages supplemented with macrophage colony-stimulating factor and RANKL, as well as in cocultures of bone marrow cells and osteoblastic UAMS-32 cells in the presence of vitamin D(3) and prostaglandin E(2). Furthermore, harmine prevented RANKL-induced bone resorption in both cell and bone tissue cultures. Treatment with harmine (10 mg/kg/day) also prevented bone loss in ovariectomized osteoporosis model mice. Structure-activity relationship studies showed that the C3-C4 double bond and 7-methoxy group of harmine are important for its inhibitory activity on osteoclast differentiation. In mechanistic studies, we found that harmine inhibited the RANKL-induced expression of c-Fos and subsequent expression of nuclear factor of activated T cells (NFAT) c1, which is a master regulator of osteoclastogenesis. However, harmine did not affect early signaling molecules such as ERK, p38 MAPK and IκBα. These results indicate that harmine inhibits osteoclast formation via downregulation of c-Fos and NFATc1 induced by RANKL and represses bone resorption. These novel findings may be useful for the treatment of bone-destructive diseases.     

Nangibotide attenuates osteoarthritis by inhibiting osteoblast apoptosis and TGF-β activity in subchondral bone

Inflammopharmacology - Osteoarthritis (OA) is a chronic joint disorder that causes cartilage degradation and subchondral bone abnormalities. Nangibotide, also known as LR12, is a dodecapeptide with...     

Alleviation of bone markers in rats induced nano-zinc oxide by qurecetin and α-lipolic acid

The purpose of this study was to evaluate the potential protective effect of qurecetin (Qur) and α-lipolic acid (ALA) to modulate the perturbation of bone turnover which is induced by nano-zinc oxide (n-ZnO). Rats were fasted overnight and randomly divided into two groups: G1, normal healthy animals and the other rats were administered zinc oxide nanoparticles orally by guava in a dose of 600?mg/kg body weight/d for 5 sequential days in Wistar albino male rats. N-ZnO-exposed animals were randomly sub-divided into three groups: G2, n-ZnO-exposed animals; G3, n-ZnO-exposed animals co-treated with Qur (200?mg/kg daily); and G4, n-ZnO-exposed animals co-treated with ALA (200?mg/kg). Qur and ALA were administered orally by guava daily for three sequential weeks from the beginning of the experiment. The results revealed a significant reduction of nitiric oxide (NO) and serum level and comet assay in n-ZnO exposure rats after treatment of Qur and ALA. It was found the alteration of pro-inflammatory markers (tumor necrosis factor alpha; TNF-α, interleukin-6; IL-6 and C-reactive protein; CRP), bone alkaline phosphatase (B-ALP, bone formation marker), and C-terminal peptide type I collagen (CTx, bone resorption marker) levels compared with the normal group. Co-administration of Qur and ALA in n-ZnO-exposed rats significantly alleviated the mentioned alterations of biochemical parameters. These results suggest that Qur and ALA as antioxidant agents may be a candidate for preventive and treatment applications of impaired bone markers induced bone loss caused by nano-particles of metal oxide.     

β-arrestin-biased agonism at the parathyroid hormone receptor uncouples bone formation from bone resorption

Parathyroid hormone (PTH) is a principle regulator of bone and calcium metabolism and PTH analogs hold great promise as a therapy for metabolic bone diseases such as osteoporosis. PTH acts principally through the type IPTH/PTH-related peptide receptor (PTH1R), a G protein coupled receptor (GPCR). GPCRs are a family of seven transmembrane cell surface receptors that share conserved structural, functional, and regulatory properties. Recent studies demonstrate that the complex metabolic effects induced by PTH1R stimulation are not entirely a consequence of conventional GPCR signaling. β-arrestins, in addition to their GPCR desensitizing actions, also serve as multifunctional scaffolding proteins linking the PTH1R to signaling molecules independent of the classic G protein coupled second messenger-dependent pathways. In vitro, D-Trp(12),Tyr(34)-bPTH(7-34) (PTH-βarr), a β-arrestin selective biased agonist for the PTH1R, antagonizes receptor-G protein coupling but activates arrestin-dependent signaling. In vivo, intermittent administration of, PTH-βarr to mice, induces anabolic bone formation, completely independent of classic G protein-coupled signaling mechanisms. While both PTH-βarr and the conventional agonist PTH(1-34) stimulate anabolic bone formation in mice, unlike PTH(1-34), which activates G protein coupling, PTH-βarr does not induce hypercalcemia or increase markers of bone resorption. This newly recognized ability of β-arrestins to serve as signal transducers for the PTH1R represents an innovative paradigm of receptor signaling which can be targeted to induce a subset of physiologic responses in bone. Exploitation of β-arrestin biased agonism may offer therapeutic benefit for the treatment of metabolic bone diseases such as osteoporosis.     

Puerarin stimulates osteoblasts differentiation and bone formation through estrogen receptor,p38 MAPK,and Wnt/β-catenin pathways

Puerarin is an isoflavone extracted from Radix Puerariae, a traditional Chinese herb used to treat many diseases such as osteoporosis. In this study, puerarin was shown to stimulate alkaline phosphatase (ALP) activity, type I collagen (Col I) secretion, and mineralized nodules formation of primary osteoblasts. Whereas the estrogen receptor (ER) antagonist ICI 182780 was able to reduce the increase in ALP activity and Col I secretion induced by puerarin. Furthermore, puerarin was shown to elevate levels of phospho-p38 mitogen-activated protein kinase (MAPK) and β-catenin proteins in a time-dependent manner. Pretreatment of osteoblasts with ICI 182780 can reduce this elevation, whereas pretreatment with p38 MAPK inhibitor SB 203580 did not affect the increase of β-catenin protein. Meanwhile, intragastric administration of puerarin protected against reduction in bone mineral density and bone mineral content in ovariectomized rats, and improved femur trabecular bone structure. Taken together, ER, p38 MAPK, and Wnt/β-catenin pathways were involved in puerarin-stimulated osteoblasts differentiation and bone formation.