Monthly Archives: May 2014

Cordyceps Increases Bone Mass in Rats

Abstract

The Protective Effect of Cordymin, a Peptide Purified from the Medicinal Mushroom Cordyceps sinensis, on Diabetic Osteopenia in Alloxan-Induced Diabetic Rats.

The aim of this study was to investigate the protective effect of cordymin on diabetic osteopenia in alloxan-induced diabetic rats and the possible mechanisms involved. The diabetic rats received daily intraperitoneal injection with cordymin (20, 50, and 100 mg/kg/day) for 5 weeks. Cordymin could restore the circulating blood glucose, glycosylated hemoglobin (HbA1c), serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP), and insulin levels in a dose-dependent manner. Also, the treatment of diabetic rats with cordymin could partially reverse the β cells death and decrease the total antioxidant status (TAOS) in the diabetic rats. The results may directly and indirectly account for the possible mechanism of the beneficial effect of cordymin on diabetic osteopenia, which was confirmed with the increased bone mineral content (BMC) and bone mineral density (BMD) in diabetic rats (P < 0.05). All those findings indicate that cordymin may play a protective role in diabetic osteoporosis.

Qi W, Zhang Y, Yan YB, Lei W…
Evid Based Complement Alternat Med 2013
PMID: 24174985 | Free Full Text

Cataracts are Associated with Osteoporosis

Abstract

Are cataracts associated with osteoporosis?

Calcium is considered an important factor in the development of both osteoporosis and cataract. This study evaluated the association between osteoporosis and cataracts.
To evaluate the prevalence of osteoporosis among patients undergoing cataract surgery, and the association between the two.
This was a retrospective observational case-control study, conducted in the Central District of Clalit Health Services (a district of the largest health maintenance organization in Israel). All Clalit members in the district older than 50 years who underwent cataract surgery from 2000 to 2007 (n=12,984) and 25,968 age- and sex-matched controls comprised the sample. Electronic medical records of all patients in the study were reviewed. The main outcome measure was the prevalence of osteoporosis and the odds ratio of having osteoporosis among cataract patients compared with controls.
Demographically, 41.8% were men with a mean age of 68.7 ± 8.2 years. A logistic regression model for osteoporosis showed that age, female sex, higher socioeconomic class, smoking, chronic renal failure, hyperthyroidism, rheumatoid arthritis, inflammatory bowel diseases, and cataract are all associated with increased prevalence of osteoporosis. Obesity is a protective factor for osteoporosis. In all age-groups, osteoporosis was more prevalent in cataract patients than in the control group.
Among other well-known risk factors, osteoporosis is associated with the presence of cataracts. Common pathophysiological associations with both conditions, such as calcium imbalance, hormonal abnormalities, and shared genetic predisposition, are discussed.

Nemet AY, Hanhart J, Kaiserman I, Vinker S
Clin Ophthalmol 2013
PMID: 24204110 | Free Full Text

We found a significant association between cataract and osteoporosis among women of all age-groups and in men older than 75 years. Smoking,8 obesity,9 chronic renal failure,10 hyperthyroidism,11 rheumatoid arthritis,12 inflammatory bowel diseases13 are well known to be associated with osteoporosis and have been reported on extensively. Obesity as a protective factor has already been reported.14 To the best of our knowledge, this is the first study to show this association. This section focuses on calcium imbalance as a common key event, hormonal abnormalities associated with both conditions, and shared ultrastructural abnormalities found in cataract and osteoporosis.

Apigenin Inhibits Osteoclasts in Mouse Cells

Abstract

Attenuation of osteoclastogenesis and osteoclast function by apigenin.

The physiological effects of the flavone, apigenin on bone cells were studied. We first show that apigenin inhibits tumor necrosis factor alpha (TNFalpha)- and interferon gamma (IFNgamma)-induced secretion of several osteoclastogenic cytokines from MC3T3-E1 mouse calvarial osteoblast cell line. Ligands of the TNF receptor family constitute the most potent osteoclastic cytokines. In MC3T3-E1 cells, apigenin dose-dependently (from 5 to 20 microM) inhibits TNFalpha-induced production of the osteoclastogenic cytokines, IL-6 (interleukin-6), RANTES (regulated upon activation, normal T cell-expressed and -secreted), monocyte chemoattractant protein-1 (MCP-1) and MCP-3. In addition, apigenin inhibits IFNgamma-stimulated secretion of monokines, CXCL-9, and -10 in MC3T3-E1 cells. Next, we show that apigenin strongly inhibits differentiation of 3T3-L1 preadipocytes to adipocytes with attendant inhibition of adipocyte differentiation-induced IL-6, MCP-1, and leptin production. Inhibition of adipogenic differentiation by apigenin could be due to induction of osteogensis as it robustly upregulates mRNA levels of bone morphogenetic protein-6 (BMP-6). Finally, the presence of apigenin inhibited osteoclast differentiation from the RAW 264.7 cell line by reducing receptor activator of nuclear factor kappa ligand (RANKL)-induced expression of tartrate-resistant acid phosphatase (TRAP), RANK, and calcitonin receptor but not CCR1, resulting in the inhibition of multinucleated osteoclast formation. Similarly, apigenin inhibited expression of the osteoclast differentiation markers TRAP, RANK, and c-Fms in osteoclast precursor cells obtained from mouse bone marrow following treatment with RANKL and macrophage colony stimulating factor (MCSF). Furthermore, apigenin induced apoptosis of mature osteoclasts obtained from rabbit long bone and inhibited bone resorption. In all instances, a structurally related compound, flavone had no significant effect. These data suggest that apigenin has multiple effects on all three bone cells that could prevent bone loss in vivo.

Bandyopadhyay S, Lion JM, Mentaverri R, Ricupero DA…
Biochem. Pharmacol. Jul 2006
PMID: 16750176

Horny Goat Weed Inhibits Osteoclasts In Vitro

Abstract

Inhibition of osteoclastogenic differentiation by Ikarisoside A in RAW 264.7 cells via JNK and NF-kappaB signaling pathways.

Osteoclasts are specialized bone-resorbing cells derived from multipotent myeloid progenitor cells. They play a crucial homeostatic role in skeletal modeling and remodeling and destroy bone in many pathologic conditions. Receptor activator of NF-kappaB ligand (RANKL) is essential to osteoclastogenesis. In this study, we investigated the effects of Ikarisoside A, isolated from Epimedium koreanum (Berberidaceae), on osteoclastogenesis in RANKL-treated murine monocyte/macrophage RAW 264.7 cells. The results indicate that Ikarisoside A is a potent inhibitor of osteoclastogenesis in RANKL-stimulated RAW 264.7 cells as well as in bone marrow-derived macrophages. The inhibitory effect of Ikarisoside A resulted in decrease of osteoclast-specific genes like matrix metalloproteinase 9 (MMP9), tartrate-resistant acid phosphatase (TRAP), receptor activator of NF-kappaB (RANK), and cathepsin K. Moreover, Ikarisoside A blocked the resorbing capacity of RAW 264.7 cells on calcium phosphate-coated plates. Ikarisoside A also has inhibitory effects on the RANKL-mediated activation of NF-kappaB, JNK, and Akt. Finally, Ikarisoside A clearly decreased the expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1) as well as the transcriptional activity of NFATc1, the master regulator of osteoclast differentiation. The data indicate that Ikarisoside A has potential for use in treatment of diseases involving abnormal bone lysis such as osteoporosis, rheumatoid arthritis, and periodontal bone erosion.

Choi HJ, Park YR, Nepal M, Choi BY…
Eur. J. Pharmacol. Jun 2010
PMID: 20353769

Vitamin K2 (MK4) Inhibits Bone Resorption Through Inhibition of PGE2 In Vitro

Abstract

Menatetrenone inhibits bone resorption partly through inhibition of PGE2 synthesis in vitro.

We studied the effect of menatetrenone, a vitamin K2 homolog, on bone resorption stimulated by interleukin-1 alpha (IL-1 alpha), prostaglandin E2 (PGE2), parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Bone-resorbing activity was assessed by measurement of calcium and hydroxyproline in the media and calvariae. IL-1 alpha (0.1-100 U/ml), 1,25-(OH)2D3 (10(-10)-10(-7) M), PGE2 (10(-9)-10(-6) M), and PTH (3 x 10(-8)-3 x 10(-7) M) dose dependently increased the levels of calcium and hydroxyproline in the medium. Indomethacin (10(-6) M) completely inhibited bone resorption induced by IL-1 alpha and partially inhibited bone resorption induced by 1,25-(OH)2D3. However, indomethacin did not affect the action of PGE2 or PTH. Menatetrenone (3 x 10(-6)-3 x 10(-5) M) inhibited the bone resorption induced by IL-1 alpha (2 U/ml), PGE2 (10(-7) M), PTH (3 x 10(-7) M), and 1,25-(OH)2D3 (3 x 10(-10) M) in a dose-dependent manner. Menatetrenone also inhibited the PGE2 production stimulated by IL-1 alpha. These results indicate that menatetrenone may inhibit bone resorption through at least two different mechanisms; one possibly is an inhibitory effect on prostaglandin production.

Hara K, Akiyama Y, Tajima T, Shiraki M
J. Bone Miner. Res. May 1993
PMID: 8511981

Review: PGE2 is Complicated

The prostaglandin E(2) system: a toolbox for skeletal repair?

Gelse K, Beyer C
Arthritis Rheum. Apr 2011
PMID: 21190302 | Free Full Text

Prostaglandin E2 (PGE2), the most widely produced member of the prostaglandin group, originates from arachidonic acid that is released from the cell membrane by phospholipase A2, followed by enzymatic conversion by cyclooxygenase (COX) and PGE synthase 1 (PGES-1). PGE2 not only triggers pain and inflammation but also promotes matrix degradation and tissue damage by stimulating the expression of matrix-degrading enzymes (2). Inflammatory cytokines such as interleukin-1 or tumor necrosis factor ’ strongly increase PGE2 levels, but PGE2 secretion may also increase in response to other stimuli including growth factors, hypoxia, and a number of hormones.

Apart from the well-defined role of PGE2 in tissue inflammation, there is increasing evidence that it is involved in the maintenance and repair of the skeletal system. At first glance, the effects of PGE2 on tissue homeostasis of bone and cartilage seem confusing, because they conflict with the long-known destructive potential of the prostaglandins. Nevertheless, both catabolic and anabolic effects have already been described for PGE2 in these tissues. In terms of catabolism, PGE2 can promote osteoclastic bone resorption (3,4) and enhance breakdown of the extracellular matrix by increasing the expression of matrix metalloproteinase 3 (MMP-3) or MMP-13 (2,5). Regarding its anabolic aspects, PGE2 may stimulate chondrogenesis, chondrocyte proliferation (6), cartilage matrix synthesis (7), as well as osteoblast activity (8). To shed light on the apparent ambivalent role of PGE2, a multidimensional view is necessary that addresses the developmental stage, type of tissue, disease status, concentration of PGE2, and specific receptor status of the different cell types.

 

PGE2 Stimulates Bone Formation and Resorption In Mouse Cells

Abstract

Prostaglandin E2 stimulates osteoclast-like cell formation and bone-resorbing activity via osteoblasts: role of cAMP-dependent protein kinase.

Prostaglandin E2 (PGE2) is an important local regulator in bone. The present study was performed to investigate the effect of PGE2 on osteoclast-like cell formation and bone-resorbing activity of mature osteoclasts in the presence or absence of osteoblasts, PGE2 (10(-8) to 10(-6) M) significantly stimulated osteoclast-like cell formation in osteoblast-containing mouse bone cell cultures, although it did not affect osteoclast-like cell formation from hemopoietic blast cells supported by granulocyte-macrophage colony-stimulating factor in osteoblast-free mouse spleen cell cultures. The conditioned medium from osteoblastic UMR-106 cells pretreated with PGE2 (10(-8) and 10(-6) M) significantly stimulated osteoclast-like cell formation from hemopoietic blast cells. PGE2 also significantly stimulated the bone-resorbing activity of mature osteoclasts in osteoblast-containing mouse bone cell cultures. In contrast, PGE2 significantly inhibited the bone-resorbing activity and osteopontin mRNA expression in isolated rabbit osteoclasts. Rp-cAMPS, a direct protein kinase (PKA) antagonist, significantly inhibited PGE2-stimulated osteoclast-like cell formation and the bone-resorbing activity of mature osteoclasts, although protein kinase C inhibitors, dantrolene (an inhibitor of calcium release from the intracellular calcium pool) and voltage-dependent calcium channel blockers did not affect PGE2-stimulated osteoclast-like cell formation. In conclusion, PGE2 stimulated osteoclast-like cell formation and bone-resorbing activity in mouse bone cell cultures presumably through osteoblasts. The activation of PKA is linked to PGE2-stimulated osteoclast-like cell formation and bone-resorbing activity.

Kaji H, Sugimoto T, Kanatani M, Fukase M…
J. Bone Miner. Res. Jan 1996
PMID: 8770698

PGE2 Increases Bone Formation and Mass in Aging Rats

Abstract

Systemic prostaglandin E2 increases cancellous bone formation and mass in aging rats and stimulates their bone marrow osteogenic capacity in vivo and in vitro.

Prostaglandin E(2) (PGE(2)) has been shown to exert a bone anabolic effect in young and adult rats. In this study we tested whether it possesses a similar effect on bone formation and bone mass in aging rats. Fifteen-month-old rats were injected daily with either PGE(2) at 5 mg/kg or vehicle for 14 days. PGE(2) treatment stimulated the rate of cancellous bone formation (a approximately 5.5-fold increase in bone formation rate), measured by the incorporation of calcein into bone-forming surfaces at the tibial proximal metaphysis. This effect resulted in increased cancellous bone area (+54%) at the same site. Since PGE(2) treatment resulted in a much higher proportion of bone surface undergoing bone formation and thus lined with osteoblasts, we tested the hypothesis that PGE(2) stimulates osteoblast differentiation from bone marrow precursor cells both in vivo and in vitro. We found that ex vivo cultures of bone marrow stromal cells from rats injected for 2 weeks with PGE(2) at 5 mg/kg per day yielded more ( approximately 4-fold) mineralized nodules and exhibited a greater (by 30-40%) alkaline phosphatase activity compared with cultures from vehicle-injected rats, attesting to a stimulation of osteoblastic differentiation by PGE(2). We also compared the osteogenic capacity of bone marrow from aging (15-month-old) versus young (5-week-old) rats and its regulation by PGE(2) in vitro. Bone marrow stromal cell cultures from aging rats exhibited a greatly diminished osteogenic capacity, reflected in reduced nodule formation ( approximately 6% of young animals) and lower alkaline phosphatase activity ( approximately 60% of young animals). However, these parameters could be stimulated in both groups of animals by incubation with 10-100 nM PGE(2). The magnitude of this stimulation was greater in cultures from aging rats (+550% vs +70% in nodule formation of aging compared with young rats). In conclusion, we demonstrate here that PGE(2) exerts a bone anabolic effect in aging rats, similar to the effect we and others have reported in young, growing rats. The PGE(2)-stimulated bone formation, which augments bone mass, most likely results from recruitment of osteoblasts from their bone marrow stromal precursors.

Keila S, Kelner A, Weinreb M
J. Endocrinol. Jan 2001
PMID: 11139777 | Free Full Text

Vitamin K Intake Not Associated with Fracture in Chinese Men and Women

Abstract

No association between dietary vitamin K intake and fracture risk in chinese community-dwelling older men and women: a prospective study.

Data on the association between dietary vitamin K intake and fracture risk are limited among Chinese. This study examined such an association in community-dwelling elderly in Hong Kong. We present data from 2,944 subjects (1,605 men, 1,339 women) who participated in a prospective cohort study. Baseline dietary intakes of energy, protein, calcium, vitamin D, and vitamin K were assessed using a food-frequency questionnaire. Data on incident hip fracture and nonvertebral fracture during a median of 6.9 follow-up years were collected from a hospital database. Cox regression analyses were performed with adjustments for age, education attainment, smoking status, alcohol use, body mass index, hip bone mineral density, physical activity, use of calcium supplement, and energy-adjusted nutrient intakes. There were 29 (1.8 %) men and 19 (1.4 %) women with incident hip fractures and 97 (6.0 %) men and 88 (6.6 %) women with nonvertebral fractures. The median (interquartile range) of dietary vitamin K intake was 241.8 (157.5-360.8) and 238.9 (162.4-343.6) μg/day in men and women, respectively. Similar dietary vitamin K intakes were observed between subjects with hip or nonvertebral fractures and subjects without hip or nonvertebral fractures. In both men and women, dietary vitamin K intake was not associated with fracture risks at all measured sites in either crude or adjusted models. In Chinese community-dwelling elderly, hip or nonvertebral fracture risk was not associated with dietary vitamin K intake. The high dietary vitamin K intake of the studied group may have limited the ability to detect the association between vitamin K intake and fracture risk.

Chan R, Leung J, Woo J
Calcif. Tissue Int. May 2012
PMID: 22451220

Low Vitamin K May Increase Hip Fracture in Women

Abstract

Vitamin K intake and hip fractures in women: a prospective study.

Vitamin K mediates the gamma-carboxylation of glutamyl residues on several bone proteins, notably osteocalcin. High serum concentrations of undercarboxylated osteocalcin and low serum concentrations of vitamin K are associated with lower bone mineral density and increased risk of hip fracture. However, data are limited on the effects of dietary vitamin K. We investigated the hypothesis that high intakes of vitamin K are associated with a lower risk of hip fracture in women.
We conducted a prospective analysis within the Nurses’ Health Study cohort. Diet was assessed in 72327 women aged 38-63 y with a food-frequency questionnaire in 1984 (baseline). During the subsequent 10 y of follow-up, 270 hip fractures resulting from low or moderate trauma were reported.
Women in quintiles 2-5 of vitamin K intake had a significantly lower age-adjusted relative risk (RR: 0.70; 95% CI: 0.53, 0.93) of hip fracture than women in the lowest quintile (< 109 microg/d). Risk did not decrease between quintiles 2 and 5 and risk estimates were not altered when other risk factors for osteoporosis, including calcium and vitamin D intakes, were added to the models. Risk of hip fracture was also inversely associated with lettuce consumption (RR: 0.55; 95% CI: 0.40, 0.78) for one or more servings per day compared with one or fewer servings per week), the food that contributed the most to dietary vitamin K intakes.
Low intakes of vitamin K may increase the risk of hip fracture in women. The data support the suggestion for a reassessment of the vitamin K requirements that are based on bone health and blood coagulation.

Feskanich D, Weber P, Willett WC, Rockett H…
Am. J. Clin. Nutr. Jan 1999
PMID: 9925126 | Free Full Text