Bone Response to Loading in Mice With Targeted Disruption of the Cartilage Oligomeric Matrix Protein Gene
4
Citation
14
Reference
10
Related Paper
Citation Trend
Abstract:
Exercise induced bone response although established, little is known about the molecular components that mediate bone response to mechanical loading (ML). In our recent QTL study, we identified one such possible molecular component responding to ML: cartilage oligomeric matrix protein (COMP). To address the COMP role in mediating ML effects on bone formation, COMP expression was evaluated as a function of duration and age in response to ML in female B6 mice. A 9N load was applied using a four-point bending device at 2Hz frequency for 36 cycles, once per day for 2-, 4- and 12-days on the right tibia. The left tibia was used as an internal control. Loading caused an increase in COMP expression by 1.3-, 2- and 4-fold respectively after 2-, 4- and 12-days of loading. This increase was also seen in 16 and 36-week old mice. Based on these findings, we next used COMP knockout (KO) mice to evaluate the cause and effect relationship. Quantitative analysis revealed 2 weeks of ML induced changes in vBMD and bone size in the KO mice (5.9 % and 21 % vs. unloaded bones) was not significantly different from control mice (7 % and 24 % vs. unloaded bones). Our results imply that COMP is not a key upstream mediator of the anabolic effects of ML on the skeleton.Keywords:
Knockout mouse
Matrix (chemical analysis)
Bone anabolic action of PTH has been suggested to be mediated by induction of IGF-I in osteoblasts; however, little is known about the molecular mechanism by which IGF-I leads to bone formation under the PTH stimulation. This study initially confirmed in mouse osteoblast cultures that PTH treatment increased IGF-I mRNA and protein levels and alkaline phosphatase activity, which were accompanied by phosphorylations of IGF-I receptor, insulin receptor substrate (IRS)-1 and IRS-2, essential adaptor molecules for the IGF-I signaling. To learn the involvement of IRS-1 and IRS-2 in the bone anabolic action of PTH in vivo, IRS-1-/- and IRS-2-/- mice and their respective wild-type littermates were given daily injections of PTH (80 mug/kg) or vehicle for 4 wk. In the wild-type mice, the PTH injection increased bone mineral densities of the femur, tibia, and vertebrae by 10-20% without altering the serum IGF-I level. These stimulations were similarly seen in IRS-2-/- mice; however, they were markedly suppressed in IRS-1-/- mice. Although the PTH anabolic effects were stronger on trabecular bones than on cortical bones, the stimulations on both bones were blocked in IRS-1-/- mice but not in IRS-2-/- mice. Histomorphometric and biochemical analyses showed an increased bone turnover by PTH, which was also blunted by the IRS-1 deficiency, though not by the IRS-2 deficiency. These results indicate that the PTH bone anabolic action is mediated by the activation of IRS-1, but not IRS-2, as a downstream signaling of IGF-I that acts locally as an autocrine/paracrine factor.
Cite
Citations (93)
The effects of methandrostenolone (M) and testosterone propionate (TP) were studied in hypophysectomized rats with or without supplementary treatment with growth hormone (GH). Dexamethasone (DEX), an anti-anabolic agent, and A-norprogesterone (ANP), a specific anti-androgen, were used to disassociate anabolic from androgenic activity. Qualitative differences in the actions of M and TP were evident. M required GH to stimulate growth of the levator ani muscle (LA), ventral prostate (VP) and seminal vesicles (SV) of hypophysectomized rats. whereas TP did not. Neither compound induced body weight gain in the absence of GH. GH alone accelerated body growth but did not influence relative organ or muscle weight. The effects of combined M and GH on LA weight were antagonized by DEX but not by ANP, whereas LA stimulation by TP plus GH was antagonized slightly by both ANP and DEX. Growth of the SV and VP induced by M plus GH was inhibited by either DEX or ANP whereas that by TP plus GH was only prevented by ANP. Thus, M is primarily an anabolic agent, requiring GH for all of its effects. In this regard M is effectively antagonized by anti-anabolic agents such as DEX. TP also requires GH for its anabolic action but exerts primarily androgenic activity on the LA, SA and VP. These latter actions are antagonized by an anti-androgen; ANP. (Endocrinology90: 1396, 1972)
Testosterone propionate
Anabolic Agents
Cite
Citations (13)
We tested whether GH is required for the anabolic effect of PTH on bone, using sham-operated (sham) and hypophysectomized (HX) young male rats. HX rats were supplemented daily with 3% sucrose water, T4, and corticosterone. Rats received vehicle or human PTH-(l-34) at 8 μg/100 g, sc, once daily, alone or in combination with rat or ovine GH at 0.2 mg/100 g, sc, twice daily or 12 ng ovine GH/100 g-day by continuous sc infusion. After 12 days, rats were sedated, and blood, femurs, and tibias were removed. Femur trabecular and cortical bone calcium (Ca), dry weight (DW), and hydroxyproline were measured. PTH increased bone Ca, DW, and hydroxyproline in shams by approximately 30%, but consistently failed to induce an anabolic response in HX rats. GH alone stimulated systemic growth in HX rats and increased their bone Ca and DW by 2-fold. The anabolic effect of PTH was restored in HX rats given both PTH and GH. Total bone mass in these rats was approximately 20% more (P < 0.05) than the bone mass of rats given GH alone. When food was restricted in shams to limit systemic growth, PTH still induced an increase in bone mass. We conclude that GH or GH-dependent factors, such as insulin-like growth factor-I, which increases in PTH-treated bones in vitro, are required for the anabolic response of bone to PTH in vivo. (Endocrinology127: 1804–1810, 1990)
Hydroxyproline
Cite
Citations (73)
OBJECTIVES The physiological effects of oestrogens on bone in men were largely unanticipated until recently, when oestrogen deficiency in males with aromatase deficiency and oestrogen resistance was found to cause osteoporosis and delayed fusion of epiphyses despite sufficient serum testosterone. This raises the possibility that in normal men oestrogens rather than androgens are of physiological importance in bone maturation. In the present study, we examined the association of serum oestradiol (E2) compared to that of free testosterone (FT) with bone mineral density (BMD) in normal men. The effect of oestrogen receptor (ER) gene polymorphism on BMD in men was also addressed. SUBJECTS Eighty‐one Thai men aged 20–79 years. All were healthy and did not take medication which may affect calcium and bone metabolism. BMD was assessed by DEXA. Dietary calcium was assessed by a 3‐day dietary record. Serum E2 and FT concentrations were measured by radioimmunoassay. Polymorphism at intron 1 of the α isoform of ER gene was determined by PCR–RFLP. Small p represents the presence of the restriction site while capital P indicates the absence of the restriction site. RESULTS Serum FT decreased with increasing age ( r = −0.58, P < 0.0001) while E2 did not. However, there was a positive association between E2 and FT ( r = 0.28, P < 0.05). Serum FT was related to BMD at femoral neck ( r = 0.26, P < 0.05) and Ward's triangle ( r = 0.30, P < 0.01) while E2 was related to BMD at anteroposterior (AP) lumbar spine ( r = 0.29, P < 0.05), femoral neck ( r = 0.23, P < 0.05) and femoral trochanter ( r = 0.27, P < 0.05). Besides FT and E2, age, body weight, fat mass and fat‐free mass were also correlated to BMD at various skeletal sites. Using stepwise multiple linear regression to control for the confounding effects among these factors, fat‐free mass was found to be strongly associated with BMD at most skeletal sites. Serum E2 was related to BMD independently of other factors including FT at AP lumbar spine ( r = 0.22, P < 0.05), femoral neck ( r = 0.26, P < 0.01), femoral trochanter ( r = 0.22, P < 0.05) and Ward's triangle ( r = 0.26, P < 0.01) while serum FT was not associated with BMD at any site after controlling for E2 and other related factors. Concerning ERα gene polymorphism, 27 (33.3%) of the subjects had pp genotype, while 42 (51.9%) and 12 (14.8%) Pp and PP genotypes, respectively. After controlling for age, body weight, fat mass, fat‐free mass, calcium intake, FT and E2, the presence of P allele was associated with higher BMD at AP L2‐L4 ( P < 0.05). CONCLUSIONS Serum oestradiol is more related to bone mass than free testosterone in normal men. Oestrogen‐receptor gene polymorphism is also associated with bone mass in men independently of oestradiol levels. Serum oestradiol together with oestrogen‐receptor genotype may partly determine bone mass in males.
Estrogen receptor alpha
Bone remodeling
Cite
Citations (179)
Feeding mice an arginine-deficient diet decreased plasma concentrations of arginine, citrulline and ornithine in the females and arginine in the males, abolishing the sexual dimorphic pattern of these amino acids found in mice fed the standard diet. In addition, the restriction of dietary arginine produced a marked decrease in body and renal weights as well as in the activity of renal ornithine decarboxylase, decreases that were gender dependent since they were observed exclusively in males. The fact that these changes were not associated with the decrease in the circulating levels of testosterone and that the dietary arginine restriction prevented the body weight gain induced by testosterone treatment of female mice fed the standard diet indicates that dietary arginine is required for the anabolic action of androgens. Moreover, under certain conditions that could compromise the renal synthesis of arginine, as in the compensatory renal hypertrophy that follows unilateral nephrectomy, the myotrophic effect of testosterone was transiently impaired. The results also revealed that arginine deficiency produced an opposite effect in the expression of IGF-I and IGF-binding protein 1 in the liver and kidney. Taken together, our results indicate that dietary arginine may be relevant to the anabolic action of testosterone, and suggest that this effect may be mediated by changes in the insulin-like growth factor system.
Testosterone propionate
Cite
Citations (17)
Cite
Citations (27)
Cite
Citations (5)
Knockout mouse
Leptin receptor
Cite
Citations (17)
Different anabolic steroids can exercise different effects on the pituitary-gonadal axis in males. During a pilot study regarding the possible beneficial effect of the anabolic steroid nandrolondecanoate (ND) on bone metabolism in patients with rheumatoid arthritis additional endocrinological parameters were studies. A significant decrease was found in the serum levels of testosterone, androstenedione and FSH and the ratio of testosterone/oestradiol. There was a significant increase in the serum levels of oestrone. The levels of oestradiol, SHBG, LH and cortisol remained unchanged. An inhibitory effect of ND on testicular testosterone secretion is assumed. The decrease in androstenedione levels is explained by the diminished testosterone secretion. The rise in oestrone levels is explained by peripheral aromatizing of ND to oestrogens. The presented findings are in accordance with the hypothesis that sex steroids can act directly on the pituitary resulting in selective FSH and LH secretion. The possible role of the ratio testosterone/oestradiol in controlling gonadotrophin output is discussed.
Cite
Citations (30)
ABSTRACT Adult male rats were administered 19-nortestosterone phenylpropionate (NTPP), methandrostenolone (MA) (2 mg/100 g/day), cortisol (1 mg/100 g/day) and a combination of these steroids for 10 consecutive days. Cortisol caused a decrease in the adrenal weight on the 5th day and this effect was partially inhibited by NTPP or MA on the 8th and 11th day. The adrenal cholesterol content fell after NTPP on the 5th, 8th and 11th day, after cortisol treatment on the 8th and 11th day, and after MA on the 11th day. The cholesterol depleting effect of cortisol was counteracted only by simultaneous treatment with NTPP on the 11th day. The decrease in wet and dry weight of adrenals and of their nitrogen and protein content induced by the injection of cortisol for 10-days was markedly inhibited by the simultaneous administration of NTPP or MA. Neither of these anabolic-androgenic steroids affected the enhanced water retention in the adrenals caused by cortisol. NTPP or MA alone did not influence the parameters mentioned above.
Cite
Citations (2)