Suboptimal health status and psychological symptoms among Chinese college students: a perspective of predictive, preventive and personalised health.

BACKGROUND: Suboptimal health status (SHS) is an intermediate health status between health and illness, a syndrome characterised by the perception of health complaints, general weakness and low energy. This study aimed to investigate the prevalence of SHS and the correlation between SHS and psychological symptoms among Chinese college students and to identify the SHS-related risk factors from the perspective of predictive, preventive and personalised medicine (PPPM). METHODS: A cross-sectional study was conducted among 4119 college students who were enrolled from Taishan Medical University and Baoji Vocational and Technical College in the eastern and western areas of China. SHS levels of the participants were measured by an established self-reporting Suboptimal Health Status Questionnaire-25 (SHSQ-25). Psychosomatic conditions were estimated by the self-rating Symptom Checklist-90 (SCL-90) scale. Spearman correlation analysis was applied to analyse the relationship between SHSQ-25 scores and SCL-90 estimates. Logistic regression analysis was applied for multivariate analysis. RESULTS: The prevalence of SHS was 21.0% (864/4119), with 23.3% (701/3005) for female students and 14.6% (163/1114) for male students. The prevalence of general positive psychological symptom was 14.2% (586/4119), with 15.6% (470/3005) for female students and 10.4% (116/1114) for male students. A strong correlation was identified between SHS score and SCL-90 estimates, with the correlation coefficient (r) of 0.719. Logistic regression showed that variables significantly associated with SHS were somatisation (adjusted odds ratio (aOR) = 3.185, 95% confidence interval [CI] = 2.048-4.953), obsessive-compulsive (aOR = 3.518, 95% CI = 2.834-4.368), interpersonal sensitivity (aOR = 1.883, 95% CI = 1.439-2.463) and depression (aOR = 1.847, 95% CI = 1.335-2.554). CONCLUSIONS: Our findings confirm that there is a high prevalence of SHS among college students and there is a strong association between SHS and psychological symptoms among Chinese college students. High susceptibility of SHS occurs particularly in vulnerable groups: female students, sophomore students, medical students and students from rural area. Identification of SHS and prompt application of personalised psychological health-supporting activities will promote college students' health status.

Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models.

Purpose: Radium-223 dichloride (radium-223, Xofigo), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models.Experimental Design: Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups (n = 12-17) based on lesion grade and/or serum PSA level and administered radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Soft tissue tumors were observed macroscopically at sacrifice. Tibiae were analyzed by gamma counter, micro-CT, autoradiography and histology.Results: Radium-223 inhibited tumor-induced osteoblastic bone growth and protected normal bone architecture, leading to reduced bone volume in LNCaP and abiraterone-resistant LuCaP 58 models. Furthermore, radium-223 resulted in lower PSA values and reduced total tissue and tumor areas, indicating that treatment constrains prostate cancer growth in bone. In addition, radium-223 suppressed abnormal bone metabolic activity as evidenced by decreased number of osteoblasts and osteoclasts and reduced level of the bone formation marker PINP. Mode-of-action studies revealed that radium-223 was deposited in the intratumoral bone matrix. DNA double-strand breaks were induced in cancer cells within 24 hours after radium-223 treatment, and PSA levels were significantly lower 72 hours after treatment, providing further evidence of the antitumor effects.Conclusions: Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathologic bone formation in tumor microenvironment of osseous CRPC growth in mice. Clin Cancer Res; 23(15); 4335-46. ©2017 AACR.

Expression of metastasin S100A4 is essential for bone resorption and regulates osteoclast function.

OBJECTIVE: S100A4 is a Ca-binding protein that regulates cell growth, survival, and motility. The abundant expression of S100A4 in rheumatiod arthritis contributes to the invasive growth of joint tissue and to bone damage. In the present study, we analysed the role of S100A4 in bone homeostasis. METHODS: Peripheral quantitative computed tomography and histomorphometric analysis were performed in mice lacking the entire S100A4 protein (S100A4KO) and in wild-type (WT) counterparts treated with shRNA-lentiviral constructs targeting S100A4 (S100A4-shRNA). Control groups consisted of sex-matched WT counterparts and WT mice treated with a non-targeting RNA construct. RESULTS: S100A4 deficiency was associated with higher trabecular and cortical bone mass, increased number and thickness of trabeculi combined with larger periosteal circumference and higher predicted bone strength. S100A4 inhibition by shRNA led to an increase in cortical bone in WT mice. S100A4-deficieny was associated with a reduced number of functional osteoclasts. S100A4KO and S100A4-shRNA-treated bone marrow progenitors gave rise to a large number of small TRAP+ cells with few nuclei and few pseudopodial processes. Poor osteoclastogenesis and the low resorptive capacity in S100A4Ko mice may be linked to low levels of surface integrins, impaired adhesion capacity, and poor multinucleation in S100A4-deficient osteoclasts, as well as a low content of proteolytic enzymes cathepsin K and MMP3 and MMP9 to break down the organic matrix. CONCLUSION: S100A4 emerges as a negative regulator of bone metabolism potentially responsible for the excessive bone turnover in conditions marked by high levels of S100A4 protein, such as inflammation and rheumatoid arthritis.

ZP2307, a novel, cyclic PTH(1-17) analog that augments bone mass in ovariectomized rats.

Daily injections of human parathyroid hormone (1-34), hPTH(1-34), provide a highly effective treatment option for severe osteoporosis. However, PTH analogs shorter than 28 amino acids do not retain any bone augmenting potential. Here, we present ZP2307 ([Ac5c¹, Aib³, Leu8, Gln¹°, Har¹¹, Ala¹², Trp¹4, Asp¹7]PTH(1-17)-NH2), a novel, chemically modified and cyclized hPTH(1-17) analog, that augments bone mass in ovariectomized, osteopenic rats. Subcutaneous administration of this structurally constrained, K¹³-D¹7 side-chain-to-side-chain cyclized peptide reversed bone loss and increased bone mineral density (BMD) up to or above baseline levels in rat long bones and vertebrae. Highly significant effects of ZP2307 were achieved at doses of 40-320 nmol/kg. Micro-CT and histomorphometric analyses showed that ZP2307 improved quantitative and qualitative parameters of bone structure. Biomechanical testing of rat femora confirmed that ZP2307 dramatically increased bone strength. Over a broad maximally effective dose range (40-160 nmol/kg) ZP2307 did not increase serum concentrations of ionized free calcium above normal levels. Only at the highest dose (320 nmol/kg) ZP2307 induced hypercalcemic calcium levels in the ovariectomized rats. To our knowledge ZP2307 is the smallest PTH peptide analog known to exert augmentation of bone. Our findings suggest that ZP2307 has the potential to effectively augment bone mass over a broad dose range without a concomitant increase in the serum concentration of ionized free calcium above the normal range.

Effects of diet-induced obesity and voluntary wheel running on bone properties in young male C57BL/6J mice.

Both physical activity and body mass affect bone properties. In this study we examined how diet-induced obesity combined with voluntary physical activity affects bone properties. Forty 7-week-old male C57BL/6J mice were assigned to four groups evenly: control diet (C), control diet + running (CR), high-fat diet (HF, 60% energy from fat), and high-fat diet + running (HFR). After 21-week intervention, all mice were killed and the left femur was dissected for pQCT and mechanical measurements. Body mass increased 80% in HF and 62% in HFR, with increased epididymal fat pad weight and impaired insulin sensitivity. Except for total and trabecular volumetric bone mineral density (BMD), bone traits correlated positively with body mass, fat pad, leptin, and osteoprotegerin. Obesity induced by a high-fat diet resulted in increased femoral bone cross-sectional area, mineral content (BMC), polar moment of inertia, and mechanical parameters. Of the mice accessing the running wheel, those fed the control diet had thinner cortex and less total metaphyseal BMC and BMD, with enlarged metaphyseal marrow cavity, whereas mice fed the high-fat diet had significantly higher trabecular BMD and smaller marrow cavity. However, the runners had a weaker femoral neck as indicated by decreased maximum flexure load. These results suggest that voluntary running exercise affects bone properties in a site-specific manner and that there is a complex interaction between physical activity and obesity. Thus, both diet and exercise should be considered when optimizing the effects on body composition and bone, even though the underlying mechanisms remain partly unknown.

Overexpression of human hydroxysteroid (17beta) dehydrogenase 2 induces disturbance in skeletal development in young male mice.

To understand the function of human hydroxysteroid (17beta) dehydrogenase 2 (HSD17B2) in the peripheral tissues in vivo, we studied the bone development in transgenic male mice ubiquitously expressing human HSD17B2. Bones of HSD17B2TG and WT males (26 days and 2 and 6 mo old) were analyzed by pQCT and histomorphometry, and data were correlated with serum testosterone (T), IGF-I, and osteocalcin concentrations. At the age of 26 days, the body weight of HSD17B2TG males was significantly lower, and the lengths of the tibia and femur of the HSD17B2TG males were significantly shorter. Histomorphometric and pQCT analyses showed lower trabecular and cortical BMD, a markedly smaller area of cortical bone at both of the diaphyses, and a smaller percentage of trabecular bone volume and thickness in the HSD17B2TG males. The data suggested slower osteoblast differentiation and a slower bone formation rate of femoral diaphysis on the periosteum but faster on the endocortical surface in HSD17B2TG males. The altered bone parameters were correlated with low serum T, IGF-I, and osteocalcin concentrations at the prepubertal age. Interestingly, after puberty, the bone parameters analyzed in the adult HSD17B2TG males were mostly normal, consistent with the normal body weight and normalized serum concentrations of IGF-I and T. In conclusion, HSD17B2TG males presented with growth retardation and a decreased bone formation rate at prepubertal age. These changes were associated with lower serum IGF-I, osteocalcin, and T concentrations. It is concluded that the enforced constitutive expression of HSD17B2 disturbs the coordinated action of IGF-I and sex steroids essential for pubertal bone growth.

Short-term changes in serum PINP predict long-term changes in trabecular bone in the rat ovariectomy model.

Serum procollagen I N-terminal propeptide (PINP) is a sensitive bone formation marker in humans. We have developed a nonradioactive immunoassay for rat PINP and studied PINP as a bone formation marker in the rat ovariectomy (OVX) model. Two OVX studies were performed with 3-month-old rats, both including measurement of PINP, C-terminal cross-linked telopeptide of type I collagen (CTX), and N-terminal mid-fragment of osteocalcin. A pilot 14-day study contained a sham-operated control group and an OVX group, and an extensive 8-week study contained a sham-operated control group and OVX groups receiving vehicle and 17 beta-estradiol (E2, 10 microg/kg/day s.c.). The bone markers were measured before the operation and at days 2, 4, 7, 10, and 14 in the pilot study and before the operations and at 2 and 8 weeks in the extensive study. Trabecular bone parameters were determined by peripheral quantitative computed tomography and histomorphometry from tibial metaphysis in the extensive study. The rat PINP immunoassay had the following characteristics: intra-assay coefficient of variation (CV) 2.8%, interassay CV 7.5%, dilution linearity 95%, and recovery 107%. PINP increased significantly during the first 2 weeks after OVX and returned to sham level at 8 weeks. E2 prevented the increase caused by OVX. Changes in PINP at 2 weeks correlated strongly with changes in CTX and osteocalcin at 2 weeks and with trabecular bone parameters at 8 weeks. As a conclusion, short-term changes in PINP predict long-term changes in trabecular bone parameters, suggesting that PINP is a reliable marker of bone formation in the rat OVX model.

Secreted tartrate-resistant acid phosphatase 5b is a Marker of osteoclast number in human osteoclast cultures and the rat ovariectomy model.

PURPOSE: To study the effects of estrogen withdrawal on osteoclast number and osteoclast activity in the rat ovariectomy (OVX) model. METHODS: We first cultured human CD34+ osteoclast precursor cells on bovine bone slices, allowing them to differentiate into mature resorbing osteoclasts. Secreted tartrate-resistant acid phosphatase 5b (TRACP 5b) and C-terminal cross-linked telopeptides of type I collagen (CTX) were determined from the culture medium. TRACP 5b correlated strongly with osteoclast number and CTX with osteoclast activity, facilitating their subsequent use in the rat OVX model. An 8 week OVX study was then performed including sham-operated rats receiving vehicle, OVX rats receiving vehicle, and OVX rats receiving 10 microg/kg/day 17 beta-estradiol (E2). Trabecular bone parameters were determined from the tibial metaphysis using peripheral quantitative computed tomography and histomorphometry. Osteoclast number was normalized with bone perimeter (N.Oc/B.Pm) and tissue area (N.Oc/T.Ar, indicating absolute number of osteoclasts). TRACP 5b and CTX were determined from fasting serum samples. RESULTS: Trabecular bone parameters indicated substantial bone loss after OVX that was prevented by E2. N.Oc/B.Pm increased after OVX, while N.Oc/T.Ar and TRACP 5b decreased, and TRACP 5b correlated strongly with N.Oc/T.Ar. However, CTX values increased after OVX, and the "resorption index" CTX/TRACP 5b showed more substantial changes than either CTX or TRACP 5b alone. CONCLUSION: These results show that TRACP 5b is a reliable marker of osteoclast number, and the index CTX/TRACP 5b is a useful parameter in rat OVX model. The high elevation of CTX/TRACP 5b values by OVX demonstrates that estrogen withdrawal generates high activity of osteoclasts in the rat OVX model.

High dietary phosphate intake reduces bone strength in the growing rat skeleton.

UNLABELLED: Nutrition influences peak bone mass development in early adulthood. The effect of high dietary phosphate intake on the growing skeleton of 1-month-old male rats (n = 30) was assessed in an 8-week intervention. High dietary phosphate intake increased bone remodeling and impaired bone material properties, diminishing bone mechanical strength. INTRODUCTION: High dietary phosphate intake is typical in the Western diet. Abundant phosphate intake enhances parathyroid secretion and bone metabolism. To study the influence of high dietary phosphate intake on growing bone homeostasis and structure, we submitted growing rats to experimental diets that varied in their phosphate content. MATERIALS AND METHODS: One-month-old intact male rats (n = 30) were fed a control diet (Ca:P 1:1) or an experimental diet of either Ca:P 1:2 or Ca:P 1:3 for 8 weeks. At the beginning and the end of the study period, the right femurs were measured using DXA. Double labeling with tetracycline injection was performed 12 and 2 days before death. After death, hind legs were cut loose. Left femurs were processed for histomorphometry. Right femurs were measured with pQCT. Mechanical testing was performed on the right femoral neck and tibial shaft. Six right tibias were analyzed with microCT. Serum PTH, calcium, and phosphate contents were analyzed. RESULTS: High-phosphate intake impaired growth of the animal, limited bone longitudinal growth, and restricted femur BMC and BMD build-up. Osteoclast number, osteoblast perimeter, and mineral apposition rate were increased, and trabecular area and width were decreased. Phosphate decreased femur midshaft total bone BMD, cortical bone BMD, and mean cortical thickness. High-phosphate diet reduced femoral neck and tibial shaft ultimate strength and tibia stiffness and toughness. In addition, serum PTH increased. CONCLUSIONS: High dietary phosphate intake reduced growth, skeletal material, and structural properties and decreased bone strength in growing male rats. Adequate calcium could not overcome this.

Death of osteocytes turns off the inhibition of osteoclasts and triggers local bone resorption.

Osteocytes have been suggested to play a role in the regulation of bone resorption, although their effect on bone turnover has remained controversial. In order to study this open question, we developed an organ culture system based on isolated rat calvaria, where the osteocyte viability and its effect on osteoclastic bone resorption can be monitored. Our results suggest that osteocytes are constitutively negative regulators of osteoclastic activity. Osteoclasts, which were cultured on calvarial slices with living osteocytes inside, failed to form actin rings which are the hallmarks of resorbing cells. A similar inhibitory effect was also achieved by the conditioned medium obtained from calvarial organ culture, suggesting that living osteocytes produce yet unrecognized osteoclast inhibitors. On the contrary, when osteocyte apoptosis was induced, this inhibitory effect disappeared and strong osteoclastic bone resorption activity was observed. Thus, local apoptosis of osteocytes may play a major role in triggering local bone remodeling.

Estrogen responsiveness of bone formation in vitro and altered bone phenotype in aged estrogen receptor-alpha-deficient male and female mice.

OBJECTIVE: Although the beneficial effects of estrogen on bone are well known, the roles of estrogen receptors (ERs) in mediating these effects are not fully understood. METHODS: To study the effects of long-term ER alpha deficiency, bone phenotype was studied in aged ER alpha knockout (ERKO) mice. In addition, ERKO osteoclasts and osteoblasts were cultured in vitro. DESIGN AND RESULTS: Histomorphometric analysis showed that the trabecular bone volume and thickness were significantly increased and the rate of bone formation enhanced in both male and female ERKO mice in comparison to the wild-type animals. In ERKO males, however, the bones were thinner and their maximal bending strengths decreased. Consistent with previous reports, the bones of knockout mice, especially of female mice, were shorter than those of wild-type mice. In addition, the growth plates were totally absent in the tibiae of aged ERKO females, whereas the growth plate cartilages were detectable in wild-type females as well as in all the males. Analysis of cultured bone marrow cells from 10- to 12-week-old mice demonstrated that 17 beta-estradiol could stimulate osteoblastic differentiation of bone marrow cells derived from ERKO mice relatively to the same extent as those derived from wild-type mice. This was demonstrated by increases in synthesis of type I collagen, activity of alkaline phosphatase and accumulation of calcium in cultures. Total protein content was, however, reduced in ERKO osteoblast cultures. CONCLUSIONS: These results show altered bone phenotype in ERKO mice and demonstrate the stimulatory effect of estrogen on osteoblasts even in the absence of full-length ER alpha.

Skeletal changes in transgenic male mice expressing human cytochrome p450 aromatase.

UNLABELLED: In this study, we showed that overexpressing P450 aromatase in male mice can increase bone mass and strengthen the tibia. Probably as a result of the action of products of local estrogen biosynthesis at different stages of life, the increased bone mass in young mice was induced by decreased bone turnover, but in aged animals, it was induced by increased bone formation. INTRODUCTION: To understand the skeletal responses to the testosterone/estrogen balance, especially to excess estrogen produced by extragonadal biosynthesis, we investigated the bone changes in transgenic mice overexpressing human aromatase. MATERIALS AND METHODS: Sixty-one young (40 days) and 25 aged (9 months) transgenic and wildtype (WT) mice were used. Bone samples were analyzed using pQCT, histomorphometry, and mechanical testing. Concentrations of testosterone (T) and estradiol (E2) were measured in serum and testicular interstitial fluid. RESULTS AND CONCLUSIONS: Young P450 aromatase-positive (AROM+) mice had much higher trabecular BMD in the proximal tibia than WT mice, and the tissue area was significantly smaller in the former. Histomorphometric data further showed that the longitudinal growth rate of the tibia was decreased in AROM+ mice, and the bone formation rate (BFR) was decreased in trabecular bone and periosteum. All the changes were more striking in males than in females. Aged male AROM+ mice showed similar changes in trabecular bone as young animals, but their BFR was obviously increased. Another dramatic change was in the tibias of aged AROM+ mice: length was shorter (-23.2%), whereas ash weight was much heavier (+24.0%), and bending strength was markedly higher (+21.2%) compared with WT mice. The concentration of T was decreased in both serum and testicular interstitial fluid in young AROM+ mice versus WT animals; E2 levels were increased only in the testes of young AROM+ mice. However, in aged AROM+ mice, the levels of T and E2 were highly increased in both serum and testis versus WT animals. These results are in agreement with the suggestion that enhanced production of estrogen from testosterone in the peripheral tissues as a result of aromatase action can affect skeletal growth and strengthen bone in males. The results also suggest a marked difference in response between femur and tibia.

A novel immunoassay for the determination of tartrate-resistant acid phosphatase 5b from rat serum.

Osteoclasts secrete tartrate-resistant acid phosphatase 5b (TRACP 5b) into the circulation. We have developed an immunoassay for the determination of rat TRACP 5b activity. Intra-assay variation of the immunoassay was 4.5%, interassay variation was 3.8%, dilution linearity was 104.6 +/- 7.6%, and recovery of recombinant rat TRACP was 99.1 +/- 5.8%. We studied serum TRACP 5b as a marker of bone resorption using orchidectomized (ORC) rats as a model for osteoporosis and age-matched sham-operated rats as controls in a 6-month study. After the operation, trabecular bone mineral density decreased significantly more in the ORC group than in the sham group, whereas cortical bone mineral density increased similarly in both groups. Serum TRACP 5b activity was significantly elevated within the first week after ORC, returned to the control level in the third week, and was not increased above the sham level at any of the later time points. At 6 months, trabecular bone volume was 80% lower in ORC rats than in controls. Osteoclast number per trabecular bone perimeter was slightly increased, but the absolute number of osteoclasts in trabecular bone was significantly decreased. These results suggest that absolute bone resorption is increased within the first week after ORC. Later, it is decreased because there is less bone to be resorbed. However, relative bone resorption (compared with the amount of remaining bone) is still increased, leading to further bone loss. We conclude that serum TRACP 5b is a useful marker for monitoring changes in the bone resorption rate in rat ORC model.