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Skeletal development is a complex event that requires a delicate balance between bone formation and bone resorption. Multiple transcription factors expressed in the bone-forming cells, osteoblasts, play crucial roles during the process of bone formation. Among them, ATF4 (Activating Transcription Factor 4) is a basic domain-leucine zipper transcriptional activator that is responsible for osteoblast differentiation, osteoblast-specific genes expression, synthesis of type I collagen, and osteoclast differentiation. Mice deficient for ATF4 are runted and exhibit severe skeletal dysplasia. Our laboratory has discovered Factor Inhibiting ATF4-mediated Transcription (FIAT), whose name was coined for its interaction with ATF4 and subsequent repression of ATF4-mediated osteocalcin gene transcription. FIAT is a leucine zipper nuclear molecule lacking a basic domain for DNA binding. We hypothesize that FIAT suppresses the bone-forming activities of osteoblasts by interacting with ATF4 and thereby blocking ATF4 attachment to the DNA to mediate downstream signalling pathways. To prove this hypothesis, we monitored the expression profiles of FIAT in parallel with ATF4 during osteoblastogenesis. Mechanism of FIAT repression of ATF4 was investigated through structure-function and mutation analysis. The physiological significance of FIAT expression in osteoblasts was studied through silencing FIAT in osteoblasts by RNA interference, as well as through characterization of two genetic mouse models: FIAT transgenic mice which overexpress FIAT in osteoblasts, and osteoblast-specific FIAT knockout mice. These studies showed that FIAT and ATF4 are co-expressed in osteoblasts, and that FIAT inhibition of matrix mineralization requires dimerization with ATF4 through the second leucine zipper. Furthermore, transgenic mice overexpressing FIAT exhibited osteopenia whereas FIAT knockout mice showed enhanced bone formation. These results support our hypothesis and demonstrate that FIAT is a key transcriptional repressor that modulates osteoblast function.

Osteoporosis is a significant public health problem for individuals over age 50 (55% are at risk), particularly for women. A key preventive strategy is increasing peak bone mass in youth. Limited information exists on the role that competitive sport activities can play in developing bone mass. Volleyball is a popular sport for girls and involves high impact activity and plyometric training. The purpose of the study was to compare bone mineral density (BMD) between high school and college competitive volleyball players to age matched controls. Relationships between BMD and age, and years of competitive play were also analyzed. The calcium intake, and time spent jumping in practice (volleyball players only) for each group were also assessed. Subject inclusion criteria were: no eating disorders, not amenorrhoeic, did not use calcium supplements (doctor recommended). The volleyball players followed the criteria above and played volleyball >7 months in a year. Subjects were 13 high school volleyball players (HSVB), 10 high school non-athletes (HSN), and 13 college volleyball players (CVB), and 13 college nonathlees (CN). The mean (+ SD) age, weight, body fat percentage, calcium intake, and years of competitive volleyball for the HSVB players were 16.2 + 1.3 yr, 67.5 + 8.0 kg, 27.2 ± 5.3 %, 1269.7 ± 581.7 mg, and 7.2 ± 1.2 yr. and for the CVB players were 19.5 + 1.0 yr, 74.2 ± 9.2 kg, 28.4 ± 4.7 %, 1059.6 ± 462.2 mg, and 8.5 ± 2.3 yr. respectively. The mean (+SD) age, weight, body fat percentage, and calcium intake for the HSN 16.2 ± 1.3 yr, 66.8 ± 12.4 kg, 34.7 + 6.1 %, and 857.9 + 469.5 mg and for the CN were 19.5 ± 1.0 yr, 73.9 + 9.1 kg, 40.1 + 4.4 %, and 1216.4 + 551.9 mg. Dual energy x-ray absorptiometry (DEXA) was used to determine the body composition and BMD at the following regions: AP spine, dual femur, and total body. The only significant descriptive difference was in percent body fat (P>0.05-0.01). The significant difference (P>0.01) between the athletes and non-athletes occurred in the AP spine (1.38 + 0.1 g.cm-2 and 1.20 ± 0.1 g•cm-2), dual femur (1.22 + 0.1 g•cm 2 and 1.05 ± 0.1 g•cm-2), and total body measurements (1.26 ± 0.1 g•cm 2 and 1.16 ± 0.1 ?cm-2). The athleticism and age was not significant for the BMD in the AP spine, total body, and dual femur. Likewise, the correlations between years playing volleyball and jumping in practice were not significant. The correlation between calcium intake in volleyball players and non-athletes showed no significant difference. In conclusion BMD is higher in volleyball players compared to non-athletes however there was no difference between the college and high school volleyball players. / School of Physical Education, Sport, and Exercise Science

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Discordance in bone mass between young adult swimmers and soccer players may be a direct result of differences in bone loading patterns that influence bone mineralization during growth. Our aim was to evaluate whether sports participation (soccer and swimming) had an independent effect on bone mass accrual at the hip and lumbar spine in adolescent female athletes. We recruited boys and girls 10 to 14-years of age from Corvallis, Albany, Sweet Home, Salem, Eugene, and the greater Portland area. Bone mineral content (BMC, g) and bone mineral density (BMD, g/cm²) of the proximal left hip, spine, and whole body were assessed by dual energy x-ray absorptiometry (Hologic QDR 4500A; Hologic Inc., Waltham, MA, USA). We used ANCOVA and report that baseline BMC and BMD values of girl soccer players at the greater trochanter were significantly higher compared to controls and the swim group, and femoral neck BMC was significantly greater than the swimmers. At baseline, all boy groups were similar at the hip and spine. After 12-months, ANCOVA was also used to assess absolute change for BMC and BMD at the hip and spine. The girl soccer players had significantly more BMC and BMD at the greater trochanter as well as total hip BMD and lumbar spine BMC compared to the swimmers, but not the controls. The girl control group showed a significantly greater 12-month change for femoral neck and greater trochanter BMC than swimmers. Overall, the girl swimmers demonstrated a lower accumulation of bone mass during the 12-month study period. As for the boys, soccer players had a significantly higher 12-month change for femoral neck BMC than swimmers, but were similar at the spine. There were no differences between the boy control subjects and the swimmers for 12-month change values at the hip and spine. While preliminary and limited by the small sample size, our results indicate that after controlling for growth, soccer players gained significantly more BMC at the femoral neck than swimmers. Furthermore, exposing the young skeleton to impact loading exercise has site-specific benefits at the hip whereas prolonged training in a non-weight bearing environment may compromise skeletal acquisition. / Graduation date: 2004

The CYP27B1 enzyme that synthesizes 1alpha,25-(OH) 2D, is expressed in chondrocytes, suggesting that local production of 1alpha,25-(OH)2D could play an autocrine or paracrine role in the differentiation of these cells. To test this hypothesis, we have engineered mutant mice that do not express the Cyp27b1 gene in chondrocytes. This led to increased width of the hypertrophic zone of the growth plate at E15.5, increased bone mass in neonatal long bones, and increased expression of the chondrocytic differentiation markers Indian Hedgehog and PTH/PTHrP receptor. VEGF mRNA levels were decreased, accompanied by decreased PECAM-1 immunostaining, suggesting a delay in vascularization. We have also engineered mice overexpressing a Cyp27b1 transgene in chondrocytes. The transgenic mice showed a partial mirror image phenotype compared to the tissue-specific inactivation model. These results support an autocrine/paracrine role of 1alpha,25-(OH) 2D in endochondral ossification and chondrocyte development in vivo. / The CYP24A1 enzyme is involved in the catabolic breakdown of 1alpha,25-(OH)2D but also synthesizes the 24R,25-(OH) 2D metabolite. Studies in chicken suggest a role for 24R,25-(OH) 2D in fracture repair. We induced stabilized transverse mid-diaphysial fractures of the tibia in four-month-old wild-type and Cyp24a1-deficient mice. Examination of the callus sections showed delayed hard callus formation in the homozygous mutant animals compared to wild-type littermates. RT-qPCR showed perturbed levels of type X collagen transcripts in mutant mice at 14 and 21 days post-fracture, reflecting the delayed healing. Rescue of the impaired healing by subcutaneous injection of 24R,25-(OH)2D3 normalized the histological appearance of the callus, static histomorphometric index and type X collagen mRNA expression, while 1alpha,25-(OH)2D 3 did not. These results show that Cyp24a1 deficiency delays fracture repair and strongly suggest that vitamin D metabolites hydroxylated at position 24, such as 24R,25-(OH)2D, play an important role in the mechanisms leading to normal fracture healing.

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