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Urszula T Iwaniec and Russell T Turner

Weight-dependent loading of the skeleton plays an important role in establishing and maintaining bone mass and strength. This review focuses on mechanical signaling induced by body weight as an essential mechanism for maintaining bone health. In addition, the skeletal effects of deviation from normal weight are discussed. The magnitude of mechanical strain experienced by bone during normal activities is remarkably similar among vertebrates, regardless of size, supporting the existence of a conserved regulatory mechanism, or mechanostat, that senses mechanical strain. The mechanostat functions as an adaptive mechanism to optimize bone mass and architecture based on prevailing mechanical strain. Changes in weight, due to altered mass, weightlessness (spaceflight), and hypergravity (modeled by centrifugation), induce an adaptive skeletal response. However, the precise mechanisms governing the skeletal response are incompletely understood. Furthermore, establishing whether the adaptive response maintains the mechanical competence of the skeleton has proven difficult, necessitating the development of surrogate measures of bone quality. The mechanostat is influenced by regulatory inputs to facilitate non-mechanical functions of the skeleton, such as mineral homeostasis, as well as hormones and energy/nutrient availability that support bone metabolism. Although the skeleton is very capable of adapting to changes in weight, the mechanostat has limits. At the limits, extreme deviations from normal weight and body composition are associated with impaired optimization of bone strength to prevailing body size.

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Kenneth A Philbrick, Carmen P Wong, Adam J Branscum, Russell T Turner, and Urszula T Iwaniec

Leptin, the protein product of the ob gene, is essential for normal bone growth, maturation and turnover. Peripheral actions of leptin occur at lower serum levels of the hormone than central actions because entry of leptin into the central nervous system (CNS) is limited due to its saturable transport across the blood–brain barrier (BBB). We performed a study in mice to model the impact of leptin production associated with different levels of adiposity on bone formation and compared the response with well-established centrally mediated actions of the hormone on energy metabolism. Leptin was infused (0, 4, 12, 40, 140 or 400 ng/h) for 12 days into 6-week-old female ob/ob mice (n = 8/group) using sc-implanted osmotic pumps. Treatment resulted in a dose-associated increase in serum leptin. Bone formation parameters were increased at EC50 infusion rates of 7–17 ng/h, whereas higher levels (EC50, 40–80 ng/h) were required to similarly influence indices of energy metabolism. We then analyzed gene expression in tibia and hypothalamus at dose rates of 0, 12 and 140 ng/h; the latter dose resulted in serum leptin levels similar to WT mice. Infusion with 12 ng/h leptin increased the expression of genes associated with Jak/Stat signaling and bone formation in tibia with minimal effect on Jak/Stat signaling and neurotransmitters in hypothalamus. The results suggest that leptin acts peripherally to couple bone acquisition to energy availability and that limited transport across the BBB insures that the growth-promoting actions of peripheral leptin are not curtailed by the hormone’s CNS-mediated anorexigenic actions.

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Russell T Turner, Kenneth A Philbrick, Amida F Kuah, Adam J Branscum, and Urszula T Iwaniec

Leptin, critical in regulation of energy metabolism, is also important for normal bone growth, maturation and turnover. Compared to wild type (WT) mice, bone mass is lower in leptin-deficient ob/ob mice. Osteopenia in growing ob/ob mice is due to decreased bone accrual, and is associated with reduced longitudinal bone growth, impaired cancellous bone maturation and increased marrow adipose tissue (MAT). However, leptin deficiency also results in gonadal dysfunction, disrupting production of gonadal hormones which regulate bone growth and turnover. The present study evaluated the role of increased estrogen in mediating the effects of leptin on bone in ob/ob mice. Three-month-old female ob/ob mice were randomized into one of the 3 groups: (1) ob/ob + vehicle (veh), (2) ob/ob + leptin (leptin) or (3) ob/ob + leptin and the potent estrogen receptor antagonist ICI 182,780 (leptin + ICI). Age-matched WT mice received vehicle. Leptin (40 µg/mouse, daily) and ICI (10 µg/mouse, 2×/week) were administered by subcutaneous injection for 1 month and bone analyzed by X-ray absorptiometry, microcomputed tomography and static and dynamic histomorphometry. Uterine weight did not differ between ob/ob mice and ob/ob mice receiving leptin + ICI, indicating that ICI successfully blocked the uterine response to leptin-induced increases in estrogen levels. Compared to leptin-treated ob/ob mice, ob/ob mice receiving leptin + ICI had lower uterine weight; did not differ in weight loss, MAT or bone formation rate; and had higher longitudinal bone growth rate and cancellous bone volume fraction. We conclude that increased estrogen signaling following leptin treatment is dispensable for the positive actions of leptin on bone and may attenuate leptin-induced bone growth.

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Russell T Turner, Kenneth A Philbrick, Carmen P Wong, Dawn A Olson, Adam J Branscum, and Urszula T Iwaniec

Leptin-deficient ob/ob mice are morbidly obese and exhibit low total bone mass and mild osteopetrosis. In order to disassociate the skeletal effects of leptin deficiency from those associated with morbid obesity, we evaluated bone mass, architecture, gene expression, and indices of bone turnover in WT mice, ob/ob mice allowed to feed ad libitum (ob/ob), and ob/ob mice pair-fed equivalent to WT mice (pair-fed ob/ob). Mice were maintained at 32 °C (thermoneutral) from 6 to 18 weeks of age to minimize differences in resting energy expenditure. ob/ob mice were heavier, had more abdominal white adipose tissue (WAT), and were hyperglycemic compared with WT mice. Femur length, bone mineral content (BMC) and bone mineral density, and midshaft femur cortical thickness were lower in ob/ob mice than in WT mice. Cancellous bone volume (BV) fraction was higher but indices of bone formation and resorption were lower in ob/ob mice compared with WT mice; reduced bone resorption in ob/ob mice resulted in pathological retention of calcified cartilage. Pair-fed ob/ob mice were lighter and had lower WAT, uterine weight, and serum glucose than ob/ob mice. Similarly, femoral length, BMC, and cortical thickness were lower in pair-fed ob/ob mice compared with ob/ob mice, as were indices of cancellous bone formation and resorption. In contrast, bone marrow adiposity, calcified cartilage, and cancellous BV fraction were higher at one or more cancellous sites in pair-fed ob/ob mice compared with ob/ob mice. These findings indicate that the skeletal abnormalities caused by leptin deficiency are markedly attenuated in morbidly obese ob/ob mice.

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Kenneth A Philbrick, Stephen A Martin, Amy R Colagiovanni, Adam J Branscum, Russell T Turner, and Urszula T Iwaniec

Impaired resorption of cartilage matrix deposited during endochondral ossification is a defining feature of juvenile osteopetrosis. Growing, leptin-deficient ob/ob mice exhibit a mild form of osteopetrosis. However, the extent to which the disease is (1) self-limiting and (2) reversible by leptin treatment is unknown. We addressed the first question by performing histomorphometric analysis of femurs in rapidly growing (2-month-old), slowly growing (4-month-old) and skeletally mature (6-month-old) wild-type (WT) and ob/ob male mice. Absent by 6 months of age in WT mice, cartilage matrix persisted to varying extents in distal femur epiphysis, metaphysis and diaphysis in ob/ob mice, suggesting that the osteopetrotic phenotype is not entirely self-limiting. To address the second question, we employed hypothalamic recombinant adeno-associated virus (rAAV) gene therapy to restore leptin signaling in ob/ob mice. Two-month-old mice were randomized to one of the three groups: (1) untreated control, (2) rAAV-Leptin or (3) control vector rAAV-green fluorescent protein and vectors injected intracerebroventricularly. Seven months later, rAAV-leptin-treated mice exhibited no cartilage in the metaphysis and greatly reduced cartilage in the epiphysis and diaphysis. At the cellular level, the reduction in cartilage was associated with increased bone turnover. These findings (1) support the concept that leptin is important for normal replacement of cartilage by bone, and (2) demonstrate that osteopetrosis in ob/ob mice is bone-compartment-specific and reversible by leptin at skeletal sites capable of undergoing robust bone turnover.

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Russell T Turner, Adam J Branscum, Carmen P Wong, Urszula T Iwaniec, and Emily Morey-Holton

The gravitostat is purported to function as a leptin-independent, osteocyte-dependent mechanism for regulation of energy balance. If correct, reduced activation of gravitostat signaling caused by prolonged sitting may contribute to obesity. The gravitostat concept is supported by reduced body mass in rodents following surgical implantation of weighted capsules. However, the procedure induces a confounding injury response. We, therefore, sought to confirm a gravitostat by decreasing (microgravity and simulated microgravity) or increasing (simulated gravity) weight using less invasive models (spaceflight, hindlimb unloading and centrifugation). We also evaluated changes in weight following non-surgical injury (radiation). Male rats (Wistar, Sprague–Dawley and Fischer 344) ranging in age from 5–12 weeks at launch and flown for 4–19 days in low Earth orbit exhibited slightly lower (4-day flight) or no difference (all other studies) in weight compared to ground controls. Rats subjected to inflight (1.0 G) or ground (1.04 G and 1.56 G) centrifugation during a 19-day mission did not differ in weight. In female rats (Fischer 344), spaceflight (14 days) did not alter ovariectomy-induced weight gain. Finally, hindlimb unloading resulted in weight loss in lean and obese mice. The aforementioned findings are inconsistent with outcomes predicted by a gravitostat namely increased mass during weightlessness and decreased mass when subjected to >1 G simulated gravity. Injury (dose-associated graded increases in radiation) mimicked the leptin-independent weight changes attributed to a gravitostat. Taken together, these findings do not support gravitostat regulation of energy balance and suggest injury/stress as an alternative mechanism for weight loss induced by weighted capsules.

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Russell T Turner, Michael Dube, Adam J Branscum, Carmen P Wong, Dawn A Olson, Xiaoying Zhong, Mercedes F Kweh, Iske V Larkin, Thomas J Wronski, Clifford J Rosen, Satya P Kalra, and Urszula T Iwaniec

Excessive weight gain in adults is associated with a variety of negative health outcomes. Unfortunately, dieting, exercise, and pharmacological interventions have had limited long-term success in weight control and can result in detrimental side effects, including accelerating age-related cancellous bone loss. We investigated the efficacy of using hypothalamic leptin gene therapy as an alternative method for reducing weight in skeletally-mature (9 months old) female rats and determined the impact of leptin-induced weight loss on bone mass, density, and microarchitecture, and serum biomarkers of bone turnover (CTx and osteocalcin). Rats were implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either recombinant adeno-associated virus encoding the gene for rat leptin (rAAV-Leptin, n=7) or a control vector encoding green fluorescent protein (rAAV-GFP, n=10) and sacrificed 18 weeks later. A baseline control group (n=7) was sacrificed at vector administration. rAAV-Leptin-treated rats lost weight (−4±2%) while rAAV-GFP-treated rats gained weight (14±2%) during the study. At study termination, rAAV-Leptin-treated rats weighed 17% less than rAAV-GFP-treated rats and had lower abdominal white adipose tissue weight (−80%), serum leptin (−77%), and serum IGF1 (−34%). Cancellous bone volume fraction in distal femur metaphysis and epiphysis, and in lumbar vertebra tended to be lower (P<0.1) in rAAV-GFP-treated rats (13.5 months old) compared to baseline control rats (9 months old). Significant differences in cancellous bone or biomarkers of bone turnover were not detected between rAAV-Leptin and rAAV-GFP rats. In summary, rAAV-Leptin-treated rats maintained a lower body weight compared to baseline and rAAV-GFP-treated rats with minimal effects on bone mass, density, microarchitecture, or biochemical markers of bone turnover.

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Lara H Sattgast, Adam J Branscum, Natali Newman, Steven W Gonzales, Mary Lauren Benton, Erich J Baker, Kathleen A Grant, Russell T Turner, and Urszula T Iwaniec

Insulin-like growth factor 1 (IGF-1) influences bone turnover. Transient decreases in IGF-I levels and/or bioavailability may contribute to the detrimental effects of alcohol on bone. The goals of this non-human primate study were to i) evaluate the 20-h response of bone turnover markers to ethanol consumption and ii) assess how ethanol consumption influences the relationship between IGF-1 and these markers. Osteocalcin (bone formation), carboxyterminal cross-linking telopeptide of type 1 collagen (CTX, bone resorption), IGF-1, and IGF binding protein 1 (IGFBP-1) were measured in plasma from male rhesus macaques (N = 10, 8.4 ± 0.3 years) obtained at 12:00, 16:00, and 06:00 h during two phases: pre-ethanol (alcohol-naïve) and ethanol access. During the ethanol access phase, monkeys consumed 1.5 g/kg/day ethanol (4% w/v) beginning at 10:00 h. Osteocalcin and CTX were lower, and the ratio of osteocalcin to CTX was higher at each time point during ethanol access compared to the pre-ethanol phase. Pre-ethanol marker levels did not vary across time points, but markers varied during ethanol access. IGF-1 levels, but not IGFBP-1 levels, varied during the pre-ethanol phase. In contrast, IGF-1 levels were stable during ethanol access but IGFBP-1 levels varied. There were positive relationships between IGF-1 and turnover markers during the pre-ethanol phase, but not during ethanol access. In conclusion, chronic ethanol consumption reduces levels of bone turnover markers and blocks the normal positive relationship between IGF-1 and turnover markers and alters the normal relationship between IGF-1 and IGFBP-1. These findings support the hypothesis that chronic alcohol consumption leads to growth hormone/IGF-1 resistance.