RESUMEN
PURPOSE: Obesity is thought to negatively impact bone quality and strength despite improving bone mineral density. We hypothesized that 1) continuous consumption of a high-fat, high-sugar (HFS) diet would impair bone quality and strength, and 2) a change from an HFS diet to a low-fat, low-sugar (LFS) would reverse HFS-induced impairments to bone quality and strength. METHODS: Six-week-old male C57Bl/6 mice ( n = 10/group) with access to a running wheel were randomized to an LFS diet or an HFS diet with simulated sugar-sweetened beverages (20% fructose in place of regular drinking water) for 13 wk. HFS mice were subsequently randomized to continuing HFS feeding (HFS/HFS) or transition to the LFS diet (HFS/LFS) for four additional weeks. RESULTS: HFS/HFS mice exhibited superior femoral cancellous microarchitecture (i.e., greater BV/TV, Tb.N, Tb.Th, and decreased Tb.Sp) and cortical bone geometry (i.e., lower Ct.CSA and pMOI) compared with all other groups. At the femoral mid-diaphysis, structural, but not material, mechanical properties were greatest in HFS/HFS mice. However, HFS/HFS exhibited greater femoral neck strength only when compared with mice assigned to diet transition (HFS/LFS). Osteoclast surface and the percentage of osteocytes staining positive for interferon-gamma were greater in HFS/LFS mice, consistent with reduced cancellous microarchitecture postdiet transition. CONCLUSIONS: HFS feeding enhanced bone anabolism and structural, but not material, mechanical properties in exercising mice. A change from an HFS to LFS diet returned the bone structure to that of continuously LFS-fed mice while compromising strength. Our results indicate rapid weight loss from obese states should be performed with caution to prevent bone fragility. A deeper analysis into the altered bone phenotype in diet-induced obesity from a metabolic standpoint is needed.
Asunto(s)
Densidad Ósea , Fructosa , Animales , Masculino , Ratones , Huesos/metabolismo , Dieta con Restricción de Grasas , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL , Obesidad/metabolismoRESUMEN
Chronic pediatric inflammatory bowel disease (IBD) leads to lack of bone accrual, bone loss, and increased fractures. Presently there is no cure, and many IBD treatments incur negative side effects. We previously discovered treatment with exogenous irisin resolved inflammatory changes in the colon, gut lymphatics, and bone in a mild IBD rodent model. Here we assess irisin treatment in severe IBD induced via dextran sodium sulfate (DSS). Male Sprague Dawley rats (2-mo-old) were untreated (Con) or given 2% DSS in drinking water. In week two, half of each group (Con + Ir and DSS + Ir) received injections of recombinant irisin (i.p., 2x/wk). After 4 weeks, gut inflammation was associated with declines in bone mineral density and cancellous bone volume. Furthermore, elevated osteocyte TNF-α, interleukin-6, RANKL, OPG, and sclerostin corresponded with higher osteoclast surfaces and lower bone formation rate in DSS animals as well as lower ultimate load. While irisin treatment improved colon inflammation, there were no improvements in bone density or bone mechanical properties; however, irisin elevated bone formation rate, decreased osteoclast surfaces, and reduced osteocyte pro-inflammatory factors. These data highlight the negative impact of chronic gut inflammation on bone as well as the therapeutic potential of irisin as an anti-inflammatory treatment.
Asunto(s)
Resorción Ósea/etiología , Huesos/patología , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Fibronectinas/uso terapéutico , Tracto Gastrointestinal/patología , Inflamación/complicaciones , Animales , Fenómenos Biomecánicos , Peso Corporal , Densidad Ósea/efectos de los fármacos , Proteínas Morfogenéticas Óseas/metabolismo , Resorción Ósea/fisiopatología , Huesos/diagnóstico por imagen , Huesos/efectos de los fármacos , Huesos/fisiopatología , Hueso Esponjoso/efectos de los fármacos , Hueso Esponjoso/patología , Hueso Esponjoso/fisiopatología , Colitis/patología , Colitis/fisiopatología , Colon/efectos de los fármacos , Colon/patología , Sulfato de Dextran , Cuello Femoral/diagnóstico por imagen , Cuello Femoral/efectos de los fármacos , Cuello Femoral/patología , Fibronectinas/farmacología , Tracto Gastrointestinal/efectos de los fármacos , Marcadores Genéticos , Inflamación/tratamiento farmacológico , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Vasos Linfáticos/efectos de los fármacos , Vasos Linfáticos/patología , Masculino , Osteocitos/metabolismo , Osteogénesis/efectos de los fármacos , Osteoprotegerina/metabolismo , Ligando RANK/metabolismo , Ratas Sprague-Dawley , Tibia/diagnóstico por imagen , Tibia/efectos de los fármacos , Tibia/patología , Tomografía Computarizada por Rayos X , Factor de Necrosis Tumoral alfa/metabolismo , Soporte de PesoRESUMEN
Osteocytes are believed to be the primary mechanosensors of bone tissue, signaling to osteoblasts and osteoclasts by releasing specific proteins. Sclerostin, interleukin-6 (IL-6), and insulin-like growth factor-I (IGF-I) are osteocyte proteins that signal to osteoblasts. The primary objective of this study was to determine if osteocyte protein response to mechanical unloading is restricted to the unloaded bone using the hindlimb unloading (HU) rodent model. We also examined tumor necrosis factor-α (TNF-α) due to its interactions with all three osteocyte proteins. We hypothesized that unloaded hindlimb cancellous bone would have an altered osteocyte protein (sclerostin, IL-6, and IGF-I) response compared to controls, while the response in the weight-bearing forelimb would not differ from ambulating controls. Male Sprague Dawley rats (7-mo old) experienced either HU (n=7) or normal cage activity (CON; n=7) for 28days. The unloaded distal femur and the weight-bearing proximal humerus were compared in HU vs CON. Metaphyseal bone density was reduced in the HU rats' hindlimb, but not in the proximal humerus, compared to CON values. Osteocyte density was 30% lower in the HU distal femur, but not different from CON in the proximal humerus. %Sclerostin+osteocytes in the distal femur were higher in HU compared to CON, but lower in the proximal humerus. Both %IGF-I+ and %IL-6+ osteocytes were lower in the distal femur for HU, but higher in the proximal humerus for HU. Osterix surface, a marker of osteoblasts, was lower in HU in the distal femur; however, the proximal humerus had more %osterix+surface in HU. In HU %Cathepsin K+ surface, a marker of osteoclasts, was higher in the distal femur and lower in the proximal humerus. %TNF-α+osteocytes were no different from CON in either bone site. HU proximal humerus osteocyte protein responses of sclerostin, IL-6, and IGF-I changed in the opposite direction as observed in the distal femur within the same animal. The opposite response of osteocyte proteins and osteoblast surface in hind- and forelimb bones within the same animal suggests that, while osteocytes in the unloaded hindlimb sense a lack of mechanical strain, osteocytes in the weight-bearing forelimb in HU animals sense some increase in local strain and generate molecular signaling to osteoblasts.