Postnatal administration of 2-oxoglutaric acid improves articular and growth plate cartilages and bone tissue morphology in pigs prenatally treated with dexamethasone.
The potential effects of prenatal administration of dexamethasone (DEX) and postnatal treatment with 2-oxoglutaric acid (2-Ox) on postnatal development of connective tissue of farm animals were not examined experimentally. The aim of this study was to establish changes in morphological parameters of bone and articular and growth plate cartilages damaged by the prenatal action of DEX in piglets supplemented with 2-Ox. The 3 mg of DEX was administered by intramuscular route every second day from day 70 of pregnancy to parturition and then piglets were supplemented with 2-Ox during 35 days of postnatal life (0.4 g/kg body weight). The mechanical properties, BMD and BMC of bones, and histomorphometry of articular and growth plate cartilages were determined. Maternal treatment with DEX decreased the weight by 48%, BMD by 50% and BMC by 61% of the tibia in male piglets while such action of DEX in female piglets was not observed. DEX led to thinning of articular and growth plate cartilages and trabeculae thickness and reduced the serum GH concentration in male piglets. The administration of 2-Ox prevented the reduction of trabeculae thickness, the width of articular and growth plate cartilages in male piglets connected with higher growth hormone concentration compared with non-supplemented male piglets. The result showed that the presence of 2-Ox in the diet had a positive effect on the development of connective tissue in pigs during suckling and induced a complete recovery from bone and cartilage damage caused by prenatal DEX action.
Tomaszewska E, Dobrowolski P, Wydrych J
J. Physiol. Pharmacol. Oct 2012
PMID: 23211309 | Free Full Text
The effect of dietary administration of 2-oxoglutaric acid on the cartilage and bone of growing rats.
2-Oxoglutaric acid (2-Ox), a precursor to hydroxyproline – the most abundant amino acid in bone collagen, exerts protective effects on bone development during different stages of organism development; however, little is known about the action of 2-Ox on cartilage. The aim of the present study was to elucidate the influence of dietary 2-Ox supplementation on the growth plate, articular cartilage and bone of growing rats. A total of twelve male Sprague-Dawley rats were used in the study. Half of the rats received 2-oxoglutarate at a dose of 0·75 g/kg body weight per d in their drinking-water. Body and organ weights were measured. Histomorphometric analyses of the cartilage and bone tissue of the femora and tibiae were conducted, as well as bone densitometry and peripheral quantitative computed tomography (pQCT). Rats receiving 2-Ox had an increased body mass (P<0·001) and absolute liver weight (P=0·031). Femoral length (P=0·045) and bone mineral density (P=0·014), overall thickness of growth plate (femur P=0·036 and tibia P=0·026) and the thickness of femoral articular cartilage (P<0·001) were also increased. 2-Ox administration had no effect on the mechanical properties or on any of the measured pQCT parameters for both bones analysed. There were also no significant differences in histomorphometric parameters of tibial articular cartilage and autofluorescence of femoral and tibial growth plate cartilage. Dietary supplementation with 2-Ox to growing rats exerts its effects mainly on cartilage tissue, having only a slight influence on bone. The effect of 2-Ox administration was selective, depending on the particular bone and type of cartilage analysed.
Dobrowolski P, Tomaszewska E, Bienko M, Radzki RP…
Br. J. Nutr. Aug 2013
Can 2-oxoglutarate prevent changes in bone evoked by omeprazole?
Proton-pump inhibitors, such as omeprazole, are widely used in the prevention and treatment of gastroesophageal diseases. However, an association between proton-pump inhibitors and the increased risk of bone fractures has been observed, especially in patients treated for extended periods. Conversely, 2-oxoglutarate, a precursor of hydroxyproline, the most abundant amino acid in bone collagen, counteracts the bone loss. The aim of the present study was to elucidate the influence of omeprazole on bone and investigate whether dietary 2-oxoglutarate supplementation could prevent the effects of omeprazole.
Eighteen male Sprague-Dawley rats were used. Rats received omeprazole in the diet and 2-oxoglutarate in the drinking water. Body and organ weights and serum concentrations of cholecystokinin and gastrin were measured. The femurs, tibias, and calvarias were collected. Histomorphometric analysis of bone and cartilage tissues was conducted. Bone densitometric and peripheral quantitative computed tomographic analyses of the femur and tibia were performed.
Omeprazole decreased the femur and tibia weights, the mechanical properties of the femur, the volumetric bone density and content, the trabecular and cortical bone mineral content, the total, trabecular, and cortical bone areas, the mean cortical thickness, and the periosteal circumference of the femur. Omeprazole had a minor effect on the examined bone morphology and exerted negligible effects on the cartilage. 2-Oxoglutarate lowered the gastrin concentration.
Omeprazole treatment exerts its effects mostly on bone mineralization and cancellous bone, adversely affecting bone properties. This adverse effect of omeprazole was not markedly abolished by 2-oxoglutaric acid, which acted as an anti-hypergastrinemic agent.
Dobrowolski P, Tomaszewska E, Radzki RP, Bienko M…
Nutrition Mar 2013
2-Oxoglutaric acid administration diminishes fundectomy-induced osteopenia in pigs.
Partial surgical removal of the stomach (fundectomy, FX) leads to osteopenia in animals and humans. FX adversely affects the bone. 2-oxoglutaric acid is a precursor of glutamine and hydroxyproline–the most abundant amino acid of collagen. The aim of the study was to investigate the effects of 2-oxoglutaric acid on FX-evoked osteopenia in pigs.
Eighteen castrated male pigs of the Puławska breed were used. Twelve pigs were subjected to FX and divided into two groups: FX + AKG (the AKG group; AKG at the daily dosage of 0.4 g/kg of body weight) and FX + Placebo (the FXC group; received CaCO(3) as placebo). Remaining six pigs were sham-operated (the SHO group). The pigs were euthanized at the age of 8 months and long bones were collected. Area bone mineral density (aBMD) and bone mineral content (BMC) were measured; morphology, geometry and biomechanical properties were determined. Moreover, the serum concentrations of selected hormones and one marker of bone metabolism were determined. FX caused osteopenia in the pigs and treatment with AKG greatly reduced these effects of FX in pigs. Negative effect of fundectomy on the skeletal system leading to decreased bone mass in pigs is associated with lowered body gain and activity of the gastric-hypothalamic-pituitary axis. Better definitions of each of the local and systemic hormonal and structural components associated with fundectomy-induced decreased bone mass that separately and together determine the whole bone properties may lead to identify opportunities for prevention.
J Anim Physiol Anim Nutr (Berl) Oct 2010
Alpha-ketoglutarate decreases serum levels of C-terminal cross-linking telopeptide of type I collagen (CTX) in postmenopausal women with osteopenia: six-month study.
Several studies have shown that alpha-ketoglutaric acid (AKG) increases serum levels of proline and has beneficial effects on skeletal development. We studied the effect of alpha-ketoglutaric (AKG) acid calcium salt (6 g AKG and 1.68 Ca/day) or calcium alone (1.68 Ca/day) on serum C-terminal cross-linked telopeptide of type I collagen (CTX) and osteocalcin (OC), as well as on lumbar spine bone mineral density (BMD) in a randomized, parallel group, double-blind, 6-month study conducted on 76 postmenopausal women with osteopenia. The maximum decrease of the mean CTX level in the AKG-Ca group was observed after 24 weeks (37.0%, p = 0.006). The differences in CTX between study groups were statistically significant after 12 and 24 weeks. The OC serum level was not affected by treatments. The BMD of the AKG-Ca group increased by 1.6% from baseline; however, the difference between treatment groups was estimated as 0.9% (non-significant). This study suggests the potential usefulness of AKG-Ca in osteopenic postmenopausal women. AKG-Ca induced beneficial changes in serum CTX, which was consistent with preserving the bone mass in the lumbar spine; however, the long-term effect needs to be further investigated.
Filip RS, Pierzynowski SG, Lindegard B, Wernerman J…
Int J Vitam Nutr Res Mar 2007
Dietary alpha-ketoglutarate reduces gastrectomy-evoked loss of calvaria and trabecular bone in female rats.
Surgical removal of the stomach (gastrectomy, Gx) leads to osteopenia in animals and in humans. In the rat, Gx adversely affects calvaria and trabecular bone. alpha-Ketoglutarate (AKG) is a precursor of hydroxyproline–the most abundant amino acid in bone collagen. The purpose of this study was to investigate the effects of dietary AKG on Gx-induced osteopenia.
Twenty female Sprague-Dawley rats were subjected to Gx and divided between two groups: Gx+AKG in the drinking water and Gx+Vehicle (i.e. drinking water without AKG). Another 20 rats were sham-operated and divided between two groups: Sham+AKG and Sham+Vehicle. The daily dose of AKG was 0.43 g per 100 g rat. All the rats were killed 8 weeks later and the calvariae, femora and tibiae were collected. The integrity of the calvariae was analysed planimetrically, following transillumination and photography. The bone mineral content (BMC) and bone mineral density (BMD) were measured in the right femorae and tibiae (bone densitometry), leaving the left femorae and tibiae to be analysed histomorphometrically (measurement of trabecular bone volume and trabecular fractal dimension).
Gx caused calvarial bone degradation, reduced trabecular bone (femur and tibia) and impaired trabecular architecture. In addition, Gx lowered the femoral/tibial BMC and BMD (mainly cortical bone). Dietary AKG counteracted the Gx-evoked impairment of calvaria and trabecular bone but failed to affect the BMC and the BMD in either sham- operated or Gx rats.
Gx resulted in loss of calvarial, trabecular and cortical bone in the rat. AKG counteracted the effect of Gx on calvaria and trabecular bone but not on cortical bone.
Dobrowolski PJ, Piersiak T, Surve VV, Kruszewska D…
Scand. J. Gastroenterol. 2008
The long-term effect of alpha-ketoglutarate, given early in postnatal life, on both growth and various bone parameters in pigs.
The long-term effect of alpha-ketoglutarate (AKG) given for 21-24 days post-partum, on the skeleton of commercial pigs, was investigated. In experiment A, 12 pigs were given AKG [0.1 g/kg of body weight (b.w.) per day per os], while 12 controls were administered vehicle. At day 169, the left and right femur, humerus and sixth ribs were analysed for mechanical and geometrical properties and quantitative computed tomography. In experiment B, 32 piglets were divided equally into an AKG group (0.3 g/kg of b.w. per day) or a control group. Blood, taken at days 24 and 53 was analysed for plasma 17 beta-oestradiol. The main bone effect of AKG was to increase bone length in the sixth rib (7.3%, p < 0.01), ultimate strength (23%, p < 0.05), Young s modulus (52%, p < 0.001) and maximum elastic strength (31%, p = 0.056) compared with controls. In both experiments, AKG preferentially increased the growth of female piglets, whilst for male piglets AKG had the opposite effect. In addition, AKG elevated plasma 17 beta-oestradiol levels compared to those of controls at the end of the period of treatment (20%, p = 0.002). It is concluded that AKG has long-term effects on rib properties when given early in postnatal life whilst it elevates plasma 17 beta-oestradiol levels only so long as it is being administered.
Andersen NK, Tatara MR, Krupski W, Majcher P…
J Anim Physiol Anim Nutr (Berl) Oct 2008
Anti-osteopenic effect of alpha-ketoglutarate sodium salt in ovariectomized rats.
The purpose of the study was to determine the effect of alpha-ketoglutarate sodium salt (AKG) treatment on the mineralization of the tibia in female rats during the development of osteopenia (Experiment-1) and in the condition of established osteopenia (Experiment-2). Thirty-two female rats were ovariectomized (OVX) to induce osteopenia and osteoporosis and another 32 female rats were sham-operated (SHO) and then randomly divided between the two experiments. In Experiment-1, the treatment with AKG started after a 7-day period of convalescence, whereas in Experiment-2 the rats were subjected to a 60-day period of osteopenia fixation, after which the actual experimental protocol commenced. AKG was administered in the experimental solution for drinking at a concentration of 1.0 mol/l and a placebo (PLC) was used as a control solution. After 60 days of experimental treatment the rats in both experiements were sacrificed, the body weight recorded, and blood serum and isolated tibia were stored for further analysis. The bones were analyzed using tomography and densitometry, and for estimation of mechanical properties the 3-point bending test was used. Serum concentrations of osteocalcin and collagen type I crosslinked C-telopeptide were measured. The anabolic effects of AKG on bone during osteopenia development in Experiment-1 not only stopped the degradation of bone tissue, but also stimulated its mineralization. The usage of AKG in animals with established osteopenia (Experiment-2) was not able to prevent bone atrophy, but markedly reduced its intensity. The stimulation of tibia mineralization after AKG treatment has been also argued in healthy SHO animals. The results obtained prove the effectiveness of AKG usage in the prophylaxis and therapy of osteopenia and osteoporosis, induced by bilateral gonadectomy. Additionally, the results clearly prove that treatment with AKG improves the mineralization of bone tissue in healthy animals.
Radzki RP, Bienko M, Pierzynowski SG
J. Bone Miner. Metab. Nov 2012
Effects of alpha-ketoglutarate on bone homeostasis and plasma amino acids in turkeys.
The objective of the study was to evaluate the effect of denervation and alpha-ketoglutarate (AKG) administration on the development of osteopenia in the turkey radius. At 22 d of age, all turkeys were subjected to neurectomy of the right radius. Control turkeys were given a saline solution into the crop each day for 97 d. Experimental turkeys were given 0.4 g of AKG/kg of BW into the crop each day. After 98 d, BW was not affected by the AKG treatment. Volumetric bone mineral density of the radius was measured by quantitative computed tomography. Mechanical properties were tested using a 3-point bending test. Cross-sectional area, second moment of inertia, and mean relative wall thickness were measured as well. Amino acid concentrations were assessed with the use of ion-exchange chromatography. Denervation had a negative effect on all bone characteristics that were measured except bone length. The AKG had a positive effect on all bone characteristics except bone length. Plasma concentrations of proline and leucine were increased by AKG, whereas concentrations of taurine and glutamine were decreased. The turkey radius appears to be a good model for studying osteopenia because its development can be affected by treatments such as denervation and AKG administration.
Tatara MR, Brodzki A, Krupski W, Sliwa E…
Poult. Sci. Oct 2005
The influence of alpha-ketoglutarate (AKG) on mineralisation, mechanical and structural properties of ulna in turkey under conditions of osteotomy and denervation.
Background: Mechanical endurance of bones to acting forces is a result of geometrical properties, mineralisation and quality of the material they are built. Bone mineral density decrease influences lower bone mechanical endurance and its higher susceptibility on fractures. Among many factors that condition proper growth, development and repair processes of skeletal system, nervous system plays very important role in processes of bone metabolism regulation and its homeostasis maintenance. Bone fractures occurrence as a result of osteopenia and its fractures connected with peripheral nervous system injury require investigations of new and effective treatments that would guarantee correct repair processes of bone tissue and its physiological function maintenance.
Material and methods: All investigation was performed on 16 turkeys divided into two groups. Right ulnae were subjected to denervation, osteotomy and osteosynthesis. The first group of turkeys served as control, the second group were administered alpha-ketoglutarate (AKG) directly to crop at the dosage of 0.4g/kg b.w./day by 14 weeks, starting on the next day after surgery. After finishing breeding part of experiment, the influence of AKG on mineralisation, structural and mechanical properties of denervated and osteotomied ulna was investigated.
Results: Performed investigations on ulna after its osteotomy and denervation elucidated different callus formation in turkeys belong to control group and receiving AKG. The positive influence of alpha-ketoglutarate administration on morphology, mineralisation and mechanical properties of experimentally osteotomied and denervated ulna was stated.
Conclusions: Obtained results prove anabolic effect of alpha-ketoglutarate on bone tissue, after its administration via digestive tract. Considering increased mineralisation, higher volumetric cortical bone density and increased trabecular bone density, AKG can be utilised as a factor in prevention of osteopenia and osteoporosis. Achieved results indicate possibility of existence connection by AKG between digestive system and skeletal system.
Tatara MR, Pierzynowski GS, Majcher P, Krupski W…
Ortop Traumatol Rehabil Oct 2003