Discuss About The Emerging Opportunities Novel Therapeutic.
Osteocalcin is one of the most abundant protein hormone produced by osteoblasts. It is vitamin k dependent, skeletal derived proteins mostly found in vertebrates. When this protein hormone is transcribed the protein went through post-translational changes within the cells before its secretion. The other transformation includes the carboxylation of 3-glutamic acid, which is significant for the biding of hydroxyapatite and its deposition in the bone matrix. Vitamin k is responsible for the carboxylation of osteocalcin. While vitamin D directly stimulates osteocalcin transcription (Maure & Jähn, 2017). From the various research, it has been found that when osteocalcin is released into the blood stream it exerts effects mainly on adipose tissue and pancreatic beta cells. The undercarboxylated osteocalcin is active isoform which stimulates the insulin secretion and in turn enhances the insulin sensitivity in muscles and adipose tissue. The leptin and insulin acts on bone which initiates the osteocalcin secretion. Hence, these functions make the bone as an endocrine organ. The non-carboxylate osteocalcin has less affinity for hydroxyapatite which is why it is easily released into circulation. Although, both the undercarboxylated and carboxylate forms can be at peripheral of the blood but the osteocalcin is normally measured as a marker responsible for bone formation (Caputo, 2016). The undercarboxylated osteocalcin levels is influenced by vitamin k, while in whole the total circulations are not influenced by vitamin k but are influenced by bone cells activity.
Osteocalcin also helps in binding calcium to bone tissue which is the reason behind bone flexibility and strength. Osteocalcin has to be activated by vitamin k2 for the occurrence of above process. As osteocalcin is vital to bone strength, its level is higher during early age of children and puberty. The organisms having lower level of osteocalcin tend to have weaker bone than in comparison to the organism having higher level (Teti, 2013). However, it’s not always true as high level of osteocalcin in older adult are also indicator of lower bone density. Hence, the high blood level of osteocalcin can also lead to fracturing of bones due to low bone density.
The high level of osteocalcin is also linked to muscle strength which further reduces the risk of bone fractures. It also increases the production of dopamine, serotonin and noradrenaline in the brain of mouse. These all monoamine neurotransmitters have vital role in learning, motivation and memory. Similarly, the low level of osteocalcin was also linked to negative results and the poor development of brain function (Brotto, et al., 2016).
It not only helps in the formation of bones but is also essential for the maintenance of bones. Its other functions also include insulin and glucose level, improving muscle strength, increasing the level of testosterone and improving cognitive function (Zanatta, et al., 2014).
There are various factors which are associated with low osteocalcin and high osteocalcin which are discussed below:
The low osteocalcin is linked with diabetes and insulin resistance:
In most of the health subjects and research it was found that, people having low production of insulin had lower levels of osteocalcin had high blood sugar level. Similarly, high level of osteocalcin was associated with controlled blood glucose level. It protects the rat beta cells, which are responsible for producing insulin in the pancreas from damage caused by increased glucose levels thereby improving the function of human beta cells (Anon., 2018).
The low levels of osteocalcin may be responsible for heart disease risk:
From the various evidences and studies, it has been found that there is a relationship between osteocalcin and blood vessels and overall health of the body. As per 247 cases of the patient with heart disease, those having lower level of osteocalcin had higher risk of heart diseases in future.
It was also observed that people who did not had any heart related problems were also at higher risk of heart diseases due to low osteocalcin level.
Lower level of osteocalcin is linked with atherosclerosis:
The relationship between osteocalcin and hardening of the arteries is complex. In one of the study, the outcomes were mixed. As per the meta-analysis, 26 were positive, 29 neutral and 17 negatives (Sophie A. Millar, et al., 2017). As per the study conducted on 774 men, the hardening of artery was lower in people who had high osteocalcin. By increasing the level of osteocalcin, the hardening of arteries was prevented.
In contrast to the above statement, according to another study conducted on 1691 men and 1913 women, the relationship between osteocalcin level and hardening of arteries is inversely J shaped curve”. This further means, that both the people either with high or low level of osteocalcin can increases the risk of hardening of arteries but people with lower level of osteocalcin were at higher risk than people with higher level of function.
The low level of osteocalcin was also associated with obesity and fatty liver:
As per the meta-analysis the people with lower level of osteocalcin had higher body mass index(BMI). This may lead to chronic inflammation and insulin resistance. The pathology of osteocalcin blood may help in predicting the fatty liver disease (Poggiogalle, et al., 2017 ). The study conducted on 120 children between 7 to 1 years old, it was found that children with low osteocalcin level had healthy liver compared to the children having higher levels of osteocalcin.
The high level of osteocalcin may result in osteoporosis:
In a series of study conducted on 417 postmenopausal women, it was found that women with high level of osteocalcin had lower bone mineral density and osteoporosis. The pathology of osteocalcin blood can diagnose the condition of osteoporosis in patients. Due to the low bone density, the chances of fracture increase especially in older age people (Levinger, et al., n.d.).
The high level of osteocalcin is linked with diabetes in pregnant women:
According to the survey conducted on 130 pregnant women, it was fond that high level of osteocalcin in blood increases the insulin resistance during pregnancy. This may lead to as condition known as gestational diabetes i.e. diabetes which is temporary and is related to child birth and pregnancy (Winhofer, et al., 2010). The level of osteocalcin remained higher throughout the pregnancy period.
The high level of osteocalcin is also linked with increased breast density:
The obese women in their post-menopausal phase having higher blood osteocalcin level were more likely to have breast with higher density which can be a factor for breast cancer in future. This was concluded by conducting a survey on 239 pre and post-menopausal women having age between 40 to 60.
The increased level of osteocalcin in blood can affect the formation of red blood cells. As per the study, among 939 elderly men between 72 to 79 years of age were having low levels of red blood cells due to increased level of osteocalcin in their blood (Katsumata, et al., 2009).
Osteocalcin does influence muscle function:
I agree with the statement that osteocalcin does influence muscle function.
While exercising our bones produces a hormone called osteocalcin which increases the muscle performance (Basso, n.d.). Apart from other hormones responsible for adaptation to exercise in human osteocalcin is the only one bone derived from hormones which increases and enhances the exercise capacity. There is only one or two percent of osteocalcin in bone mineralized matrix but several studies have confirmed that the protein present in the blood stream acts like a hormone for organs. It was only noticed that amount of osteocalcin in blood stream almost doubles during exercise. Until Gerald Karsenty, a geneticist at Columbia university medical it was never found before that bone actually influences muscle functions (Mera, et al., 2016).
Ina an experiment over mice and humans, it was found that the level of osteocalcin increases depending upon the age of the organism the researchers concluded that the osteocalcin level in three-month-old mice were four times as higher than 12 months old mice when the rodents ran for 40 minutes on a treadmill. The younger mice ran for 1200 meters before it became exhausted. While the older mice could only run half of the distance ran by 3 months old mice (Wei & Karsenty, 2015).
For further investigation, Karsenty and his colleagues used the mice which were genetically engineered so that the hormone could not show its effects on muscle. In the absence of adequate amount of osteocalcin in the muscle, the mice ran for 20% to 30% less time and distance then in comparison to the healthy mice before reaching their exhaustion limit.
It was very surprising to see said Karsenty, when the healthy mice of age between 12 to 14 months having low osteocalcin level which decreased naturally with their age were given osteocalcin which matched their running performance to that of a healthy mouse of 3 months old (Patti, et al., 2013). The 12 months old mouse ran for 1200 meters like the 3 months old mice before reaching their exhaustion point. It was indeed very surprising to see that a single dose of osteocalcin injection in a 12 months old mouse matched the performance to 3 months old mice by restoring their muscle function. The osteocalcin provides the muscle the kick for the intake of extra fuel and increasing the body ability to breakdown the fuel for energy making the body easier to exercise harder and longer (Connorab & Duracka, 2017).
The osteocalcin level decreases with the decrease in age in humans also. The rate of declination was 15 to 20 years faster in women than compared to that of men. Even at the time of evolution. Even at the time of evolution, men were involved in fishing and hunting making them more active than women (Levin, 2016). This further proves the statement that declination in the level of osteocalcin occurs slower in men than in women.
Karsenty and his team also measured the amount of glycogen, glucose as well as acylcarnitine with and without osteocalcin which are all the indicator of fatty acid use in mice. Due to this research, it was found that osteocalcin helped muscle fibers uptake and breaking of glucose and fatty acids as nutrients during exercise.
Hence, from the above study we can conclude that, the osteocalcin has significant impact on muscle functioning and its strength.
References
Anon., 2018. Osteocalcin: Function, Levels, and 18 Factors that Increase or Decrease It. [Online]
Available at: https://www.selfhacked.com/blog/osteocalcin/#4_Osteocalcin_May_Improve_Muscle_Strength
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Basso, J., n.d. Improve Muscle Function: Osteocalcin. [Online]
Available at: https://foreverfitscience.com/improve-muscle-function-osteocalcin/
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Brotto, M., Bonewald & Lynda, 2016. Bone and Muscle: Interactions beyond Mechanical. NCBI, p. 109–114..
Caputo, J., 2016. Bone hormone boosts muscle performance during exercise but declines with age. [Online]
Available at: https://www.eurekalert.org/pub_releases/2016-06/cp-bhb060716.php
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Connorab, E. M. & Duracka, E., 2017. Osteocalcin: The extra-skeletal role of a vitamin K-dependent protein in glucose metabolism. Journal of Nutrition & Intermediary Metabolism, Volume 7, pp. 8-13.
Katsumata, S.-i., Uehara, M. & Suzuki, K., 2009. Severe Iron Deficiency Decreases Both Bone Formation and Bone Resorption in Rats. The Journal of Nutrition, 139(2), p. 238–243.
Levinger, I., Scott, D. & Nicholson, G. C., n.d. Undercarboxylated osteocalcin, muscle strength and indices of bone health in older women, Melbourne: Institute of Sport, Exercise and Active Living.
Levin, J., 2016. Regulation of muscle function and mass by the bone-derived hormone osteocalcin, New York: Department of Genetics and Development.
Maure, D. B. & Jähn, K., 2017. Muscle–Bone Crosstalk: Emerging Opportunities for Novel Therapeutic Approaches to Treat Musculoskeletal Pathologies. [Online]
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Poggiogalle, E. et al., 2017 . Non-alcoholic fatty liver disease connections with fat-free tissues: A focus on bone and skeletal muscle. NCBI, 23(10), p. 1747–1757.
Sophie A. Millar, 1. H., Anderson, S. I. & England, T. J., 2017. Osteocalcin, Vascular Calcification, and Atherosclerosis: A Systematic Review and Meta-analysis. PMC, Volume 8.
Teti, A., 2013. Mechanisms of osteoclast-dependent bone formation. [Online]
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Wei, J. & Karsenty, G., 2015. An overview of the metabolic functions of osteocalcin. NCBI, 16(2), p. 93–98.
Winhofer, Y. et al., 2010. Osteocalcin Is Related to Enhanced Insulin Secretion in Gestational Diabetes Mellitus. NCBI, 33(1), p. 139–143.
Zanatta, L. C., Boguszewski, C. L. & Borba, V. Z., 2014. Osteocalcin, energy and glucose metabolism. [Online]
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