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Osteo-REP
Introduction
Bones provide a rigid frame work, known as the skeleton that support and protect the soft organs of the body. Skeleton supports the body against the pull of gravity. The large bones of the lower limbs support the trunk when standing. The fused bones of the cranium surround the brain to make it less vulnerable to injury. Vertebrae surround and protect the spinal cord and bones of the rib cage help protect the heart and lungs of the thorax. Bones work together with muscles as simple mechanical lever systems to produce body movement.
Bones contain more calcium than any other organ. The intercellular matrix of bone contains large amounts of calcium salts, the most important being calcium phosphate. When blood calcium levels decrease below normal, calcium is released from the bones so that there will be an adequate supply for metabolic needs. When blood calcium levels are increased, the excess calcium is stored in the bone matrix. The dynamic process of releasing and storing calcium goes on almost continuously.
Hematopoiesis, the formation of blood cells, mostly takes place in the red marrow of the bones. In infants, red marrow is found in the bone cavities. With age, it is largely replaced by yellow marrow for fat storage. In adults, red marrow is limited to the spongy bone in the skull, ribs, sternum, clavicles, vertebrae and pelvis. Red marrow functions in the formation of red blood cells, white blood cells and blood platelets.
The skeletal architecture is remarkably adapted to provide adequate strength and mobility. However, it is also a storehouse for two minerals, calcium and phosphorus that are essential for the functioning of other body systems, such as the intestine and the kidney. A complex hormonal system regulates the replenishment and depletion of these minerals from the bone. Thus one reason that bone health is difficult to maintain is that the skeleton is simultaneously serving two contradictory functions. First, bone must be responsive to changes in mechanical loading or weight bearing, which require strong bones with ample deposits of calcium and phosphorus. Secondly, these two minerals are continuously withdrawn by regulatory hormones to support vital functions elsewhere in the body [Falahati-Nini et al, 2000]. Thus the skeleton is similar to a bank where minerals are deposited and subsequently withdrawn later in times of need. However, too many withdrawals weaken the bone, which may lead to the most common risk – fractures. To respond to its dual roles of support and regulation of calcium and phosphorus, as well as to repair any damage to the skeleton, bone is constantly changing. Old bone breaks down and new bone is formed on a regular basis. In fact, the tissue of the skeleton is replaced many times during life. This requires a well balanced ‘Bio-Replenishment’ system to regulate specific cells responsible for bone formation [Favus, 2003].
During childhood and adolescence bones are sculpted by a process called ‘modeling’, which allows for the formation of new bone at one site and the removal of old bone from another site within the same bone. This process allows individual bones to grow in size and to shift in space. Much of the cellular activity in a bone consists of removal and replacement at the same site, a process called ‘remodeling’. The remodeling process occurs throughout life and vast majority of adult levels of bone mass are achieved by age 18 or so, with only a small amount added until about 28 years old. Remodeling continues throughout life so that most of the adult skeleton is replaced about every 10 years [Parfitt, 2001].
Bone is a vibrant, living tissue that constantly regenerates. Just as our muscles strengthen or weaken according to how we use them, bones gain mass and change shape when we are active. A healthy function of the skeletal system depends on two interacting cells called ‘osteoblasts’ and ‘osteoclasts’; essential for bone nourishment, growth and regeneration [Roodman, 2001]. In a dynamic collaboration, osteoblasts or bone-forming cells, deposit calcium on the protein framework of the bone. This bone mineralization process needs Vitamin D and parathormone (PTH) for calcium regulation; lack of the former or excess of the latter leads to bone mineral depletion. Osteoblasts also synthesize and lay down precursors of collagen 1, which comprises 90-95% of the organic matrix of bone [Feldman, 1999].
Osteoblasts also produce osteocalcin – the most abundant non-collagenous protein of bone matrix and the proteoglycans of ground substance. When bone becomes old or fatigued, osteoclasts reabsorb old or fatigued bone, paving the way for fresh, new osteoblast cells. The actions of these two cells are directed by a variety of regulatory hormones and a metal-transport protein – the lactoferrin. Therefore, maintenance of optimum levels of these regulatory hormones and lactoferrin through physiological replenishment is important for healthy bones.
Ninety percent of your bone mass forms before 20 years of age. Up until the age of about 25, bone still gradually increases in mass and density, as calcium and other minerals are deposited. Bone breakdown begins when the osteoclasts dissolve the old bone faster than the osteoblasts can keep up with the 'replacement'. As this continues, the honeycomb-like structure becomes thinner, more brittle and disconnected. Over time, the entire structure of the bone starts to erode. This can cause the bone to lose its density and strength.
A healthy skeletal system with strong bones is essential to overall health and quality of life. Yet, today, far too many individuals suffer from bone disease and fractures, much of which could be prevented. An estimated 10 million Americans over age 50 have osteoporosis (the most common bone disease), while another 34 million are at risk. The number of sufferers is however set to increase steadily with growing numbers of elderly living longer, and obesity adding extra strain on bones. In recognition of the importance of promoting bone health and preventing fractures, President George W. Bush has declared 2002–2011 as the Decade of the Bone and Joint. With this designation, the United States has joined with other nations throughout the world in committing resources to accelerate progress in a variety of areas related to the musculoskeletal system, including bone disease and arthritis [US-DHHS, 2000; 2004].
Diet and physical activity are critically important to bone health throughout life.
Nutritional deficiencies can result in the formation of weak, poorly mineralized bone. Many hormonal disorders can also affect the skeleton. Lack of exercise, immobilization, and smoking can also have negative effects on bone mass and strength [Kelly et al, 2000; New et al, 2000; Baron et al, 2001].
A healthy, balanced diet rich in essential bone nutrients will help to achieve optimal bone maintenance. It is also important to exercise at least 30 minutes of weight bearing activity on most days, and to limit smoking and the consumption of alcohol, coffee and other caffeinated beverages. Bone nutrients are needed every day to help you achieve optimal bone maintenance. These essential nutrients include proteins, calcium, vitamin D, magnesium and zinc. Together with the right balance of exercise and bone nutrition, it is possible to reduce the rate of bone breakdown with aging.
Bone is living tissue that is continually being broken down and rebuilt. As we age bone breakdown begins to outweigh bone rebuilding, and certain life style adjustments can alter the rate at which this occurs. However, certain bone conditions that are triggered due to a disease condition or age are difficult to reverse. In most such cases, these bone conditions are adversely compounded by other underlying factors such as chemical imbalances, physiological deficiencies and/or disorders.
Bio-replenishment of innate chemical regulator(s) that are functionally associated with a physiological deficiency/imbalance could reverse such specific abnormal conditions. Insulin is an example of such functional bio-regulator for glucose metabolism. Research studies at N-terminus laboratories have indicated that a combination of lactoferrin with specific types of ribonucleases in milk could positive affect bone health.
Milk contains a number of growth factors that are vital for mammalian growth and development, in general. While milk calcium provides raw material for bone growth, other, specific milk compounds directly stimulate the modeling and remodeling of bone [Cadogan et al, 1997]. Recent studies have indicated that a specific milk protein called ‘lactoferrin (LF)’ is uniquely able to boost the growth-multiplication of human osteoblast cells [Cornish et al, 2004]. Furthermore, LF could reduce, up to 50-70%, the rate at which osteoblast cells die, and decrease the formation of osteoclasts. LF affects osteoblasts by binding to cell-surface proteins called low-density lipoprotein receptors. In addition, LF has also been shown to increase the multiplication of chondrocytes, the cells that build cartilage [Naot et al, 2005]. In mammals, LF production rises in an embryo during the last half of gestation, an indication that it promotes skeletal development. Its high concentrations in milk, particularly in colostrum, the rich milk produced immediately after an infant is born; suggest that it might also be important to newborns [Naidu, 2000].
LF is also a major bioactive component of the synovial fluid in the bone joints with a regulatory role in bone growth and repair. Biosynthesized in the bone marrow, LFcan modulate inflammatory responses by scavenging toxic ‘free’ iron [Olsson et al, 1988]. This mechanism is important at the sites of inflammation, such as in the rheumatoid joint. LF can bind ‘free’ iron in the synovial fluid and reduce joint inflammation during arthritis [Guillen et al, 2000]. Orally administered LF has preventive and therapeutic effects on joint inflammation and pain. The ability of LF to modulate the immune system could be beneficial in the treatment of rheumatoid arthritis [Hayashida et al, 2004].
LF is present in milk, saliva, tears, gastric mucus, bronchial mucus, synovial fluid, seminal fluid, amniotic fluid, cerebrospinal fluid, blood and tissue throughout the body. This metal-binding protein is secreted by exocrine glands located at the gateways of digestive, respiratory and reproductive systems [Naidu, 2005]. Specific receptors for LF are present on immune cells including neutrophils, monocytes, lymphocytes and on tissues of liver, intestinal, urogenital and respiratory tracts. Interaction of LF with these receptors is essential for several body functions such as hormone regulation, tissue repair, bone regeneration, blood detoxification and energy generation. Numerous functions have been reported and continue to be reported for LF, some of which are related to its iron-binding properties [Naidu and Bidlack, 1998]. LF plays a critical role in the intestinal absorption and physiological transport of several essential metals including iron, zinc, manganese, and selenium. The ability of LF to bind iron in the presence of bicarbonate anion contributes to antibacterial, antiviral, antifungal, anti-inflammatory, antioxidant and immuno-modulatory activities [Naidu and Arnold, 1997]. LF is a multifunctional replenishment highly critical for a bone health, in particular.
Angiogenin (RNases type-4 and type-5 forms) is an active secretory protein found in milk. In cow’s milk the concentrations are about 2 mg/L for RNase 4 and between 1 and 8 mg/L for RNase 5 [Komolova et al., 2002]. RNases have been shown to be a key mediating factor in the underlying cascade of chemical events leading to angiogenesis, which makes it a very important precursor molecule for both muscle development and vascular generation [Strydom, 1998].
Scientists at the N-terminus Research laboratories are extensively exploring various structure-function relationships of lactoferrin, angiogenin are other bioactive replenishments critical for bone health management in vivo.
1) Baron JA et al (2001) Cigarette smoking, alcohol consumption, and risk of hip fracture in women. Arch Intern Med 161(7):983–988.
2) Cadogan J et al (1997) Milk intake and bone mineral acquisition in adolescent girls: Randomised, controlled intervention trial. BMJ 315:1255-1260.
3) Cornish J et al (2004) Lactoferrin is a potent regulator of bone cell activity and increases bone formation in vitro. Endocrinology 145:4366-4374.
4) Cox TM et al (1979) Iron-binding proteins and influx of iron across the duodenal brush border. Evidence for specific lactotransferrin receptors in the human small intestine. Biochim Biophys Acta 588:120-128.
5) Davidson L, Lönnerdal B (1988) Specific binding of lactoferrin to brush border membrane: Ontogeny and effect of glycan chain. Am J Physiol 257:930-934.
6) Falahati-Nini A et al (2000) Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest 106:1553-1560.
7) Favus MJ (2003) Primer on the metabolic bone diseases and disorders of mineral metabolism. 5th Edition. Washington (DC): American Society for Bone and Mineral Research.
8) Feldman D (1999) Vitamin D, parathyroid hormone, and calcium: A complex regulatory network. Am J Med 107:637-639.
9) Guillen C et al (2000) The effects of local administration of lactoferrin on inflammation in murine autoimmune and infectious arthritis. Arthritis Rheum 43:2073-2080.
10) Hayashida K et al (2004) Oral administration of lactoferrin inhibits inflammation and nociception in rat adjuvant-induced arthritis. J Vet Med Sci 66:149-154.
11) Kelley GA et al (2000) Exercise and bone mineral density in men: A meta-analysis. J Appl Physiol 88(5):1730-1736.
12) Naidu AS (2000) Lactoferrin. In: Natural Food Antimicrobial Systems, ed. AS Naidu. CRC Press, Boca Raton, FL: (ISBN:0-8493-0909-3)
13) Naidu AS (2005) Ultra-cleansing of lactoferrin – nutraceutical implications. European Journal of Nutraceuticals & Functional Foods 16(2):7-13.
14) Naidu AS et al (2004) Antifungal synergism of activated lactoferrin and fluconazole against Candida albicans and Candida glabrata vaginal isolates. J Reprod Med 49:800-807.
15) Naidu AS, Arnold RR (1994) Lactoferrin interaction with salmonellae potentiates antibiotic susceptibility in vitro. Diagn Microbiol Infect Dis 20:69-75.
16) Naidu AS, Arnold RR (1997) Influence of lactoferrin on host-microbe interactions. In. Lactoferrin - Interactions and Biological Functions, ed. T.W. Hutchens, and B. Lonnerdal, 259-275. Totowa, NJ: Humana Press.
17) Naidu AS, Bidlack WR (1998) Milk lactoferrin - Natural microbial blocking agent (MBA) for food safety. Environ Nutr Interact 2:35-50.
18) Naidu SS et al (1993) Relationship between antibacterial activity and porin binding of lactoferrin in Escherichia coli and Salmonella typhimurium. Antimicrob Agents Chemother 37:240-5.
19) Naot D et al (2005) Lactoferrin: A novel bone growth factor. Clin Med Res 3:93-101.
20) New SA et al (2000) Dietary influences on bone mass and bone metabolism: Further evidence of a positive link between fruit and vegetable consumption and bone health? Am J Clin Nutr 71(1):142-151.
21) Olsson I, Lantz M, Persson A-M, Arnljots K (1988) Biosynthesis and processing of lactoferrin in bone marrow cells, a comparison with processing of myeloperoxidase. Blood 71:441-447.
22) Parfitt AM (2001) The bone remodeling compartment: A circulatory function for bone lining cells. J Bone Miner Res 16(9):1583-1585.
23) Roodman GD (2001) Biology of osteoclast activation in cancer. J Clin Oncol 19(15):3562-3571.
24) U.S. Department of Health and Human Services (2000) Healthy People 2010. Washington, DC.
25) U.S. Department of Health and Human Services (2004) Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD.
26) Komolova GS, Federova TV (2002) Milk angiogenin. Appl Biochem Microbiol 38:199-204.
27) Strydom DJ (1998) The angiogenins. Cell Mol Life Sci 54:811-824.
