BMP Body Modify Phenotype

BMP is a revolutionary new non-hormonal supplement targeting upregulation of specific bone morphogenetic proteins that have only recently been discovered to be a fundemental signal for muscle growth. By dramatically shifting the anabolic/catabolic pathways, this groundbreaking formula just made muscle building a whole lot easier

We are extremely excited to open the door to a new frontier in anabolic supplementation. The pathway targeted in this formula doesn’t involve any of the well-known traditional methods, and will require no PCT or additional supplements to counteract side effects, because there aren’t any. Once user feedback gets around, you will certainly start seeing copycat formulas, as the concept of this formula has huge potential to accelerate muscle growth.

BMP, for the sake of our new groundbreaking formula, stands for Body Modify- Phenotype. For the sake of the physiology it happens to be targeting, it stands for Bone Morphogenetic Protein. Based on new research, it turns out that a pathway once thought to only regulate bone growth/turnover is actually tightly and crucially linked to muscle growth as well. Since this research began to surface, we’ve been watching it like a hawk and researching ingredients that might take advantage of this pathway. Now that more and more research has confirmed the previous conclusions, we are confident that EvoMuse BMP is about to dig its heels in as a serious player in the toolbox for natural and assisted bodybuilders.

Much of the research we have at this point is looking at bone anabolism as opposed to muscle, as the BMP-muscle link is such a new area. So we will have to extrapolate a bit and look at implications of the ingredients’ effects on bone growth through BMP, knowing that the same pathway is going to target muscle growth as well. At this point, when we find something that targets bone growth through supporting the BMP pathway, we can assume increased rates of muscle growth will accompany.

Important Description Definitions for BMP

Since this is quite a dense topic, it will be exponentially easier to understand, and flow through reading the write-up if several terms/concepts are at least superficially understood. Scan through these definitions first, and then refer back to them as you go through the write-up as you need

clarification.

Bone Morphogenetic Proteins (BMPs)

BMPs are a class of growth factors belonging to the Transforming Growth Factor beta (TGF-b) superfamily. Another, contrasting part of this superfamily is the myostatin/activin subfamily. These two subfamilies have directly opposing functions on muscle mass, namely that BMPs are

anabolic and myostatin is catabolic. Originally it was thought that BMPs were responsible, solely, for bone and cartilage formation, but recently it has been discovered that they are also key players in skeletal muscle growth.

Interestingly, BMPs are actually dominant over myostatin signaling; when levels are high they win the anabolic/catabolic battle. BMPs are divided into specific proteins, namely BMP2, BMP4, and BMP7.

BMP’s promote chondrocyte proliferation AND hypertrophy, and SMAD signaling (see below) regulates chondrocyte hypertrophy (1). BMP’s are unique in that they not only induce differentiation of mesenchymal stem cells to osteoblasts, and they also enhance the function of

the osteoblast once differentiated (2).

A 2013 study published in the journal Nature Genetics provided some compelling conclusions about BMP and muscle tissue (3).

BMP signaling is the fundamental signal for hypertrophy.

Inhibiting BMP signaling causes atrophy, abolishes myostatin deficient mice from gaining the enormous amount of muscle they normally do, and increases the negative effect from fasting.

BMP plays a critical role in adult muscle growth.

Now we’ll take a look at the specific types of BMPs.

BMP2

BMP2 plays a major role in bone and cartilage formation, as well as osteoblast differentiation. Differentiation is an important point here, as will be discussed below. BMP2 is the secondary target of this formula, with BMP7 being the primary target.

BMP4

BMP4, while still important, is our lowest priority of the three for targeting muscle growth. Like the other BMPs it is involved in bone and cartilage development, although more specifically for teeth and limbs, as well as being a key player during embryonic development.

BMP7

BMP7 is our priority target for muscle growth. It is a major player in osteoblast differentiation as well as the induction of SMAD1 and SMAD5 (see below).

SMADs

SMADs are a family of nine proteins that live inside the cell, which fall into one of three categories (receptor-regulated, common-mediator, or inhibitory). The first two classes help to mediate BMP by bringing the extracellular signal into the nucleus of the cell where they trigger

gene transcription downstream.

SMAD4, which makes up the entirety of the common-mediator class, is a helper protein for SMAD1/2/3/5/8/9, which make up the receptor-regulated class. Once BMPs hit the cell membrane, this triggers the phosphorylation of SMAD1/5/8; they then form a complex with SMAD4 and are translocated to the nucleus. SMADs basically act as an executive assistant to BMPs.

Chondrocyte

This is just a cartilage cell. That was easy.

Chondrogenesis

The formation of cartilage. Another gimmie.

Mesenchymal Stem Cell (MSC)

MSC’s are stem cells located in connective tissue throughout the body, which can differentiate down different pathways into chondrocytes, osteoblasts, or adipocytes.

Osteoblast

Formed from MSC’s, these cells, once grouped together are responsible for synthesizing bone. Since bone is a dynamic tissue, these cells are constantly working in anabolic opposition to the catabolic osteoclasts.

Osteoclast

A catabolic bone cell, osteoclasts oppose osteoblasts and encourage bone resorption (the process of breaking down bones which pushes calcium into the blood).

Wnt Signaling Pathways

These pathways are made up of proteins that function in a way similar to SMADs, helping pass signals from outside to inside a cell, as well as regulating b-catenin from the cytoplasm to the nucleus. This pathway is also responsible for regulating calcium inside the cell, as well as aiding

in differentiation and proliferation.

Notch Signaling Pathway

This pathway involves cell to cell communication; for example when one cell expresses a specific trait, this pathway can be used to switch that trait off in a neighboring cell to allow a process of many cells gathering together to form large structures. It is also upstream of several differentiation processes, and encourages the osteoblast pathway from stem cells (4).

Proliferation

Proliferation is simply the increase in cell number through the process of cell division.

Differentiation

This is the process where a non-specific stem cell becomes a specific type of cell, like an osteoblast.

Feel smarter? Good. Time to break down the ingredients in the formula and see what this stuff is all about.

BMP Ingredient Breakdown:

Kaempferol Cyclodextrin

Kaempferol is a flavonol found in a variety of plants. The Cyclodextrin has been added to increase bioavailability. In the past Kaempferol has been shown to increase cellular energy expenditure and enhance thyroid function which has landed it a spot in several fat burning formulas, however it has been included in this formula for an entirely different reason (5).

Kaempferol appears to have quite a strong effect on bone anabolism, and has been called a possible “promising agent for the prevention or treatment of bone loss” (6). A 2013 in vitro study demonstrated that Kaempferol enhanced the expression of chondrogenic marker genes, and

greatly increased expression of BMP2 (7). In addition to increasing BMP2, it has also been shown to increase the number of BMP2 receptors in animals (8). More BMP and more places to dock, that’s a solid combo.

Through a complex signaling cascade involving TAZ, RUNX2, and PPARy, MSC’s differentiate into osteoblasts or adipose tissue. Kaempferol facilitates the ability of TAZ and RUNX2 to suppress gene transcription of PPARy targets (9). Yeah, that’s confusing. So what that means to us, is that Kaempferol causes those undifferentiated MSC’s to shift to bone cells instead of fat cells. Which is pretty cool.

Finally, Kaempferol has been shown to have a significant inhibitory effect on bone resorption, shifting the pendulum in favor of bone anabolism (10). It is worth noting, that at least part of this effect is attributable to bone specific estrogenic activity from Kaempferol which is the mechanism in which drugs like tamoxifen and toremifene help increase bone density.

Salidroside

Salidroside is an extremely interesting glucoside found in Rhodiola Rosea, which boasts numerous studies demonstrating a wide range of health benefits. Two very recent studies looked at the effect of Salidroside on bone anabolism. In the first study, they found that Salidroside increased the mRNA level of genes controlling the BMP pathway. It elevated BMP2 and BMP7 as well as SMAD1/5/8 (SMAD6/7 are the inhibitory ones we don’t want to activate) (11).

The second study, carried out by different researchers, confirmed the increased phosphorylation and expression of SMAD1/5/8. Then to be sure this was mediated by BMP, they added in a BMP antagonist to block the signaling pathway. As suspected, this attenuated the effect, demonstrating that BMP was indeed the target of Salidroside (12).

Osthole Cyclodextrin

Found in cnidium monnieri and a few other plants, Osthole is classified as a coumarin. It has been used in supplement form for liver health, cognitive enhancement and vasodilation. Research shows it can activate AMPK and ACC, regulate blood glucose and GLUT4 activity, and decrease liver fat (13–15). One study even demonstrated that in mice, a high dose of Osthole had an androgenic effect and boosted LH and testosterone levels (16).

All these things are nice, but what about BMP? Fear not, Osthole has been shown to activate Wnt/beta-catenin signaling, increase BMP2 expression, and stimulate MSC differentiation to osteoblasts (17). Early phase differentiation involves BMP2, SMAD1/5/8, RUNX2, and p38,

whereas later phase differentiation involves ERK1/2. Osthole has been shown to enhance both phases, it sticks around until the job is done (18,19).

Tocopherols (Mixed)

Vitamin E is a fat soluble vitamin made up of four tocotrienols and four tocopherols, all with different functions. We have selected mixed tocopherols for this formula based on their potential benefits for BMP signaling. In certain conditions where BMP7 is reduced, Vitamin E has been shown to prevent this (20). However, supplementation with normal synthetic Vitamin E will increase alpha tocopherol while lowering gamma tocopherol in the blood. High gamma:alpha ratios are associated with increased biomarkers of bone formation. The mixed tocopherols in the formula will help tip the balance in favor of Gamma Tocopherol over a traditional Vitamin E supplement. Gamma tocopherol demonstrates the ability to facilitate uncoupling of bone turnover, encouraging more bone formation than resorption (21). We know when this is happening, that the BMPs are working in our favor. If you typically take a synthetic Vitamin E supplement, you may want to consider shelving that while you’re taking BMP.

Alfacalcidol

Alfacalcidol can be considered sort of a “super” Vitamin D3. Research has shown that elevated levels of Vitamin D3 plus BMP4/6 has a potent bone inducing effect (22). Typically during high stress, one of the things that gets left behind as the body redirects its resources, is optimal bone

turnover. In rats treated with glucocorticoids to mimic stress, alfacalcidol preserved bone mineral density, strength, muscle volume, and prevented fatigue vs. controls (23). Research has also shown that alfacalcidol, but not regular Vitamin D, has pleiotropic effects

improving bone and muscle metabolism (24).

Retinoic Acid

Retinoic Acid (RA) is a Vitamin A metabolite, which aids the functions of Vitamin A necessary for growth and development. Due to the preferred differentiation of MSC’s to adipocytes in obesity, overweight or obese people are at a higher risk for osteoporosis due to less MSC’s converting to

osteoblasts. RA has been shown to activate BMP & SMAD signaling, thereby shifting the direction of MSC’s to the osteoblast pathway (25). Interestingly, an increase in BMP2 stimulates MSC proliferation, but not always towards the osteoblast pathway. The addition of RA to elevated

BMP2 seems to cooperate with BMP2 to further enhance proliferation, yet inhibits conversion of MSC’s to adipocytes, promoting early osteoblastic differentiation (26). Another study showed that RA was also synergistic with BMP9 in promoting the osteoblastic pathway (27). RA has also been

shown to directly upregulate BMP7 activity (28).

Lactoferrin

Lactoferrin is a bioactive protein with “unique properties towards musculo-skeletal cells and anabolic to bone in vivo”, according to a new 2014 study (29). It is derived from whey protein, and will typically make up less than 1% of the protein content of an average whey supplement, yet a whopping 15% of mother’s milk. Ironically whey concentrate powders contain much higher levels than the more expensive isolate forms. While some lactoferrin can be obtained from food and/or protein powders, the average American male consumes less than 100mg/day from dietary sources, whereas we have included a large dose of 400mg in our formula.

Lactoferrin appears to have diverse pathways, signaling through multiple membrane bound receptors to initiate anabolic muscle and bone effects (30). Quite a bit of research in the past few years has looked at the anabolic effect of lactoferrin on bone, so lets take a look at the bullet

points:

Accelerates bone regeneration/anabolic in bone (31–37).

Promotes proliferation, differentiation, and anti-apoptosis in MSC’s & osteoblast (32,34,35)

Inhibits osteoclastogenesis/bone resorption (32,34–36).

Taken orally, preserves bone mass and improves bone microarchitecture, and is an “important physiological regulator of bone growth (35,36).

Specifically targets BMP7 over BMP2/4, through the MAPK/ERF and RANKL pathways (36,37).

So in summary, lactoferrin does exactly what we want it to do across the board for anabolism, while also including several bonuses such as supporting immune function, optimal insulin/glucose levels, fat loss, blood lipids, and more. For those interested, Will Brink has some great info on his site here.

Hwanggeumchal Sorghum Extract (HSE)

Sorghum refers to a genus of grasses, typically used in livestock feed. As you can probably assume by now, we didn’t just throw some grass clippings in this advanced formula. We have found a very specific extract of Sorghum that boasts some cool properties. HSE works, for our purposes, in a unique way that should synergize with the other ingredients in the formula. Growth Hormone (GH) is a well-known regulator of bone growth. When GH is elevated, it triggers something called the Jak/STAT pathway, which regulates IGF-1, a major player in bone and

muscle growth. HSE has been shown to act almost exactly like GH in activating this Jak/STAT pathway, which then increases the expression of GH related proteins, (one of which, STAT5b triggers BMP7), the GH receptor itself, IGF-1, the IGF-1 receptor, and BMP7 (38). The science nerds might have noticed something particularly intriguing about that. When we trigger more BMP7, we trigger more MSC differentiation towards osteoblasts, giving the (now also elevated by HSE) anabolic IGF-1 more beneficial places to exert its effects. And for the bonus round, HSE has been shown to reduce plasma Total Cholesterol and Triglycerides when given to obese rats on a high fat diet (39).

Aspergillus Awamori (AA)

AA (not to be confused with Aspergillus niger), in addition to being a possible bonus source of lactoferrin (40), has several interesting properties relating to muscle building and blood lipid support. Most of the current research on AA has used broiler chicks as subjects, which are basically the chickens that supply the breast meat for you to eat insane quantities of. It turns out that AA causes a major shift in feed efficiency, so that every gram of protein eaten becomes more anabolic. So in these chickens (and one rat study) here’s the consensus from AA supplementation:

Protein digestibility, protein utilization, and feed efficiency improved (41–44).

Increased expression of GH and IGF-1 and their receptors (41).

Improved muscle growth by favorably shifting anabolism/catabolism (41,43).

Even with decreased food intake, muscle mass increased (43,44).

Improved blood lipids and glucose (lower total cholesterol, LDL, TAG, BG, with an

increase in HDL) (41,42,44).

Things to Avoid/Monitor When Taking BMP:

Synthetic Vitamin E -The synthetic form of Vitamin E (dl-alpha tocopherol) lowers gamma tocopherol, which potentially interferes with anabolic bone signaling. If you are taking Vitamin E for a medical reason, please consult with your doctor before cessation.

Nicotine – Nicotine has been shown to interfere with bone formation. The addition of mixed tocopherols to the BMP formula could help counteract this, but it would still be a good idea to limit use of nicotine while using this product to prevent negative interactions with the BMP signaling

cascade.

Things to stack with BMP

While certainly not necessary, these should provide a synergistic effect.

Test Infusion

MyoSynergy

X-Factor

T-base

BMP Conclusion:

As you can see, we have found a highly specific combination of ingredients to optimize this exciting, untapped pathway for muscle growth. In consistent EvoMuse fashion, we have spared no cost ensuring optimal dosing of each ingredient for maximum effect. If you’re working out hard and eating right, you owe it to yourself to include EvoMuse BMP in your arsenal.

Whats the recommended dosage for Evo Muse BMP?

Take 2 capsules in the morning and 2 capsules an hour before workout.

Research and References:

1. Tsumaki N, Horiki M, Murai J, Yoshikawa H. [Role of BMPs and Smads during endochondral bone formation]. Clin Calcium [Internet]. 2004 Jul [cited 2014 Sep 12];14(7):52–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15577076

2. Canalis E, Economides AN, Gazzerro E. Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr Rev [Internet]. 2003 Apr [cited 2014 Aug 14];24(2):218–35. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12700180

3. Sartori R, Schirwis E, Blaauw B, Bortolanza S, Zhao J, Enzo E, et al. BMP signaling controls muscle mass. Nat Genet [Internet]. 2013 Nov [cited 2014 Jul 16];45(11):1309–18. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24076600

4. Nobta M, Tsukazaki T, Shibata Y, Xin C, Moriishi T, Sakano S, et al. Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling. J Biol Chem [Internet]. 2005 Apr 22 [cited 2014 Sep 9];280(16):15842–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15695512

5. da-Silva WS, Harney JW, Kim BW, Li J, Bianco SDC, Crescenzi A, et al. The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation. Diabetes [Internet]. 2007 Mar [cited 2014 Sep 12];56(3):767–76. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17327447

6. Miyake M, Arai N, Ushio S, Iwaki K, Ikeda M, Kurimoto M. Promoting effect of kaempferol on the differentiation and mineralization of murine pre-osteoblastic cell line MC3T3-E1. Biosci Biotechnol Biochem [Internet]. 2003 Jun [cited 2014 Aug 1];67(6):1199–205. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12843643

7. Nepal M, Li L, Cho HK, Park JK, Soh Y. Kaempferol induces chondrogenesis in ATDC5 cells through activation of ERK/BMP-2 signaling pathway. Food Chem Toxicol [Internet]. 2013 Dec [cited 2014 Aug 11];62:238–45. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23989061

8. Long M, Li S-X, Xiao J-F, Wang J, Scott L, Zhang Z-G, et al. Kidney tubular-cell secretion of osteoblast growth factor is increased by kaempferol: A scientific basis for “The Kidney Controlling the Bone” theory of chinese medicine. Chin J Integr Med [Internet]. 2014 Jul 10 [cited 2014 Aug 11]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/25012631

9. Byun MR, Jeong H, Bae SJ, Kim AR, Hwang ES, Hong J-H. TAZ is required for the osteogenic and anti-adipogenic activities of kaempferol. Bone [Internet]. 2012 Jan [cited 2014 Aug 11];50(1):364–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22108137

10. Wattel A, Kamel S, Mentaverri R, Lorget F, Prouillet C, Petit J-P, et al. Potent inhibitory effect of naturally occurring flavonoids quercetin and kaempferol on in vitro osteoclastic bone resorption. Biochem Pharmacol [Internet]. 2003 Jan 1 [cited 2014 Jul 31];65(1):35–42. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12473376

11. Chen J-J, Zhang N-F, Mao G-X, He X-B, Zhan Y-C, Deng H-B, et al. Salidroside stimulates osteoblast differentiation through BMP signaling pathway. Food Chem Toxicol [Internet]. 2013 Dec [cited 2014 Aug 11];62:499–505. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24055767

12. Zhao H-B, Qi S-N, Dong J-Z, Ha X-Q, Li X-Y, Zhang Q-W, et al. Salidroside induces neuronal differentiation of mouse mesenchymal stem cells through Notch and BMP signaling pathways. Food Chem Toxicol [Internet]. 2014 Sep [cited 2014 Aug 11];71:60–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24929042

13. Lee W-H, Lin R-J, Lin S-Y, Chen Y-C, Lin H-M, Liang Y-C. Osthole enhances glucose uptake through activation of AMP-activated protein kinase in skeletal muscle cells. J Agric Food Chem [Internet]. 2011 Dec 28 [cited 2014 Aug 18];59(24):12874–81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22098542

14. Liang H-J, Suk F-M, Wang C-K, Hung L-F, Liu D-Z, Chen N-Q, et al. Osthole, a potential antidiabetic agent, alleviates hyperglycemia in db/db mice. Chem Biol Interact [Internet]. 2009 Oct 30 [cited 2014 Aug 18];181(3):309–15. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19682441

15. Zhang Y, Xie M, Xue J, Gu Z. Osthole improves fat milk-induced fatty liver in rats: modulation of hepatic PPAR-alpha/gamma-mediated lipogenic gene expression. Planta Med [Internet]. 2007 Jul [cited 2014 Aug 18];73(8):718–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17611927

16. Yuan J, Xie J, Li A, Zhou F. [Effects of osthol on androgen level and nitric oxide synthase activity in castrate rats]. Zhong Yao Cai [Internet]. 2004 Jul [cited 2014 Sep 12];27(7):504–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15551966

17. Tang D-Z, Hou W, Zhou Q, Zhang M, Holz J, Sheu T-J, et al. Osthole stimulates osteoblast differentiation and bone formation by activation of beta-catenin-BMP signaling. J Bone Miner Res [Internet]. 2010 Jun [cited 2014 Aug 18];25(6):1234–45. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3153131&tool=pmcentrez&re ndertype=abstract

18. Kuo P-L, Hsu Y-L, Chang C-H, Chang J-K. Osthole-mediated cell differentiation through bone morphogenetic protein-2/p38 and extracellular signal-regulated kinase 1/2 pathway in human osteoblast cells. J Pharmacol Exp Ther [Internet]. 2005 Sep [cited 2014 Aug 18];314(3):1290–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15956019

19. Ming L-G, Zhou J, Cheng G-Z, Ma H-P, Chen K-M. Osthol, a coumarin isolated from common cnidium fruit, enhances the differentiation and maturation of osteoblasts in vitro. Pharmacology [Internet]. 2011 Jan [cited 2014 Aug 18];88(1-2):33–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21734431

20. Tasanarong A, Kongkham S, Thitiarchakul S, Eiam-Ong S. Vitamin E ameliorates renal fibrosis in ureteral obstruction: role of maintaining BMP-7 during epithelial-to- mesenchymal transition. J Med Assoc Thai [Internet]. 2011 Dec [cited 2014 Aug 18];94 Suppl 7:S10–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22619901

21. Hamidi MS, Corey PN, Cheung AM. Effects of vitamin E on bone turnover markers among US postmenopausal women. J Bone Miner Res [Internet]. 2012 Jun [cited 2014 Aug 18];27(6):1368–80. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22308007

22. Sammons J, Ahmed N, El-Sheemy M, Hassan HT. The role of BMP-6, IL-6, and BMP-4 in mesenchymal stem cell-dependent bone development: effects on osteoblastic differentiation induced by parathyroid hormone and vitamin D(3). Stem Cells Dev

[Internet]. 2004 Jun [cited 2014 Aug 18];13(3):273–80. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15186723

23. Miyakoshi N, Sasaki H, Kasukawa Y, Kamo K, Shimada Y. Effects of a vitamin D analog, alfacalcidol, on bone and skeletal muscle in glucocorticoid-treated rats. Biomed Res [Internet]. 2010 Jan [cited 2010 Dec 29];31(6):329–36. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21187643

24. Scharla SH, Schacht E, Lempert UG. Alfacalcidol versus plain vitamin D in inflammation induced bone loss. J Rheumatol Suppl [Internet]. 2005 Sep [cited 2014 Sep 16];76:26–32. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16142848

25. Liu Y, Liu Y, Zhang R, Wang X, Huang F, Yan Z, et al. All-trans retinoic acid modulates bone morphogenic protein 9-induced osteogenesis and adipogenesis of preadipocytes through BMP/Smad and Wnt/β-catenin signaling pathways. Int J Biochem Cell Biol [Internet]. 2014 Feb [cited 2014 Aug 10];47:47–56. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24300824

26. Skillington J, Choy L, Derynck R. Bone morphogenetic protein and retinoic acid signaling cooperate to induce osteoblast differentiation of preadipocytes. J Cell Biol [Internet]. 2002 Oct 14 [cited 2014 Aug 18];159(1):135–46. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2173483&tool=pmcentrez&re ndertype=abstract

27. Zhang W, Deng Z-L, Chen L, Zuo G-W, Luo Q, Shi Q, et al. Retinoic Acids Potentiate BMP9-Induced Osteogenic Differentiation of Mesenchymal Progenitor Cells. Linden R, editor. PLoS One [Internet]. 2010 Jul 30 [cited 2014 Aug 7];5(7):e11917. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2912873&tool=pmcentrez&re ndertype=abstract

28. Paralkar VM, Grasser WA, Mansolf AL, Baumann AP, Owen TA, Smock SL, et al. Regulation of BMP-7 expression by retinoic acid and prostaglandin E(2). J Cell Physiol [Internet]. 2002 Feb [cited 2014 Aug 18];190(2):207–17. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11807825

29. Amini AA, Nair LS. Recombinant human lactoferrin as a biomaterial for bone tissue engineering: mechanism of antiapoptotic and osteogenic activity. Adv Healthc Mater [Internet]. 2014 Jun [cited 2014 Aug 18];3(6):897–905. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24352833

30. Cornish J, Palmano K, Callon KE, Watson M, Lin JM, Valenti P, et al. Lactoferrin and bone; structure-activity relationships. Biochem Cell Biol [Internet]. 2006 Jun [cited 2014 Aug 18];84(3):297–302. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16936800

31. Yoshimaki T, Sato S, Tsunori K, Shino H, Iguchi S, Arai Y, et al. Bone regeneration with systemic administration of lactoferrin in non-critical-sized rat calvarial bone defects. J Oral Sci [Internet]. 2013 Jan [cited 2014 Aug 18];55(4):343–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24351923

32. Amini AA, Nair LS. Lactoferrin: a biologically active molecule for bone regeneration. Curr Med Chem [Internet]. 2011 Jan [cited 2014 Aug 18];18(8):1220–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21291364

33. Naot D, Grey A, Reid IR, Cornish J. Lactoferrin–a novel bone growth factor. Clin Med Res [Internet]. 2005 May [cited 2014 Aug 18];3(2):93–101. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1183439&tool=pmcentrez&re ndertype=abstract

34. Cornish J. Lactoferrin promotes bone growth. Biometals [Internet]. 2004 Jun [cited 2014 Aug 18];17(3):331–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15222486

35. Cornish J, Callon KE, Naot D, Palmano KP, Banovic T, Bava U, et al. Lactoferrin is a potent regulator of bone cell activity and increases bone formation in vivo. Endocrinology [Internet]. 2004 Sep [cited 2014 Aug 18];145(9):4366–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15166119

36. Hou J-M, Xue Y, Lin Q-M. Bovine lactoferrin improves bone mass and microstructure in ovariectomized rats via OPG/RANKL/RANK pathway. Acta Pharmacol Sin [Internet]. 2012 Oct [cited 2014 Sep 2];33(10):1277–84. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22902986

37. Betteridge DJ. Cardiovascular endocrinology in 2012: PCSK9-an exciting target for reducing LDL-cholesterol levels. Nat Rev Endocrinol [Internet]. 2013 Feb [cited 2013 Nov 11];9(2):76–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23296165

38. Joung YH, Lim EJ, Darvin P, Jang JW, Park K Do, Lee HK, et al. Hwanggeumchal sorghum extract enhances BMP7 and GH signaling through the activation of Jak2/STAT5B in MC3T3E1 osteoblastic cells. Mol Med Rep [Internet]. 2013 Sep [cited 2014 Aug 18];8(3):891–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23877734

39. Chung I-M, Yeo M-A, Kim S-J, Kim M-J, Park D-S, Moon H-I. Antilipidemic activity of organic solvent extract from Sorghum bicolor on rats with diet-induced obesity. Hum Exp Toxicol [Internet]. 2011 Nov [cited 2014 Aug 18];30(11):1865–8. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/21078773

40. Sun XL, Baker HM, Shewry SC, Jameson GB, Baker EN. Structure of recombinant human lactoferrin expressed in Aspergillus awamori. Acta Crystallogr D Biol Crystallogr [Internet]. 1999 Feb [cited 2014 Sep 11];55(Pt 2):403–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10089347

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ndertype=abstract

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WARNING

Consult your physician before using this or any dietary supplement. Do not take if you are pregnant or breast feeding, elderly or under the age of 18, chronically ill, or taking any prescription or over-the-counter medicine, including but not limited to antidepressants (such as MAO inhibitors), stimulants, allergy medications, and medications for high blood pressure or oth