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Journal of the American College of Nutrition, Vol. 20, No. 90005, 410S-416S (2001)
Published by the American College of Nutrition

Nutraceutical Fatty Acids as Biochemical and Molecular Modulators of Skeletal Biology

Bruce A. Watkins, PhD, FACN, Yong Li, PhD and Mark F. Seifert, PhD

Department of Food Science, Lipid Chemistry and Molecular Biology Laboratory, Purdue University, West Lafayette, and Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana

Address reprint requests to: Bruce A. Watkins, PhD, Department of Food Science, Lipid Chemistry and Molecular Biology Laboratory, Purdue University, West Lafayette, IN 47907. E-mail: watkins{at}foodsci.purdue.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 LIPIDS AND BONE HEALTH
 NUTRACEUTICAL PUFA: AGENTS FOR...
 DIETARY PUFA AND BONE...
 CONCLUSION
 REFERENCES
 
Several systemic hormones and localized growth factors coordinate events of bone formation and resorption to support bone growth in the young and maintain bone mineral content in the adult. Some of the more important factors produced in the bone microenvironment that impact skeletal biology include prostaglandins, cytokines, and insulin-like growth factors. Dietary fat sources that exert potent biological effects on the skeletal tissues belong to the omega-6 and omega-3 families of essential fatty acids. Specific long-chain polyunsaturated fatty acids (PUFA) belonging to these families are substrates for prostanoids that influence the differentiation and activity of cells in bone and cartilage tissues. These PUFA appear to alter prostanoid formation, cell-to-cell signaling processes, and impact transcription factors in vivo. Hence, these biologically active PUFA can be called nutraceutical fatty acids. This review highlights the role of nutraceutical fatty acids on bone metabolism and joint disease. The recent discovery of transcription factors controlling osteoblast function, and soluble proteins directing osteoclastogenesis and osteoblastogenesis offer new research opportunities for studying nutraceutical fatty acids in skeletal biology.

Key words: bone, cyclooxygenase, polyunsaturated fatty acids, eicosapentaenoic acid, osteoprotegerin, Cbfa1

Abbreviations: Cbfa1 = Core binding factor alpha-1 • COX = Cyclooxygenase • EPA = Eicosapentaenoic acid • ODF = Osteoclast differentiation factor • OPG = Osteoprotegerin • PGE2 = Prostaglandin E2 • PUFA = Polyunsaturated fatty acids • RANKL = Receptor activator of NF{kappa}B ligand • TRANCE = Tumor necrosis factor related activation-induced cytokine

Key teaching points:

• Numerous systemic hormones and localized growth factors, including prostaglandin E2, orchestrate bone formation and bone resorption.

• Dietary sources of long-chain n-3 polyunsaturated fatty acids appear to modulate bone formation and resorption in vivo by altering the interaction and signaling events of localized factors in bone.

• Recently discovered transcription factors and signaling proteins controlling osteoblastogenesis and osteoclastogenesis may serve as targets for modification by nutraceutical PUFA.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
LIPIDS AND BONE HEALTH
 NUTRACEUTICAL PUFA: AGENTS FOR...
 DIETARY PUFA AND BONE...
 CONCLUSION
 REFERENCES
 
Osteoporosis and degenerative joint diseases are widespread public health problems of the aging population. These diseases generally afflict the adult and elderly; however, the risk for developing these disorders may be influenced by lifestyle practices established during adolescent years. Osteoporosis is a state of decreased bone mass that is prevalent in postmenopausal women and places them at risk for fractures. Although there is no cure for this disease, optimizing bone development in the young and reducing bone resorption to maintain bone mass in the adult may minimize osteoporosis. The recent discovery of signaling factors associated with osteoclastogenesis and transcription factors that control osteoblast differentiation and function offer novel methods for therapeutic intervention to support bone formation and restore skeletal integrity in the adult. Osteoclast differentiation factor [ODF, also known as OPGL (osteoprotegerin ligand), RANKL (receptor activator of NF{kappa}B ligand), TRANCE (TNF-related activation-induced cytokine)] and osteoprotegerin [OPG, also known as OCIF (osteoclastogenesis inhibitory factor)] are proteins that participate in bone cell differentiation. New findings about the hormone leptin and certain statin drugs, both associated with lipid metabolism, indicate that these agents impact bone metabolism in both animal models and human subjects. In addition, experiments using animal and cell culture models, and epidemiological studies suggest that n-3 PUFA may afford benefits to reduce the risk for osteoporosis and improve symptoms of degenerative joint disease. Specific dietary fatty acids were found to modulate prostanoid synthesis in bone tissues, and improve bone formation rates in animal models. This review presents evidence that certain hormones, pharmaceutical agents, and nutraceutical fatty acids influence bone metabolism and may serve as a means to promote bone health and reduce the risk of skeletal disease.


   LIPIDS AND BONE HEALTH
TOP
 ABSTRACT
 INTRODUCTION
 LIPIDS AND BONE HEALTH
NUTRACEUTICAL PUFA: AGENTS FOR...
 DIETARY PUFA AND BONE...
 CONCLUSION
 REFERENCES
 
Prostanoids and Bone Metabolism
Prostaglandin E2 (PGE2) is produced by a variety of cells associated with the bone microenvironment and mediates the effects of systemic hormones and localized factors on bone formation and resorption during bone modeling and remodeling. For example, PGE2 mediates the effects of 1,25-(OH)2 vitamin D3 [1], cytokines (TNF-{alpha} [2], IL-3 [1]), and growth factors (TGF-ß [3], PDGF [4], bFGF [5]) in promoting bone resorption. Moreover, elevated production of PGE2 has been associated with osteolytic disorders in humans, including bone loss associated with dental cysts, failing joint prostheses, chronic osteomyelitis, and certain neoplasms of bone [6]. Also, the production of PGE2 is associated with osteoclastogenesis. By eliminating the COX-2 gene, a step-limiting enzyme in PGE2 formation, osteoclast formation stimulated by 1,25-(OH)2 vitamin D3 or PTH was reduced 60% to 70% in mouse marrow cultures [7]. The addition of exogenous PGE2 reversed the inhibition of osteoclast formation. The stimulatory effect of ODF on bone resorption may also be mediated by PGE2. In ovariectomized mice, ODF expression in bone marrow stromal cells [8] and pre-B cells [9] was enhanced by elevated production of PGE2 in bone marrow induced by increased concentrations of proinflammatory cytokines such as IL-1 and TNF-{alpha} [10,11].

PGE2 also exerts a biphasic effect on bone formation. For example, the local concentration of PGE2 modulates the stimulatory effect of bone morphogenetic protein-2 (BMP-2) on osteoblast differentiation. At lower levels (10-10 to 10-8 M), PGE2 enhances alkaline phosphatase activity, a marker for bone formation, in osteoblastic cultures while it suppresses cell differentiation at a higher concentration (10-6 M) [12]. Other studies also indicate that the PGE2 effects on bone formation in animal models seem to be dose-related, stimulatory at low concentrations and inhibitory at high concentrations [13–15].

Osteoblast and osteoclast progenitor cell proliferation and differentiation are influenced by interactions of PGE2 with its receptors (EP1, EP2, EP3, and EP4) in osteoblastic and marrow stromal cells. PGE2 stimulated osteoblast differentiation but inhibited proliferation through the EP1-IP3 pathway in cells from young rats. Moreover, it inhibited differentiation but stimulated proliferation via the EP2/EP4-cAMP pathway in cells regardless of the age of the donor rats [16]. EP4 has been shown to mediate the PGE2 effect on bone resorption. PGE2 stimulated bone resorption by a cAMP-dependent mechanism via the EP4 receptor [17]. In the same study, it was found that PGE2’s stimulatory action on bone resorption was significantly compromised in calvarial and long bone cultures from EP4 gene knockout mice [17]. Osteoblast-mediated bone resorption induced by PGE2 also appeared to involve EP2. Furthermore, PGE2-stimulated bone resorption via its induction of ODF was partially mediated by its EP2 receptor in mouse calvarial cultures [18].

Leptin and Statins: A Role in Skeletal Biology?
New investigations in skeletal biology and leptin suggest a role for this systemic hormone in bone remodeling. Leptin is a regulator of appetite and lipid metabolism. Besides its lipostatic action, leptin is further involved in more diverse physiological processes than originally defined in its regulation of lipid metabolism. White adipose tissue, brown fat, placenta, and fetus all produce leptin [19]. Among its many biological effects, leptin was recently proposed to be a neuroendocrine regulator of bone mass and is thought to exert an effect on the local bone cell microenvironment.

Leptin may affect bone mass through the central nervous system. In a recent study by Ducy et al. [20], bone mass was significantly increased in ob/ob mice, which lack signaling of leptin, compared to that of the wild-type littermates. Osteoblasts from ob/ob mice were more active in bone matrix production. Moreover, there was no particular defect in osteoclast function in these mice. Intraventricular infusion of leptin in ob/ob and wild-type mice induced bone loss, which strongly supports that leptin imparts some control over bone mass. Leptin may also act as a local regulator of bone cell differentiation. Recently, leptin was demonstrated to have a direct osteogenic effect on human marrow stromal cells (hMS2-12) that are capable of differentiating into either osteoblasts or adipocytes [21]. Thus it is possible that local production of leptin plays a role in bone metabolism. Results from epidemiological studies also support the regulatory role of leptin on bone metabolism. Circulating leptin levels are usually higher in overweight individuals. In these subjects, moderate excess in body weight was significantly associated with the reduced vertebral bone loss observed in postmenopausal women [22].

Statins represent another group of agents that affect lipid metabolism. They act as specific inhibitors of hydroxy-methyl-glutaryl-CoA (HMG-CoA) reductase and are widely used clinically to lower serum cholesterol levels. Recently, certain statins were reported to enhance bone formation in vitro and in vivo. Lovastatin and simvastatin increased calvarial bone formation rate when injected subcutaneously in mice and improved cancellous bone volume after oral administration to rats [23]. It is believed that these statins stimulate bone formation by inducing the expression of BMP-2, which increases differentiation of osteoblasts [23]. Recent case-control studies also support the role of statin compounds in promoting bone formation. Statins reduced the risk of fractures in human subjects [24]; however, other lipid-lowering agents that function similarly to statins did not show a benefit on bone formation [25,26].

Not all statins produce an increase in bone formation. Evaluation of Japanese subjects with type 2 diabetes who received pravastatin (88.5% percent of the subjects) did not demonstrate an association between its use and higher bone mineral density (BMD) [27]. Sugiyama et al. [28] studied the effect of three statins, compactin, simvastatin, and pravastatin, in inducing BMP-2 expression in osteoblastic cells (HOS, human osteosarcoma cells). They found that pravastatin was not as effective as the other two drugs. In addition to their effect on bone formation, statins may also inhibit bone resorption. Fisher et al. [29] reported that murine osteoclast formation in culture is inhibited by lovastatin. Interestingly, the effect of lovastatin is blocked by mevalonate, a down-stream metabolite of HMG-CoA reductase.


   NUTRACEUTICAL PUFA: AGENTS FOR MODULATING OSTEOCLASTOGENESIS AND OSTEOBLASTOGENESIS?
TOP
 ABSTRACT
 INTRODUCTION
 LIPIDS AND BONE HEALTH
 NUTRACEUTICAL PUFA: AGENTS FOR...
DIETARY PUFA AND BONE...
 CONCLUSION
 REFERENCES
 
Recent discoveries of ODF, a membrane bound/soluble protein produced primarily by osteoblastic and stromal cells that stimulates osteoclastogenesis, and OPG, a soluble ODF receptor that deactivates the ODF effect on osteoclast formation, impart greater insight into the mechanisms of osteoclast differentiation and function [30]. ODF appears to be a common mediator of osteoclast formation induced by many osteotropic hormones and cytokines, such as PTH [31,32], glucocorticoids [33], TNF-{alpha}, IL-1 [34], IL-6 [35], and IL-11 [36]. OPG, a decoy receptor for ODF, works reciprocally with ODF to regulate the induction of mature osteoclastic cells.

It is believed that the ratio of ODF/OPG may be a regulatory mechanism controlling bone resorption. The mRNA ratio of ODF/OPG in osteoblasts is increased by three bone resorbing factors, namely 1,25-(OH)2 vitamin D3, PGE2, and PTH [32,36]. Hofbauer and colleagues [33] showed that glucocorticoids promote osteoclastogenesis by inhibiting OPG and concurrently stimulating ODF production by osteoblastic lineage cells resulting in enhanced bone resorption.

ODF has also been found to be involved in inflammatory and degenerative bone and joint diseases. ODF expressed on synovial fibroblasts is involved in rheumatoid bone destruction by inducing osteoclastogenesis [37]. ODF is expressed by both synovial fibroblasts and by activated T lymphocytes derived from synovial tissues from patients with rheumatoid arthritis (RA) but not from normal synovial tissues. These synovial cells may contribute directly to the expansion of osteoclast precursors and to the formation and activation of osteoclasts at sites of bone erosion in RA [38]. Evidence also suggests that the stimulatory effect of PGE2 on osteoclastogenesis may be mediated by inhibition of OPG expression in bone cells. PGE2 down-regulated OPG mRNA level in human bone marrow stromal cells (hBMSC) [39], and PGE2 decreased OPG expression in mouse calvarial osteoblasts that supported an increase in osteoclastogenesis [40]. ODF participates in enhanced bone resorption in humoral hypercalcemia of malignancy [41]. When cultured in media conditioned by SCC-4 and T3M-1 C1.2 cells (squamous cell carcinoma cell lines), HL60 human promyeloblastic leukemia cells differentiated into osteoclast-like cells. Anti-ODF antibody inhibited differentiation of HL60 cells indicating that ODF contributes to the induction of the osteoclastic phenotype observed in these cells. Since PUFA from dietary sources have been shown to influence receptor-mediated signal transduction [42], and modulate PGE2 production in bone [43,44] and in osteoblast-like cell cultures [45], they may potentially influence the ratio of ODF/OPG which could explain the differences in bone formation rates depending upon the predominant PUFA ingested [43,44].

Cbfa1
Cbfa1 is an osteoblast-specific transcription factor essential for the development of active osteoblasts. Cbfa1 directs differentiation of multipotential mesenchymal precursor cells to osteoblasts at the expense of adipocyte differentiation [46]. Inactivation of Cbfa1 in mice by gene targeting leads to a complete absence of bone in the newborn. Cartilage tissues develop normally in these mice but there is no differentiation of mesenchymal stem cells into osteoblasts [47,48]. Cbfa1 also regulates the function of differentiated osteoblasts during postnatal growth by controlling its own gene expression and the expression of extracellular matrix genes encoding for type I collagen, osteocalcin, osteopontin, and bone sialoprotein [49].

There is evidence that Cbfa1 mediates the effect of growth factors and hormones in osteoblast differentiation. Glucocorticoids were shown to suppress Cbfa1 expression in osteoblasts [50] leading to decreased bone formation. On the other hand, Cbfa1 expression is increased by factors such as TGFß1, BMP-2 [51,52], the heterodimer BMP4/7 [53], and BMP-7 [54] that promote the commitment of multipotential stromal cells to differentiate into osteoblastic cells and augment the activity of differentiated osteoblasts [52]. At present time, no studies have tested the effect of PUFA on Cbfa1 expression in vivo or in vitro; however, diets containing long-chain n-3 PUFA were associated with higher rates of bone formation in animals that might suggest an up-regulation of osteoblastogenesis [14,15,44].

Another role of Cbfa1 in bone metabolism involves its participation in controlling osteoclastogenesis and bone resorption. Cbfa1 deficiency compromised the ability of embryonic calvarial cells to support osteoclast formation in vitro, and ODF expression was absent in Cbfa1-deficient embryos in vivo, which explains why there is an absence of osteoclasts in Cbfa1-deficient mice [55]. These results suggest that the regulatory effect of Cbfa1 on osteoclastogenesis is achieved by modulating the expression of ODF. It has also been shown that Cbfa1 is required for the expression [56] and induction [57] of collagenase 3 by PTH, a metalloproteinase essential to the cleavage of bone collagen. Thus, Cbfa1 may control several genes involved in bone cell differentiation and in bone matrix production.


   DIETARY PUFA AND BONE HEALTH
TOP
 ABSTRACT
 INTRODUCTION
 LIPIDS AND BONE HEALTH
 NUTRACEUTICAL PUFA: AGENTS FOR...
 DIETARY PUFA AND BONE...
CONCLUSION
 REFERENCES
 
In postmenopausal osteoporosis, an uncoupling of bone formation with resorption occurs such that the rate of bone resorption exceeds that of bone formation contributing to excessive mineral loss and increased fracture risk. Studies have shown that a dietary source of long-chain n-3 PUFA [eicosapentaenoic acid (EPA)] appears to influence both bone formation and bone resorption in normal and ovariectomized rats. Fish oil, which is rich in this n-3 PUFA, reduced osteoclastic activity and alveolar bone resorption when fed to rats [58]. An EPA-enriched diet prevented the loss of bone weight and strength in rats caused by estrogen deficiency following ovariectomy [59]. Ovariectomized rats given diets containing different supplemental fatty acids (diesters of {gamma}-linolenic acid or EPA) and treated with estrogen implants showed increased femur calcium content and reduced urinary deoxypyridinoline and hydroxypyridinoline excretion compared with the sham-operated group [60]. These results demonstrated that long-chain n-3 PUFA worked synergistically with estrogen to exert a stimulatory effect on bone mineral deposition and an inhibitory effect on bone resorption. Therefore, the effects of long-chain n-3 PUFA in moderating bone loss in ovariectomized adult rats [59,60] and enhancing bone formation in growing rats [43,44] may involve a down-regulation of osteoclastogenesis (linked to the ratio of ODF/OPG) or an up-regulation of osteoblastogenesis associated with Cbfa1, respectively, in these two experimental situations.

Inflammatory cytokines are known to inhibit chondrocyte proliferation [61] and induce cartilage degradation and it is believed that part of this response is mediated by PGE2 [62]. Excess production of PGE2 is linked to joint pathology (rheumatoid arthritis), is known to exacerbate inflammatory responses, and results in a net loss of proteoglycan from articular cartilage [62]. The fact that selective COX-2 inhibitors provide satisfactory relief of symptoms in both osteoarthritis and rheumatoid patients [63,64] indicates that eicosanoids participate in the inflammatory processes of these severe bone and joint diseases. COX-2 and its product, PGE2, appear to be a common link between the two disease states. Since it is possible to regulate the activity and expression of COX-2, this enzyme can be a target for dietary intervention in order to optimize bone formation and help control these skeletal diseases. Nutraceutical long-chain n-3 PUFA are associated with decreased pathogenesis of rheumatoid arthritis and other inflammatory diseases [65–67]. Incorporation of n-3 PUFA into articular cartilage chondrocyte membranes resulted in a dose-dependent reduction in the expression and activity of proteoglycan degrading enzymes, the expression of inflammatory cytokines TNF-{alpha} and IL-1, and the expression of COX-2 but not COX-1 [68]. Though suggestive, convincing evidence of the effect of n-3 PUFA on COX-2 is still lacking. More carefully designed studies are needed to demonstrate the efficacy of these nutraceutical fatty acids in controlling skeletal disorders in animals and human subjects.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 LIPIDS AND BONE HEALTH
 NUTRACEUTICAL PUFA: AGENTS FOR...
 DIETARY PUFA AND BONE...
 CONCLUSION
REFERENCES
 
New evidence suggests that certain PUFA, leptin, and statins that alter lipid metabolism also play an emerging role in bone biology. Reducing PGE2 synthesis from arachidonic acid is associated with increased bone formation in growing rats, minimized bone loss in ovariectomized adult rats, and improved osteoblast function in cell culture. Moreover, in some studies dietary n-3 PUFA were found to improve symptoms for certain bone and joint diseases in the human. At present, the beneficial effects of long-chain n-3 PUFA appear to be, in part, associated with down-regulating PGE2 formation. Potential effects of these PUFA on receptor-mediated signal transduction events and on transcription factors associated with bone cell differentiation and function are important for future investigations. The prospect that nutraceutical PUFA may improve bone biology will depend on research evaluating molecular factors involved in osteoblast differentiation, bone remodeling, and disease processes of the skeletal system.


   FOOTNOTES
 
Approved as Journal Paper Number 16477 of the Purdue Agricultural Experiment Station.

Received April 26, 2001.
   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 LIPIDS AND BONE HEALTH
 NUTRACEUTICAL PUFA: AGENTS FOR...
 DIETARY PUFA AND BONE...
 CONCLUSION
 REFERENCES
 

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R. C. Poulsen, P. J. Moughan, and M. C. Kruger
Long-Chain Polyunsaturated Fatty Acids and the Regulation of Bone Metabolism
Experimental Biology and Medicine, November 1, 2007; 232(10): 1275 - 1288.
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