The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 83, Issue 12

Current Concepts Review | December 01, 2001

Brain and Bone: Central Regulation of Bone Mass : A New Paradigm in Skeletal Biology

Michael Haberland, MD; Arndt F. Schilling, MD; Johannes M. Rueger, MD; Michael Amling, MD

Investigation performed at the Department of Trauma and Reconstructive Surgery, Hamburg University School of Medicine, Hamburg, Germany

Michael Haberland, MD
Arndt F. Schilling, MD
Johannes M. Rueger, MD
Michael Amling, MD
Department of Trauma and Reconstructive Surgery, Hamburg University School of Medicine, Martinistrasse 52, 20246 Hamburg, Germany. E-mail address for M. Amling: amling@uke.uni-hamburg.de

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from German Research Community (DFG), Grant AM 103/8-1. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

J Bone Joint Surg Am, 2001 Dec 01;83(12):1871-1876

5 Recommendations (Recommend) | 3 Comments | Saved by 3 Users Save Case

Article

Comments (0)

text A A A

Extract

Bone-remodeling is the cellular process used by vertebrates to maintain a nearly constant bone mass between the end of puberty and the time of cessation of gonadal function.

Figures in this Article

Introduction

Introduction | Bone-Remodeling: Different Levels of Regulation | Clinical Observations Leading to a Molecular Basis for Understanding Bone-Remodeling | Dominant Function of Leptin: Inhibition of Bone Formation | Intelligent Skeleton: Hypothalamic ontrol of Bone Formation | Conclusion and Perspective | References

Bone-remodeling is the cellular process used by vertebrates to maintain a nearly constant bone mass between the end of puberty and the time of cessation of gonadal function.

Body weight, fertility, and bone formation are regulated, at least in part, by the same hormone, leptin, which exerts its control through hypothalamic pathways.

Bone-remodeling disorders such as osteoporosis are, in part, hypothalamic diseases, and modulation of central signaling pathways can be used to overcome the skeletal consequences of gonadal failure and to potentially restore bone mass.

Bone mass is of critical importance for skeletal integrity and skeletal function. A sufficient bone stock is required for locomotion, for protection of inner organs, as a reservoir of vital ions, and as the scaffold for skeletal repair and osteosynthesis. Bone-remodeling is the physiological process used by vertebrates to maintain a constant bone mass between the end of puberty and the time of cessation of gonadal function. In addition to the well-characterized and critical local regulation of bone-remodeling, a central control of bone formation has been shown in recent genetic studies¹. This central regulation involves leptin, an adipocyte-secreted hormone that controls body weight, reproduction, and bone-remodeling following binding to its receptor located on hypothalamic nuclei. This novel physiological concept may shed light on the etiology of osteoporosis and help to identify new therapeutic strategies for the treatment of that disease and its associated clinical problems, such as delayed fracture-healing.

Our understanding of the biology of the skeleton, like that of virtually every other subject in biology, has been transformed by recent advances in human, mouse, and chick genetics. These advances, together with findings by embryologists studying chickens, have radically enhanced our comprehension of the developmental biology of the vertebrate skeleton^2-4. In contrast, we have added very little to our understanding of skeletal physiology. Some of the many largely unanswered questions about skeletal physiology include:

• Why and how do we stop growing?

• Why and how are bones and teeth the only organs to mineralize under physiological conditions?

• Why is osteoporosis mainly a disease affecting women?

• How is bone mass maintained at a nearly constant level between the end of puberty and the arrest of gonadal function?

This review will deal with the final question.

The two clinical observations that are the basis for this review are that cessation of gonadal function favors the development of osteoporosis while obesity protects against it. Our working hypothesis has been that these two observations suggest that body mass, bone-remodeling, and reproduction are somehow controlled by the same endocrine mechanisms. Since body weight and reproduction are known to be controlled centrally, it is reasonable to hypothesize that bone-remodeling may be controlled centrally as well. In addition to the large body of evidence indicating the existence of a local regulation of bone-remodeling (which will not be discussed here), genetic evidence demonstrates the existence of a central regulation of bone-remodeling; this evidence is consistent with the concept that the two clinical observations mentioned above are mechanistically linked^1-5. This central regulation is not accessory, as its modulation can overcome the deleterious effect of cessation of gonadal function on bone-remodeling and prevent osteoporotic bone loss.

View Large | Download Slide(.ppt)
Add to My JBJS

Fig. 1:: Osteopetrosis in the vertebra of a mouse deficient for the src gene as an example of continuing osteoblast function despite a lack of functional active osteoclasts. A: Low-power photomicrograph of a lumbar vertebra of a normal mouse (20). B: Low-power photomicrograph of a lumbar vertebra of an src-deficient mouse, showing a substantial increase in bone density (20). C: High-power view of 1,A, showing normal trabecular bone volume (200). D: High-power view of 1,B, showing the massive increase of trabecular bone volume due to osteoclast malfunction (200). All photomicrographs were made of 5-mm undecalcified sections, which were stained with von Kossa stain.

View Large | Download Slide(.ppt)
Add to My JBJS

Fig. 2:: Leptin deficiency leads to high bone mass. Despite their hypogonadic and hypercortisolic state, ob/ob mice (right), in which leptin signaling is absent, have a high-bone-mass phenotype compared with wild-type controls (left). Images of lumbar vertebrae were made with micro-computed tomography with subsequent three-dimensional reconstruction (top panel) and a single-slice scan of a vertebral cross-section (bottom panel). Note the increase in trabecular thickness and trabecular number in the ob/ob mice.

View Large | Download Slide(.ppt)
Add to My JBJS

Fig. 3:: Central regulation of bone mass. Leptin, after its synthesis in adipocytes, binds to its receptor (Ob-Rb) in the hypothalamus and influences bone formation, body weight, and fertility.

Bone-Remodeling: Different Levels of Regulation

Bone-remodeling is the physiological process by which constant bone mass is maintained in vertebrates between the end of puberty and the time of cessation of gonadal function⁶. This is an unusual process as bone is the only organ that contains a cell type, the osteoclast, whose only function is to remove or resorb the tissue that supports it^7-9. Indeed, every day and simultaneously at multiple locations, bone is resorbed by osteoclasts and then replaced with new bone laid down by the osteoblasts. The fact that this process occurs simultaneously in multiple locations in the skeleton, together with the well-documented role of cells of the osteoblast lineage that direct osteoclast differentiation, has been viewed as proof that bone-remodeling is primarily an autocrine/paracrine process^10-12. Extensive experimental evidence has demonstrated that this regulation does exist^12,13, and this review will not address it in detail. For instance, many cytokines present in the extracellular matrix or synthesized by bone cells have been shown to be involved in bone-remodeling. This research has culminated recently in the discovery of osteoprotegerin (OPG), which is an inhibitor of osteoclast differentiation^14,15, and the discovery of the receptor activator of NF-kB ligand (RANKL), which is an osteoclast differentiation factor¹⁶. Genetic evidence has demonstrated that RANKL and its soluble receptor OPG play a critical role during osteoclast differentiation and can act in a paracrine way^16-19. Yet it is also well known that hormones such as sex steroid and parathyroid hormones, among others, can affect bone resorption^20,21, and OPG as well as RANKL can also act in a systemic manner^14,16. These latter observations suggest that there is also an endocrine regulation of bone-remodeling. These two types of regulation—namely, systemic and local—are not antagonistic but should be viewed as synergistic.

Moreover, clinical evidence, reproducible in mutant mouse strains, suggests that there is a systemic regulation of bone formation. In osteopetrotic patients, the osteoclasts are either absent or nonfunctional, yet bone formation is not halted. The same is true in animal models of osteopetrosis. Mice lacking the src gene, which is essential for osteoclast function, and thus showing no osteoclastic activity still have ongoing bone formation and eventually severe osteopetrosis develops (Fig. 1)^22-24. The simplest explanation for the maintenance of bone formation activity in the absence of bone resorption is that there is a systemic regulation.

In contrast to the emerging knowledge regarding the existence of a systemic regulation of bone resorption, much less is known about the molecular mechanisms regulating the rate of bone formation by the osteoblasts. The results of one experiment suggest that bone formation is regulated primarily by endocrine signals²⁵. By means of targeted overexpression in osteoblasts of a thymidine kinase gene, Corral et al. were able to induce a nearly complete and reversible osteoblast ablation²⁵. In these transgenic animals, osteoblast ablation led to bone loss, thus illustrating that bone resorption in mice is a function independent of bone formation. However, the most remarkable feature of this model lies elsewhere. Upon osteoblast repopulation, bone mass was restored with an exquisite precision to virtually the same amount as in that in the wild-type age-matched littermates. This extreme precision indicates that somehow the osteoblast has "two speeds" to make bone. It can first quickly deposit a large amount of bone matrix to restore bone mass, and then, once this has been achieved, it can slow down, decreasing the amount of bone matrix deposited, so that bone mass does not increase beyond that in wild-type mice. This "two-speed" model can be viewed as indirect evidence of an endocrine regulation of bone formation, and recognition of this concept has been an incentive to look for circulating molecules regulating the rate of bone formation by the osteoblasts²⁵.

Clinical Observations Leading to a Molecular Basis for Understanding Bone-Remodeling

One approach to understanding why bone formation is so tightly regulated is to ask what is deregulated in pathological situations. The most frequent disease affecting bone-remodeling is osteoporosis²⁶. Osteoporosis is characterized by low bone mass with an increased risk of fracture following minimal trauma²⁷. It is the most prevalent disease in developed countries, a fact that emphasizes the importance of understanding, in molecular terms, the regulation of bone homeostasis. Multiple clinical and epidemiological features characterize osteoporosis^28,29. Two long-recognized clinical findings—that osteoporosis is often triggered or worsened by the cessation of gonadal function^20,30 and that obesity protects individuals from bone loss^31-33—suggest a molecular basis for the regulation of bone mass. The latter observation was for a long time poorly understood, as illustrated by the following quote: "Heavier people generally have stronger bones as well as a lower risk of suffering from osteoporotic fractures, and our studies have shown that this is mainly due to the greater proportion of body fat. Increased weight bearing does stimulate further bone growth, and, in women, estrogen is produced by fat cells. However, these facts do not adequately explain the relationship between body weight and bone density, so it is likely that other mechanisms are operative [italics added]."³⁴ Translated into a molecular vocabulary, these two observations may be viewed as suggesting that bone mass, body weight, and gonadal function are regulated by the same secreted molecules.

Dominant Function of Leptin: Inhibition of Bone Formation

On the basis of knowledge of the hormonal regulation of body mass, leptin was thought to be the best candidate to fulfill the triple regulatory function mentioned above. Leptin is a polypeptide hormone that is the product of a gene termed ob because of its role in genetically determined obesity. Mice that lack both copies of this gene (ob/ob mice) have been an invaluable tool in obesity research^35-37. Obesity is the most visible phenotype of the ob/ob mouse, but it is not the only one. Another prominent phenotype is sterility^38,39. Clearly leptin, like most known hormones, has a broad range of action on multiple target organs^36,40. Another mutant strain of mouse, the db/db mouse, has a mutation in the gene coding for the leptin receptor (termed db for diabetes) and the same series of phenotypes as the ob/ob mouse^41,42. Likewise, fa/fa rats have an inactivating mutation in the gene encoding the leptin receptor (termed fa for fatty), and they are obese and hypogonadic⁴³. Importantly, the obesity and sterility phenotypes of these two mouse and rat mutant strains are recessive. Normally, the influences of the absence of gonadal function and of the obesity of ob/ob and db/db mice on bone integrity should antagonize each other and result in a mild low-bone-mass phenotype. However, both ob/ob and db/db mice have a massive increase in bone mass¹ (Fig. 2). The ob/ob and db/db mice are the only known animal models, in any species, in which hypogonadism and high bone mass coexist; thus, in the context of bone physiology, they are an invaluable resource for the study of bone-remodeling and diseases affecting bone-remodeling. This high-bone-mass phenotype is even more surprising because these mice have hypercortisolism, a condition usually leading to a decrease in osteoblast function and to osteoporosis²⁸.

The high-bone-mass phenotype of the ob/ob and db/db mice, which is caused by an increase in bone formation, is not secondary to obesity, as it is observed in young ob/ob mice before they become obese¹. More importantly, this phenotype is dominant, being observed in heterozygous mice that harbor one intact (+) and one disrupted gene (ob or db) and thus are termed ob/+ and db/+. The phenotype is specific for the absence of leptin signaling because it is not observed in other mouse models of obesity with intact leptin signaling. The fact that the high-bone-mass phenotype is dominant and the obesity phenotype is recessive demonstrates genetically that the control of bone mass by leptin is not an accidental function of a body-weight-regulating hormone. It indicates rather that the control of bone formation, which is as important as the control of body weight, is a function of leptin. It also demonstrates that the high-bone-mass phenotype is not secondary to any endocrine abnormalities in ob/ob and db/db mice, since ob/+ and db/+ mice do not have such abnormalities.

Intelligent Skeleton: Hypothalamic ontrol of Bone Formation

How does leptin control bone formation? Does it act through an autocrine, paracrine, or endocrine mechanism? Does it require the presence of fat or does it control bone formation as it controls body weight, by binding to its hypothalamic receptor? Before addressing these crucial questions, one has to summarize the phenotypic features of the ob/ob and db/db mice and the critical implications of this phenotype. These mutant mouse strains do make more bone, but they do it with the same number of osteoblasts as wild-type mice. In other words, this is a functional phenotype, not a phenotype based on cell differentiation. This observation implies that if leptin acts locally it has to do so by means of functional receptors on differentiated primary osteoblasts, not those on osteoblast progenitors. This is an important point as there is clear evidence that the leptin receptor can be observed on immortalized multipotential stromal cell lines in vitro⁴⁴. A multiplicity of experiments, biochemical, molecular, and genetic, failed to detect any expression of leptin or of a signal transducing receptor in osteoblasts¹, thus virtually ruling out an autocrine, paracrine, or endocrine mechanism of regulation, at least in vivo.

It was conceivable that, in the absence of leptin, adipocytes release a molecule that favors bone formation. Studies of a transgenic mouse strain deprived of white fat, however, proved the contrary to be true⁴⁵. These mice, which are called fat-free mice, have a very low level of leptin since they have virtually no adipocytes⁴⁵. Nevertheless, they have a high-bone-mass phenotype, thus ruling out the possibility that, in the absence of leptin, adipocytes release an activator of bone formation. The remaining possibility to be tested was the most simple and yet the most novel—namely, that leptin controls bone formation following binding to hypothalamic nuclei where the leptin receptor is particularly abundant. Indeed, intracerebroventricular infusion of leptin in ob/ob mice led to a massive and rapid decrease of their bone mass¹. Similarly, intracerebroventricular infusion of leptin in wild-type mice led to the development of a severe osteopenic phenotype, demonstrating that bone-remodeling or at least its bone-formation aspect is under the control of the hypothalamus. No leptin could be detected in the serum of these intracerebroventricular infusion-treated animals; this latter control demonstrates unambiguously that leptin can regulate bone formation without direct contact with the osteoblast¹. These findings, in line with the mode of regulation of body weight and gonadal function, do not necessarily negate other possible modes of action of leptin yet to be demonstrated in vivo. Rather, they should be viewed as providing investigators with a new conceptual framework with which to better understand bone physiology (Fig. 3).

To date, it is still not known if there is a single linear genetic or biochemical pathway explaining leptin’s role in the control of body weight following binding to its hypothalamic receptor^46-49. Likewise, it is not known what gene products convey to the osteoblast the information that leptin delivers to the hypothalamus. Nevertheless, leptin’s actions on body weight and bone mass seem to use different pathways. Indeed, intracerebroventricular infusion of neuropeptide Y (NPY), which is an orexigenic peptide that antagonizes leptin’s action on body weight⁴⁹, has the same osteopenic effect as leptin itself^47,48. This finding suggests that NPY may have different functions in the control of body weight and bone mass. Clearly, one of the challenges ahead will be to identify genes downstream of leptin and other molecules that regulate leptin’s action on bone. Is leptin the only systemic regulator of bone formation? Most likely it is not, as the existence of a negative regulation of bone mass suggests that positive regulators of bone formation may also exist and await identification.

Conclusion and Perspective

If we examine our initial hypothesis that bone mass, body weight, and reproduction share common regulatory pathways, how do the findings in recent studies relate to the observation that cessation of gonadal function favors osteoporosis and obesity protects against it? It is well known that obese individuals display a state of leptin resistance. The molecular basis of this leptin resistance remains poorly understood, but it results in a partial functional deficiency of leptin, a situation similar to that in the ob/+ and db/+ mice.

In vivo analysis of the role of leptin during bone-remodeling has shown that bone-remodeling is as much a centrally controlled process as it is a local one. This central regulation is of paramount importance since its disruption is the only known biological setting in which the deleterious consequences of hypogonadism on bone metabolism are overcome. An implication of this genetic finding is that the most typical and frequent bone-remodeling disease—namely, osteoporosis—is partly a central or hypothalamic disease. As such, the results of the studies noted in this review may be viewed as establishing a novel paradigm in our understanding of bone-remodeling. This does not mean, however, that we now understand everything about bone-remodeling. In particular, these findings cannot explain the low bone mass observed in anorectic patients. Indeed, this shift of concepts raises more questions than it answers. The identification of leptin as a powerful inhibitor of bone formation has potential therapeutic implications. Conceivably, since the high-bone-mass phenotype is dominant and the obesity phenotype is recessive, it should be possible to design drugs acting on this pathway that have a protective effect on skeletal integrity without leading to obesity. Finally, leptin is unlikely to be the only central regulator of bone formation and/or bone mass. Other, yet to be discovered, centrally acting hormones or neurotransmitters may positively or negatively regulate bone formation, bone mass, and possibly other aspects of bone physiology, such as bone resorption or even fracture-healing.

Note: The authors are grateful to Dr. G. Karsenty and Dr. P. Ducy. The work on TK-mice and leptin was done in collaboration between our laboratories. The results of this fruitful collaboration led to the discovery of the central aspect of bone-remodeling.

References

Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM,Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell,2000;100: 197-207. 100197 2000 [PubMed]

Schilling AF, Priemel M, Beil FT, Haberland M, Holzmann T, Català-Lehnen P, Pogoda P, Blicharski D, Müldner C, Löcherbach C, Rueger JM,Amling M. Transgenic and knock out mice in skeletal research. Towards a molecular understanding of the mammalian skeleton. J Musculoskel Neuron Interact,2001;1: 275-89. 1275 2001

Johnson RL,Tabin C. The long and short of hedgehog signaling. Cell,1995;81: 313-6. 81313 1995 [PubMed]

Karsenty G. The genetic transformation of bone biology. Genes Dev,1999;13: 3037-51. 133037 1999 [PubMed]

Ducy P, Schinke T,Karsenty G. The osteoblast: a sophisticated fibroblast under central surveillance. Science,2000;289: 1501-4. 2891501 2000 [PubMed]

Frost HM. Tetracycline-based histological analysis of bone remodeling. Calcif Tissue Res,1969;3: 211-37. 3211 1969 [PubMed]

Baron R. Molecular mechanisms of bone resorption by the osteoclast. Anat Rec,1989;224: 317-24. 224317 1989 [PubMed]

Suda T, Udagawa N, Nakamura I, Miyaura C,Takahashi N. Modulation of osteoclast differentiation by local factors. Bone,1995;17(2 Suppl): 87S-91S. 17(2 Suppl)87 1995

Teitelbaum SL. Bone resorption by osteoclasts. Science,2000;289: 1504-8. 2891504 2000 [PubMed]

Rodan GA,Martin TJ. Role of osteoblasts in hormonal control of bone resorption—a hypothesis. Calcif Tissue Int,1981;33: 349-51.. 33349 1981 [PubMed]

Hayden JM, Mohan S,Baylink DJ. The insulin-like growth factor system and the coupling of formation to resorption. Bone,1995;17(2 Suppl): 93S-8S. 17(2 Suppl)93 1995

Hauge EM, Qvesel D, Eriksen EF, Mosekilde L,Melsen F. Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers. J Bone Miner Res,2001;16: 1575-82. 161575 2001 [PubMed]

Reddi AH. Bone morphogenesis and modeling: soluble signals sculpt osteosomes in the solid state. Cell,1997;89: 159-61. 89159 1997 [PubMed]

Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Boyle WJ,et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell,1997;89: 309-19. 89309 1997 [PubMed]

Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, Sato Y, Goto M, Yamaguchi K, Kuriyama M, Kanno T, Murakami A, Tsuda E, Morinaga T,Higashio K. Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology,1998;139: 1329-37. 1391329 1998 [PubMed]

Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J,Boyle WJ. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell,1998;93: 165-76. 93165 1998 [PubMed]

Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ,Simonet WS. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev,1998;12: 1260-8. 121260 1998 [PubMed]

Mizuno A, Amizuka N, Irie K, Murakami A, Fujise N, Kanno T, Sato Y, Nakagawa N, Yasuda H, Mochizuki S, Gomibuchi T, Yano K, Shima N, Washida N, Tsuda E, Morinaga T, Higashio K,Ozawa H. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun,1998;247: 610-5. 247610 1998 [PubMed]

Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ,Penninger JM. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature,1999;397: 315-23. 397315 1999 [PubMed]

Riggs BL,Melton LJ 3rd. Involutional osteoporosis. N Engl J Med,1986;314: 1676-86. 3141676 1986 [PubMed]

Potts JT, Juppner H. Parathyroid hormone and parathyroid hormone-related peptide in calcium homeostasis, bone metabolism, and bone development: the proteins, the genes, the receptors. In: Avioli LV, Krane SM, editors. Metabolic bone disease and clinically related disorders. 3rd ed. San Diego: Academic Press; 1998. p 51-94.

Grigoriadis AE, Wang ZQ, Cecchini MG, Hofstetter W, Felix R, Fleisch HA,Wagner EF. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science,1994;266: 443-8. 266443 1994 [PubMed]

Boyce BF, Yoneda T, Lowe C, Soriano P,Mundy GR. Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J Clin Invest,1992;90: 1622-7. 901622 1992 [PubMed]

Amling M, Neff L, Priemel M, Schilling AF, Rueger JM,Baron R. Progressive increase in bone mass and development of odontomas in aging osteopetrotic c-src-deficient mice. Bone,2000;27: 603-10. 27603 2000 [PubMed]

Corral DA, Amling M, Priemel M, Loyer E, Fuchs S, Ducy P, Baron R,Karsenty G. Dissociation between bone resorption and bone formation in osteopenic transgenic mice. Proc Natl Acad Sci U S A,1998;95: 13835-40. 9513835 1998 [PubMed]

Cooper C, Melton LJ 3rd. Magnitude and impact of osteoporosis and fractures. In: Marcus R, Feldman D, Kelsey J, editors. Osteoporosis. San Diego: Academic Press; 1996. p 419-34

Consensus Development Conference on Osteoporosis. Hong Kong, April 1-2, 1993. Am J Med,1993;95: 1S-78S. 951 1993 [PubMed]

Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med,1993;94: 646-50. 94646 1993 [PubMed]

Amling M, Grote HJ, Posl M, Hahn M,Delling G. Polyostotic heterogeneity of the spine in osteoporosis. Quantitative analysis and three-dimensional morphology. Bone Miner,1994;27: 193-208. 27193 1994 [PubMed]

Riggs BL, Khosla S,Melton LJ 3rd. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res,1998;13: 763-73. 13763 1998 [PubMed]

Felson DT, Zhang Y, Hannan MT,Anderson JJ. Effects of weight and body mass index on bone mineral density in men and women: the Framingham study. J Bone Miner Res,1993;8: 567-73. 8567 1993 [PubMed]

Tremollieres FA, Pouilles JM,Ribot C. Vertebral postmenopausal bone loss is reduced in overweight women: a longitudinal study in 155 early postmenopausal women. J Clin Endocrinol Metab,1993;77: 683-6. 77683 1993 [PubMed]

Ravn P, Cizza G, Bjarnason NH, Thompson D, Daley M, Wasnich RD, McClung M, Hosking D, Yates AJ,Christiansen C. Low body mass index is an important risk factor for low bone mass and increased bone loss in early postmenopausal women. Early Postmenopausal Intervention Cohort (EPIC) study group. J Bone Miner Res,1999;14: 1622-7. 141622 1999 [PubMed]

Cornish J,Reid IR. Skeletal effects of amylin and related peptides. Endocrinologist,1999;9: 183-9. 9183 1999

Spiegelman BM,Flier JS. Adipogenesis and obesity: rounding out the big picture. Cell,1996;87: 377-89. 87377 1996 [PubMed]

Friedman JM,Halaas JL. Leptin and the regulation of body weight in mammals. Nature,1998;395: 763-70. 395763 1998 [PubMed]

Zhang Y, Proenca R, Maffei M, Barone M, Leopold L,Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature,1994;372: 425-32. 372425 1994 [PubMed]

Chehab FF, Lim ME,Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet,1996;12: 318-20. 12318 1996 [PubMed]

Ahima RS, Dushay J, Flier SN, Prabakaran D,Flier JS. Leptin accelerates the onset of puberty in normal female mice. J Clin Invest,1997;99: 391-5. 99391 1997 [PubMed]

Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E,Flier JS. Role of leptin in the neuroendocrine response to fasting. Nature,1996;382: 250-2. 382250 1996 [PubMed]

Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J,et al. Identification and expression cloning of a leptin receptor, OB-R. Cell,1995;83: 1263-71. 831263 1995 [PubMed]

Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI,Morgenstern JP. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell,1996;84: 491-. 84491 1996 [PubMed]

Takaya K, Ogawa Y, Isse N, Okazaki T, Satoh N, Masuzaki H, Mori K, Tamura N, Hosoda K,Nakao K. Molecular cloning of rat leptin receptor isoform complementary DNAs—identification of a missense mutation in Zucker fatty (fa/fa) rats. Biochem Biophys Res Commun,1996;225: 75-83. 22575 1996 [PubMed]

Thomas T, Gori F, Khosla S, Jensen MD, Burguera B,Riggs BL. Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology,1999;140: 1630-8. 1401630 1999 [PubMed]

Moitra J, Mason MM, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B, Feigenbaum L, Lee E, Aoyama T, Eckhaus M, Reitman ML,Vinson C. Life without white fat: a transgenic mouse. Genes Dev,1998;12: 3168-81. 123168 1998 [PubMed]

Inui A. Feeding and body-weight regulation by hypothalamic neuropeptides—mediation of the actions of leptin. Trends Neurosci,1999;22: 62-7. 2262 1999 [PubMed]

Elmquist JK, Ahima RS, Maratos-Flier E, Flier JS,Saper CB. Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology,1997;138: 839-42. 138839 1997 [PubMed]

Elmquist JK, Elias CF,Saper CB. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron,1999;22: 221-32. 22221 1999 [PubMed]

Erickson JC, Hollopeter G,Palmiter RD. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science,1996;274: 1704-7. 2741704 1996 [PubMed]

Topics

obesity ; osteoporosis ; bone mineral density ; bone remodeling ; hormone ; gonads ; hypothalamus ; leptin ; osteoblasts ; osteogenesis

First Page Preview

View Large

Username

Password

Access for Patients

Forgot Password?

Have a subscription to the print edition?

Not a Subscriber?

Buy this Article

Get online access for 30 days for $35

New to JBJS?

Subscribe to the online edition for 30 days for $75

Register for a FREE limited account to get full access to all CME activities, to comment on public articles, or to sign up for alerts.

Have a subscription to the print edition?

Current subscribers to The Journal of Bone & Joint Surgery in either the print or quarterly DVD formats receive free online access to JBJS.org.

Activate your online account now

Forgot your password?

Enter your username and email address. We'll send you a reminder to the email address on record.

Username:*

Email Address:*

Forgot your username or need assistance? Please contact customer service at subs@jbjs.org. If your access is provided
by your institution, please contact you librarian or administrator for username and password information. Institutional
administrators, to reset your institution's master username or password, please contact subs@jbjs.org

References

Accreditation Statement

These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.

CME Activities Associated with This Article

Submit a Comment

Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discretion of JBJS editorial staff.

* = Required Field

Comment Author(s) * (if multiple authors, separate names by comma)

Example: John Doe

Affiliation & Institution*

Disclosure

Comment Title*

Comment*

Cancel

Print
PDF
Email

Recipient(s) will receive an email with a link (good for 5 days) to 'Brain and Bone: Central Regulation of Bone Mass : A New Paradigm in Skeletal Biology'.
Your Name:*
Example: John Doe

Email Address:* CC Me:
Enter your valid email address. Example: jdoe@example.com

Recipient's Email Address:*

Separate multiple email address with semi-colons (up to 5).

Subject:* 's The Journal of Bone & Joint Surgery: 'Brain and Bone: Central Regulation of Bone Mass : A New Paradigm in Skeletal Biology'
Subject for your email.

Message:

(Optional, message will truncate at 1000 characters)

Processing your request... Please Wait...

Copyright © in the material you requested is held by The Journal of Bone & Joint Surgery, Inc. (unless otherwise noted). This email ability is provided as a courtesy, and by using it you agree that that you are requesting the material solely for personal, non-commercial use, and that it is subject to Journal of Bone & Joint Surgery, Inc.'s Terms of Use. The information provided in order to email this topic will not be used to send unsolicited email, nor will it be furnished to third parties. Please refer to The Journal of Bone & Joint Surgery Inc.'s Privacy Policy for further information.

Copyright © The Journal of Bone & Joint Surgery Inc. All rights reserved.
Share
Get Citation

Michael Haberland, Arndt F. Schilling, Johannes M. Rueger, Michael Amling; Brain and Bone: Central Regulation of Bone Mass A New Paradigm in Skeletal Biology. The Journal of Bone & Joint Surgery. 2001 Dec;83(12):1871-1876.

Download citation file:

RIS (Zotero)

EndNote

BibTex

Medlars

ProCite

RefWorks

Reference Manager

Copyright © The Journal of Bone and Joint Surgery, Inc.
Rights & Permissions
Article Alerts

Processing your request... Please Wait.
Submit a Comment