Добавил:

Sekretar kiopkiopkiop18@yandex.ru t.me/Prokururor I Вовсе не секретарь, но почту проверяю Опубликованный материал нарушает ваши авторские права? Сообщите нам.

Вуз:

Ростовский Государственный Медицинский Университет

Предмет:

Медицина общая

Файл:

Книга_3038_Библиотеки_им_академика_М_И_Перельмана

.pdf

Скачиваний:

Добавлен:

12.10.2026

Размер:

7 Мб

Скачать

☆

<<< < Предыдущая 1 2 34 / 324 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 > Следующая >>>

POSTMENOPAUSAL OSTEOPOROSIS

obvious is that persistence or adherence to thera-

peutic regimens is poor, and attempts are being

made to determine the reasons for this situation.

The enigma of patients understanding the

impact of poor compliance with treatment for a

known condition yet not continuing medication

has been well reviewed

. More specifically, early

discontinuation of treatment for osteoporosis also

remains poorly explained. It is clear that treat-

ment side-effects need to be minimized, and that

patients should be educated about the prob-

lem

. Nonetheless, that would not adequately

address the issue of poor adherence to therapy.

One effective approach has been to monitor

patients more closely and to present information

on response to therapy on an ongoing basis

This still does not explain a relationship between

global QOL and treatment adherence.

CONCLUSIONS

There is a need for recognition of the impact of

osteoporosis-related factors on global QOL as

well as an understanding of the reverse, namely,

QOL on the outcome of osteoporosis-related fac-

tors. Understanding both sides of the coin would

assist health-care providers to appreciate more

fully the importance of prevention and treat-

ment. Moreover, a clearer understanding of these

factors may well drive better adherence to and

persistence with treatments for osteoporosis.

To achieve this goal, well-validated instru-

ments to measure both health-related QOL and

global QOL must be further enhanced and

utilized. Examples of existing instruments have

been reviewed. Multiple other advantages exist

in using such tools, including assessing thera-

peutic trade-offs in randomized trials, compar-

ing the overall benefit of different interventions,

and the cost-effectiveness of such treatments.

At this time, there is little evidence to guide

the choice of one instrument or system over

another for assessing their relevance, superiority,

cost-effectiveness of interventions or overall

impact on health-outcome measures. Further

research is urgently needed to characterize these

associations.

clinical trials [Editorial]. Calcif Tissue Int 1993;

53: 75–7

6. Silverman SL, Cranney A. Quality of life meas-

urement in osteoporosis. J Rheumatol 1997; 24:

1218–21

7. Jette AM, Deniston OL. Interobserver reliability

of a functional status instrument. J Chron Dis

1978; 31: 573–80

8. Lyles KW, Gold DT, Shipp KM, et al. Association

of osteoporotic vertebral compression fractures

with impaired functional status. Am J Med 1993;

94: 595–601

9. Ware JE, Sherbourne CD. The MOS 36-item

short form health survey (SF-36) conceptual

framework and item selection. Med Care 1992;

30: 473–83

10. Bergner M, Bobbit RA, Kressel S, et al. The

Sickness Impact Profile: conceptual formulation

References

1. Utian WH, Janata JW, Kingsberg SA, et al.

Determinants and quantifications of quality of

life after the menopause: the Utian Menopause

Quality of Life Score. In Aso T, Yanaihara T, Fuji-

moto S, eds. Menopause at the Millennium. Carn-

forth, UK: Parthenon Publishing, 2000; 141–4

2. Mansfield PK, Voda AM. Hormone use among

middle-aged women: results of a three-year

study. Menopause 1994; 1: 99–108

3. Wiklund I, Karlberg J. Evaluation of quality of

life in clinical trials: selecting qualify-of-life meas-

ures. Controlled Clin Trials 1991; 12 (Suppl):

204S–16S

4. World Health Organization. Constitution of the

World Health Organization, Switzerland (Basic

Documents), 1947. Geneva: WHO, 1947

5. Greenedale GA, Silverman SL, Hays RD, et al.

Health-related quality of life in osteoporosis

https://t.me/med1917

IMPACT OF OSTEOPOROSIS ON QUALITY OF LIFE AND QUALITY OF LIFE ON OSTEOPOROSIS

and methodology for the development of a

health status measure. Int J Health Serv 1976; 6:

393–415

11. Silverman SL, Mason J, Greenwald M. The

Osteoporosis Assessment Questionnaire (OPAQ):

a reliable and valid self-assessment measure of

quality of life in osteoporosis. J Bone Miner Res

1994; 8: 343

12. Lips P, Cooper C, Agnusdei D, et al. Quality of

life as outcome in the treatment of osteoporosis;

the development of a questionnaire for quality of

life by the European Foundation for Osteoporo-

sis. Osteoporos Int 1997; 7: 36–8

13. Chandler JM, Martin AR, Girman C, et al. Reli-

ability of an osteoporosis-targeted quality of life

survey instrument for the use in the community:

OPTQOL. Osteoporos Int 1998; 8: 127–35

14. Cook DJ, Guyatt GH, Adach JD, et al. Develop-

ment and validation of the mini-osteoporosis

quality of life questionnaire (OQLQ) in osteo-

porotic women with back pain due to vertebral

fractures. Osteoporosis Quality of Life Study

Group. Osteoporos Rheumatol 1999; 10: 207–13

15. Badio X, Prieto L, Roset M, et al. Development

of a short osteoporosis quality of life question-

naire by equating items from two existing instru-

ments. J Clin Epidemiol 2002; 55: 32–40

16. Utian WH, Janata JW, Kingsberg SA, et al. The

Utian Quality of Life (UQOL) Scale: develop-

ment and validation of an instrument to quantify

quality of life through and beyond menopause.

Menopause 2002; 9: 402–10

17. Oleksik A, Lips P, Dawson A, et al. Health-related

quality of life in postmenopausal women with low

BMD with or without prevalent vertebral frac-

tures. J Bone Miner Res 2000; 15: 1384–92

18. Silverman SL, Minshall ME, Shen W, et al. The

relationship of health-related quality of life to

prevalent and incident vertebral fractures in post-

menopausal women with osteoporosis: results

from the Multiple Outcomes of Raloxifene Eval-

uation Study. Arthritis Rheum 2001; 44: 2611–19

19. Martin AR, Sornay-Rendu E, Chandler JM, et al.

The impact of osteoporosis on quality of life: the

OFELY Cohort. Bone 2002; 31: 32–6

20. Romagnoli E, Carnevale V, Notroni I, et al. Qual-

ity of life in ambulatory postmenopausal women:

the impact of reduced bone mineral density and

subclinical vertebral fractures. Osteoporos Int 2004;

15: 975–80

21. Hallberg I, Rosenqvist AM, Kartous L, et al.

Health-related quality of life after osteoporotic

fractures. Osteoporos Int 2004; 15: 834–41

22. Adachi JD, Ionnidis G, Olszynski WP, et al. The

impact of incident vertebral and non-vertebral

fractures and health-related quality of life in post-

menopausal women. BMC Musculoskelet Disord

2002; 3: 11–16

23. Cramer JA. Partial medical compliance: the

enigma in poor medical outcomes. Am J Managed

Care 1995; 1: 167–74

24. Tosteson AN, Grove MR, Hammond CS, et al.

Early discontinuation of treatment for osteoporo-

sis. Am J Med 2003; 115: 209–16

25. Clowes JA, Peel NF, Eastell R. The impact of

monitoring or adherence and persistence with

anti-resorptive treatment for postmenopausal

osteoporosis: a randomized controlled trial. J Clin

Endocrinol Metab 2004; 89: 1117–23

https://t.me/med1917

Skeletal cells and their environment determine

bone mass. Cells of the osteoblastic lineage and

signals that determine their replication and dif-

ferentiation to mature osteoblasts, and signals

determining the apoptosis of mature osteoblasts

and osteocytes, define the cell population that

regulates bone formation. Cells of the osteoclas-

tic lineage and signals that determine their

recruitment, genesis, function and death define

the cell population that regulates bone resorp-

tion. Consequently, bone remodeling is deter-

mined by two cell populations and the signals

affecting their fate and function. These signals

are systemic and local, and include hormones and

growth factors. Recent research has focused on

local signals, including cell-to-cell interactions,

their downstream events and their impact on the

fate and function of cells of the osteoblastic

lineage.

Skeletal cells synthesize a number of growth

factors (Table 1)

1,2

. Some, such as fibroblast

growth factor (FGF) and platelet-derived growth

factor (PDGF), are mostly mitogens, whereas

other factors, such as insulin-like growth factors

(IGFs), enhance the differentiated function of the

osteoblast

2,3

. It is important to note that,

whereas IGFs enhance the expression of the

osteoblastic phenotype, they do not direct the

differentiation of mesenchymal cells toward

osteoblasts (Table 2)

3,4

. In contrast, bone mor-

phogenetic proteins (BMPs) induce the differen-

tiation of cells of the osteoblastic lineage into

mature cells that express the osteoblastic pheno-

type, and also enhance the function of the

osteoblast (Table 3)

. Most BMPs are structurally

related and belong to the transforming growth

factor

β (TGFβ) superfamily of peptides

. IGFs

and BMPs act as autocrine factors that determine

osteoblast function, and play a critical role in the

maintenance of bone integrity. The activity of

IGFs and BMPs needs to be tightly regulated,

and this occurs by local feedback mechanisms,

specific binding proteins and the modulation of

their signal transduction pathways by extracel-

lular and intracellular signals. Dysregulation of

Novel signals determining skeletal cell fate

and function

E. Canalis, V. Deregowski, R. C. Pereira and E. Gazzerro

Table 3 Skeletal actions of bone morphogenetic

proteins (BMPs)

Modest mitogens

Induce differentiation of mesenchymal cells toward

osteoblasts

Enhance osteoblastic function

Table 1 Skeletal growth factors

Platelet-derived growth factor (PDGF) A and B

Fibroblast growth factor (FGF) 1 and 2

Transforming growth factor β (TGFβ) 1, 2 and 3

Insulin-like growth factor (IGF)-I and -II

Bone morphogenetic protein (BMP) 2, 4 and 6

Other cytokines and growth factors

Table 2 Skeletal effects of insulin-like growth factor

(IGF)

Increase osteoblastic function

increase collagen expression

increase bone formation

Decrease osteoblastic apoptosis

Increase remodeling

https://t.me/med1917

POSTMENOPAUSAL OSTEOPOROSIS

growth factor activity can have serious skeletal

consequences, and humans with excessive

expression of BMP 4 have fibrodysplasia ossifi-

cans progressiva, whereas overexpression of BMP

antagonists causes osteopenia in the mouse

5,7

Gain-of- and loss-of-function mutations of low-

density lipoprotein receptor-related protein 5

(LRP5), a coreceptor for Wnt signaling, result in

a respective increase and decrease in bone

mass

8,9

The effects of BMPs can be modulated by a

group of extracellular and intracellular proteins

that limit BMP action. BMP antagonists are

expressed by skeletal cells, and their presumed

role is to temper BMP activity in target tissues.

BMP antagonists are not specifically expressed in

skeletal cells. Extracellular BMP antagonists are

believed to prevent BMP signaling by binding

BMPs, therefore precluding their binding to spe-

cific cell-surface receptors

. Upon binding to

their specific receptors, BMPs signal through the

activation of Smad 1/5/8 and the mitogen-

activated protein kinase pathways

. The over-

expression of extracellular BMP antagonists has

been used to determine the autocrine role of

BMPs in various cell systems, since the null

mutation of most BMPs results in embryonic

lethality. Noggin, one of the better characterized

BMP antagonists, is a secreted glycoprotein with

a molecular mass of 64 kDa, that binds BMPs

specifically and not other members of the TGF

family of peptides

10,11

. Mice overexpressing nog-

gin under the control of the osteocalcin promoter

develop skeletal fragility, indicating that noggin

has a detrimental effect in bone by binding skele-

tal BMPs

. Homozygous null mutations of the

noggin gene in the mouse result in serious devel-

opmental abnormalities, joint lesions, axial skele-

tal defects and embryonic lethality

. These

observations indicate the need for a fine

balance between the expression of local BMPs

and their antagonists. The importance of ade-

quate noggin expression is confirmed by human

studies demonstrating that heterozygous null

mutations of the noggin gene result in multiple

joint lesions

. Transgenic mice overexpressing

noggin develop osteopenia and fractures. Total

bone mineral density (BMD) is reduced and his-

tomorphometric analysis reveals a decrease in

cancellous bone volume of 70%, secondary to

decreased osteoblastic function. To determine

whether BMPs also have an effect on stromal cell

differentiation, we compared the maturation and

cellular function of stromal and osteoblastic cells

from noggin transgenic mice as well as cell lines

in which noggin was constitutively expressed.

Stromal cells overexpressing noggin did not dif-

ferentiate into mature osteoblasts, indicating

that BMPs are essential for osteoblastic function

and differentiation

The Wnt family of secreted glycoproteins,

like BMPs, play a critical role in development,

cell fate and skeletal cell differentiation, and

abnormal Wnt signaling is implicated in osteo-

porosis and osteopetrosis

8,9,16,17

. In the absence

of Wnt proteins, Axin, adenomatous polyposis

coli,

β-catenin, glycogen-synthase kinase-3β

(GSK-3β), and other proteins form a complex in

which

β-catenin is phosphorylated by GSK-3β

leading to β-catenin degradation. The binding of

Wnt proteins to their specific Frizzled trans-

membrane receptors and to the coreceptors

LRP5 and -6 leads to inhibition of GSK-3

β and

to the stabilization of

β-catenin

16,17

. This allows

for

β-catenin nuclear translocation and its associ-

ation with members of the lymphoid enhancer-

binding factor/T cell-specific factor (LEF/TCF)

family of transcription factors and the transcrip-

tional regulation of target genes. The Wnt/

β-

catenin signaling pathway is central to osteogen-

esis and bone formation, and Wnt and BMPs

have similar and related effects. The mechanisms

of this relationship have not been established,

but LRP5 is induced by BMP 2, and TGF

β and

Wnt signaling pathways converge at the level of

LEF

8,18

. Recent clinical findings demonstrating

changes in bone mass in gain- and loss-of-func-

tion LRP5 mutations confirm the role of Wnt in

skeletal physiology. Wnt interacts with other sig-

nals determining cell fate, and its interactions

with the Notch signaling pathway are of partic-

ular relevance to osteoblastic cell fate.

Notch1, -2, -3 and -4 are closely related, con-

served transmembrane receptors that mediate

cell-to-cell interactions controlling cell fate deci-

sions

. Notch genes have an extracellular and an

intracellular domain, and their ligands Delta1–4,

and Serrate/Jagged1 and -2, are single-pass

https://t.me/med1917

NOVEL SIGNALS DETERMINING SKELETAL CELL FATE AND FUNCTION

adult bone in vivo. However, there are a number

of observations substantiating the physiological

and clinical importance of Notch in the skeleton.

Jagged2 mutants in the mouse exhibit marked

defects in limb and craniofacial development,

syndactylism and cleft palate, and delta3 muta-

tions cause vertebral and rib deformities

27,28

Frame-shift mutations leading to loss of function

of the jagged1 gene in humans cause Alagille syn-

drome, an autosomal dominant disorder charac-

terized by defects in multiple organs including

the skeleton, where butterfly vertebrae and cran-

iosynostosis are found

. Mutations of the ligand

Delta3 are linked to a developmental defect of

the axial skeleton called spondylocostal dysos-

tosis

. The observations indicate that Notch1 is

a novel regulator of skeletal metabolism.

The CCAAT-enhancer-binding proteins

(C/EBPs) are a family of transcription factors that

regulate cell differentiation

. To date, six

C/EBPs have been characterized,

α, β, δ, γ, ε and

ζ. The C/EBP proteins contain a highly con-

served DNA-binding domain and a leucine zip-

per dimerization domain, and can form homo-

and heterodimers that bind to similar sequence

motifs. C/EBPs are expressed in multiple cell

types, including osteoblasts and adipocytes, and

some are critical for adipocyte differentiation and

maturation

32,33

. It is important to note that

C/EBPs also play a central role in the regulation

of IGF-I transcription and can interact with

other transcriptional activators, including runt-

related transcription factor-2 (Runx-2), and as a

consequence, activate osteocalcin transcription

Glucocorticoids induce adipogenesis, and

enhance the expression of C/EBP

β and δ in

osteoblasts, and we demonstrated that these two

transcription factors play a role in the down-

regulation of IGF-I transcription by glucocorti-

coids

. Because C/EBP β and δ are essential for

adipogenesis, and cortisol shifts cellular differen-

tiation away from osteoblasts, the findings

suggested that C/EBP

β and δ play a role in

directing mesenchymal cells away from the

osteoblastic and toward the adipocytic pathway.

C/EBP

ζ, more often termed C/EBP homolo-

gous protein (CHOP), or growth arrest and

DNA damage-inducible gene (GADD) 153, is a

member of the C/EBP family of transcription

Table 4 Skeletal actions of Notch

Notch1 blocks osteoblastogenesis

Notch1 opposes Wnt/β-catenin signaling

Notch1 does not alter bone morphogenetic

protein (BMP) signaling

transmembrane proteins which, following bind-

ing, induce the proteolytic cleavage of Notch,

leading to the release of the Notch intracellular

domain (NotchIC) and its translocation to the

nucleus

. There, it complexes with the CSL fam-

ily of DNA-binding proteins, the primary tran-

scriptional mediators of Notch signaling. In

mammals, the CSL nuclear protein is C-

promoter binding factor 1 (CBF1), or recombi-

national signal binding protein of the J

immunoglobulin (Ig) gene (RBP-Jκ). Notch sig-

naling independent of CBF1/RBP-J

κ also occurs,

and Notch can form a complex with Deltex and

related genes

Notch1 and -2 and their ligands, Delta1 and

Jagged1, are expressed by osteoblasts, whereas

Notch3 and -4 are not

. Activated Notch1

receptors prevent osteoblast differentiation and

chondrocyte maturation, resulting in shorter

skeletal elements that lack ossification

. The

constitutive overexpression of Notch1IC in stro-

mal and osteoblastic cells impairs osteoblastic

maturation and favors adipogenesis (Table 4)

It is of interest that Notch1 and Wnt have oppo-

site effects on cell differentiation, since Wnt

signaling inhibits adipogenesis and it has the

potential to induce osteoblastic differentiation.

Recently, we demonstrated that the constitutive

overexpression of Notch1IC in stromal cells

opposes Wnt/

β-catenin signaling

. Wnt–Notch

interactions may occur at multiple levels, includ-

ing the binding of Notch by Wnt and by mole-

cules implicated in the implementation of Wnt

signaling, and by enzymes involved in the phos-

phorylation and activation/deactivation of both

signaling pathways.

Homozygous null mutations of the Notch1

and -2 and cbf1/rbp-J

genes result in serious

developmental abnormalities and embryonic

lethality

25,26

. The phenotypic lethality has not

permitted the definition of Notch1 function in

https://t.me/med1917

factors, with unique roles in cell proliferation,

differentiation and apoptosis (Table 5)

. CHOP

heterodimerizes with other C/EBPs, but does not

bind to classic C/EBP consensus DNA sequences.

In ST-2 murine stromal cells, the levels of CHOP

transcripts rise as the cells differentiate toward

osteoblasts, and recently we demonstrated that

overexpression of CHOP accelerates osteoblastic

differentiation, enhancing the effect of BMP and

sensitizing the BMP/Smad signaling pathway in

osteoblastic cells

. CHOP overexpression also

suppressed adipogenesis, suggesting that there

may be a trade between osteoblastogenesis and

adipogenesis. The role of CHOP in skeletal func-

tion was confirmed by recent studies from our

group demonstrating that chop-null mutations

lead to impaired osteoblastic function in vivo.

The chop-null skeletal phenotype is similar to the

phenotype of atf 4-null mice, and ATF 4

enhances the transcription of CHOP

. Atf 4-

null mice exhibit osteopenia due to decreased

bone formation

In conclusion, results from recent investiga-

tions demonstrate the existence of novel extra-

cellular and intracellular signals that determine

the fate and function of cells of the osteoblastic

lineage. Often these signals regulate BMP/Smad

and Wnt/

β-catenin signal transduction, either by

sensitizing or opposing their activities in cells of

the osteoblastic lineage.

ACKNOWLEDGMENTS

This work was supported by grants from the

National Institutes of Health, AR21707,

DK42424 and DK45227, and fellowship awards

by the Arthritis Foundation.

Table 5 Actions of CCAAT-enhancer-binding

protein (C/EBP) homologous protein (CHOP)

Mediates endoplasmic reticulum stress-induced

apoptosis

Forms dimers with classic C/EBPs acting as

dominant negative

Blocks adipogenesis

Enhances osteoblastogenesis by sensitizing bone

morphogenetic protein (BMP)/Smad and

Wnt/β-catenin signaling

POSTMENOPAUSAL OSTEOPOROSIS

References

1. Margolis RN, Canalis E, Partridge NC. Anabolic

hormones in bone: basic research and therapeutic

potential. J Clin Endocrinol Metab 1996; 81:

2872–7

2. Delany AM, Canalis E. Growth factors and bone.

In LeRoith D, Bondy C, eds. Growth Factors and

Cytokines in Health and Disease. Greenwich, CT:

JAI Press, 1997; 3A: 127–55

3. Zhao G, Monier-Faugere MC, Langub MC, et al.

Targeted overexpression of insulin-like growth

factor I to osteoblasts of transgenic mice:

increased trabecular bone volume without

increased osteoblast proliferation. Endocrinology

2000; 141: 2674–82

4. Thomas T, Gori F, Spelsberg TC, et al. Response

of bipotential human marrow stromal cells to

insulin-like growth factors: effect on binding

protein production, proliferation, and commit-

ment to osteoblasts and adipocytes. Endocrinology

1999; 140: 5036–44

5. Canalis E, Economides AE, Gazzerro E. Bone

morphogenetic proteins, their antagonists and

the skeleton. Endocr Rev 2003; 24: 218–35

6. Schmitt JM, Hwang K, Winn SR, et al. Bone

morphogenetic proteins: an update on basic biol-

ogy and clinical relevance. J Orthop Res 1999; 17:

269–78

7. Shafritz AB, Shore EM, Gannon FH, et al. Over-

expression of an osteogenic morphogen in

fibrodysplasia ossificans progressiva. N Engl J Med

1996; 335: 555–61

8. Gong Y, Slee RB, Fukai N, et al. LDL receptor-

related protein 5 (LRP5) affects bone accrual and

eye development. Cell 2001; 107: 513–23

https://t.me/med1917

NOVEL SIGNALS DETERMINING SKELETAL CELL FATE AND FUNCTION

9. Boyden LM, Mao J, Belsky J, et al. High bone

density due to a mutation in LDL-receptor-

related protein 5. N Engl J Med 2002; 346:

1513–21

10. Smith WC, Harland RM. Expression cloning of

noggin, a new dorsalizing factor localized to the

Spemann organizer in xenopus embryos. Cell

1992; 70: 829–40

11. Valenzuela DM, Economides AN, Rojas E, et al.

Identification of mammalian noggin and its

expression in the adult nervous system. J Neurosci

1995; 15: 6077–84

12. Devlin RD, Du Z, Pereira RC, et al. Skeletal

overexpression of noggin results in osteopenia

and reduced bone formation. Endocrinology 2003;

144: 1972–8

13. Brunet LJ, McMahon JA, McMahon AP, et al.

Noggin, cartilage morphogenesis, and joint for-

mation in the mammalian skeleton. Science 1998;

280: 1455–7

14. Gong Y, Krakow D, Marcelino J, et al. Heterozy-

gous mutations in the gene encoding noggin

affect human joint morphogenesis. Nature Genet

1999; 21: 302–4

15. Gazzerro E, Du Z, Devlin RD, et al. Noggin

arrests stromal cell differentiation in vitro. Bone

2003; 32: 111–19

16. Dale TC. Signal transduction by the Wnt family

of ligands. Biochem J 1998; 329: 209–23

17. Gumbiner BM. Propagation and localization of

Wnt signaling. Curr Opin Genet Dev 1998; 8:

430–5

18. Nishita M, Hashimoto MK, Ogata S, et al. Inter-

action between Wnt and TGF-

β signalling path-

ways during formation of Spemann’s organizer.

Nature (London) 2000; 403: 781–4

19. Mumm JS, Kopan R. Notch signaling: from the

outside in. Dev Biol 2000; 228: 151–65

20. Schroeter EH, Kisslinger JA, Kopan R. Notch-1

signalling requires ligand-induced proteolytic

release of intracellular domain. Nature (London)

1998; 393: 382–6

21. Yamamoto N, Yamamoto S, Inagaki F, et al. Role

of Deltex-1 as a transcriptional regulator down-

stream of the Notch receptor. J Biol Chem 2001;

276: 45031–40

22. Pereira RMR, Delany AM, Durant D, et al. Cor-

tisol regulates the expression of Notch in

osteoblasts. J Cell Biochem 2002; 85: 252–8

23. Crowe R, Zikherman J, Niswander L. Delta-1

negatively regulates the transition from prehy-

pertrophic to hypertrophic chondrocytes during

cartilage formation. Development 1999; 126:

987–98

24. Sciaudone M, Gazzerro E, Priest L, et al. Notch 1

impairs osteoblastic cell differentiation.

Endocrinology 2003; 144: 5631–9

25. Swiatek PJ, Lindsell CE, del Amo F, et al. Notch1

is essential for postimplantation development in

mice. Genes Dev 1994; 8: 707–19

26. Oka C, Nakano T, Wakeham A, et al. Disruption

of the mouse RBP-J

gene results in early embry-

onic death. Development 1995; 121: 3291–301

27. Kusumi K, Sun ES, Kerrebrock AW, et al. The

mouse pudgy mutation disrupts Delta homologue

DII3 and initiation of early somite boundaries.

Nature Genet 1998; 19: 274–8

28. Sidow A, Bulotsky MS, Kerrebrock AW, et al.

Serrate2 is disrupted in the mouse limb-develop-

ment mutant syndactylism. Nature (London) 1997;

389: 722–5

29. Li L, Krantz ID, Deng Y, et al. Alagille syndrome

is caused by mutations in human Jagged1, which

encodes a ligand for Notch1. Nature Genet 1997;

16: 243–51

30. Bulman MP, Kusumi K, Frayling TM, et al.

Mutations in the human delta homologue, DLL3,

cause axial skeletal defects in spondylocostal

dysostosis. Nature Genet 2000; 24: 438–41

31. Hanson RW. Biological role of the isoforms of

C/EBP minireview series. J Biol Chem 1998; 273:

28543

32. Lee YH, Sauer B, Johnson PF, et al. Disruption of

the c/ebp

α gene in adult mouse liver. Mol Cell

Biol 1997; 17: 6014–22

33. Tanaka T, Yoshida N, Kishimoto T, et al. Defec-

tive adipocyte differentiation in mice lacking the

C/EBP

β and/or C/EBPδ gene. Eur Med Biol Org J

1997; 16: 7432–43

34. Gutierrez S, Javed A, Tennant DK, et al.

CCAAT/enhancer-binding proteins (C/EBP)

and δ activate osteocalcin gene transcription and

synergize with runx2 at the C/EBP element to

regulate bone-specific expression. J Biol Chem

2002; 277: 1316–23

35. Delany AM, Durant D, Canalis E. Glucocorticoid

suppression of IGF I transcription in osteoblasts.

Mol Endocrinol 2001; 15: 1781–9

https://t.me/med1917

POSTMENOPAUSAL OSTEOPOROSIS

36. Ron D, Habener JF. CHOP, a novel developmen-

tally regulated nuclear protein that dimerizes

with transcription factors C/EBP and LAP and

functions as a dominant-negative inhibitor of

gene transcription. Genes Dev 1992; 6: 439–53

37. Pereira RC, Delany AM, Canalis E. CCAAT/

enhancer binding protein homologous protein

(CHOP) induces osteoblastic differentiation.

Endocrinology 2004; 145: 1952–60

38. Ron D. Translational control in the endoplasmic

reticulum stress response. J Clin Invest 2002; 110:

1383–8

39. Yang X, Matsuda K, Bialek P, et al. ATF4 is a

substrate of RSK2 and an essential regulator of

osteoblast biology: implication for Coffin–Lowry

syndrome. Cell 2004; 117: 387–98

https://t.me/med1917

INTRODUCTION

Estrogen replacement therapy (HRT) has been

used for over 30 years as the main therapeutic

approach for prevention of postmenopausal bone

loss. Estrogens as well as androgenic hormones

are inhibitors of bone resorption, and, although

the exact action of these steroid hormones on

osteoclastogenesis is still not completely clear, it

has been assumed that the major target cells are

cells of the osteoclastic lineage. Therefore, the

concept that estrogen may affect the osteoblast

arm of the bone remodeling cycle is still contro-

versial. A major limitation to in vitro studies is

that there is large species variability in response

to sex steroids. For example, estrogen can result

in bone-anabolic effects in rodents, but not

in humans. Therefore, some of the findings

obtained in rodents will have to be considered

with caution when extrapolating to human

biology.

Although estrogen can affect cells of the

osteoclastic lineage at multiple points during

their differentiation program, thus modulating

bone resorption (reviewed in references 1 and 2),

several lines of evidence indicate that sex steroids

can also regulate the function of cells of the

osteoblastic lineage. For example, estrogen

receptors are present in osteoblasts, and effects

on cell proliferation, expression of osteoblastic

genes and cell death (apoptosis) have all been

described in in vitro models of osteoblast differ-

entiation (reviewed in references 3 and 4). Fur-

thermore, loss of sex steroids leads to increased

bone formation in addition to increased bone

resorption, and, although this may represent an

indirect effect due to the coupling of the bone

remodeling cycle, data are emerging suggesting

that estrogen may also directly modulate bone

formation (Figure 1).

SEX STEROIDS AND OSTEOBLAST

DIFFERENTIATION

While in vitro studies pointed to a potential effect

of estrogen in modulating osteoblast function,

only an in vivo setting would establish whether a

direct action of sex steroids on osteoblasts is rel-

evant for estrogen modulation of bone mass and,

most important, for the mechanism of estrogen-

dependent bone loss. Bone loss following ovari-

ectomy (OVX) or orchiectomy (ORX) in rats or

mice is widely used to model the consequences of

estrogen or androgen failure on bone homeosta-

sis. However, the increase in bone resorption that

follows gonadal removal complicates the detec-

tion of direct effects of estrogen on osteoblasts.

The ensuing increase in bone formation may be

an indirect consequence of bone turnover activa-

tion. Important advances in this area have been

made by one group of investigators who focused

on a particular mouse model, the senescence

accelerated mouse (SAMP-6), which is thought

to reproduce many of the changes that occur in

aging in a shorter than natural time-frame. In

particular, this mouse model develops what can

be called an age-induced bone loss characterized

by decreased bone turnover, associated with

decreased osteoblastogenesis

To understand whether sex hormones do

indeed target cells of the osteoblastic lineage in

the context of decreased osteoblastogenesis, Jilka

and co-workers assessed the osteogenic poten-

tial of bone marrow cells derived from OVX or

ORX SAMP-6 mice

. The bone marrow of adult

animals contains both hematopoietic and mes-

enchymal stem cells, undifferentiated cells that

give rise to multiple lineages (chondro-

osteoblasts, adipocytes, myocytes), and are able

to self-renew, i.e. produce daughter cells with the

same multilineage potential (Figure 2). The

Sex steroid hormones and bone formation

R. Civitelli

https://t.me/med1917

<<< < Предыдущая 1 2 34 / 324 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 > Следующая >>>

Соседние файлы в папке Библиотека им академика М.И. Перельмана

#
10.10.20267 Мб0Книга_3023_Библиотеки_им_академика_М_И_Перельмана.pdf
#
10.10.20267 Мб0Книга_3027_Библиотеки_им_академика_М_И_Перельмана.pdf
#
10.10.20267 Мб0Книга_3028_Библиотеки_им_академика_М_И_Перельмана.pdf
#
10.10.20267 Мб0Книга_3029_Библиотеки_им_академика_М_И_Перельмана.djvu
#
10.10.20267 Мб0Книга_3030_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20267 Мб0Книга_3038_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20267 Мб0Книга_3042_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20267 Мб0Книга_3044_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20267 Мб0Книга_3050_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20267 Мб0Книга_3051_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20267 Мб0Книга_3053_Библиотеки_им_академика_М_И_Перельмана.pdf