Brain plays major role in bone remodeling

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Brain plays major role in bone remodeling



Sep 6, 2005



Janis



Jerusalem, Israel - Interleukin-1 (IL-1)-receptor signaling in the

brain reins in overproduction of osteoclasts, and loss of this

function may tilt the balance toward bone resorption and

osteoporosis, Dr Alon Bajayo (Hebrew University, Jerusalem, Israel)

reports in an article published online August 26, 2005 in Proceedings

of the National Academy of Sciences [1]. Senior author Dr Itai Bab

(Hebrew University) says that this study is the first to link the

central IL-1 system to bone resorption. Combined with work by Takeda

[2] and Baldock et al [3], this research confirms a brain-mediated

regulatory system that affects both osteoclast and osteoblast activity.



" These articles are the first direct evidence that the brain has a

major role in regulating bone remodeling. "



" These articles are the first direct evidence that the brain has a

major role in regulating bone remodeling, " Bab tells rheumawire.

" While the other papers deal primarily with the regulation of

osteoblast activity and bone formation, our paper is the first to

report major central effects on bone resorption. We believe that

establishing a link between the leptin-sympathetic axis reported in

the other papers and this central IL-1 system may provide an

explanation for the coupling between bone formation and resorption,

previously thought to be controlled at the local level. "

Research unveils new pathways

All of the work in this line of research has been done in mice,

usually with knockout mice. Bab et al studied two strains of mice:

the murine glial fibrillary acidic protein promoter (IL-1raTG) mice

overexpressed the secreted human IL-1 receptor antagonist (IL-1ra) in

astrocytes within the central nervous system (CNS); and the IL-1RI-

deficient mice (IL-1rKO) mice were deficient in the IL-1 receptor

type 1 (IL-1RI) cell-surface receptor. The investigators used

fluorescent microscopy and dynamic histomorphometry to assess

osteoblast activity in whole femurs and in the bodies of the third

lumbar vertebrae in these mice.

Bab et al discovered that the mice in which CNS IL-1RI signaling had

been silenced had trabecular bone-volume density 23% lower than wild-

type mice and vertebral bone-volume density 27% lower than wild-type

mice. These changes were associated with decreased trabecular number

and decreased trabecular connectivity density. Skeletal growth was

also impaired in these mice, which had femurs 0.6 mm shorter than

wild-type mice.

The investigators write: " Unlike the proinflammatory action of

peripheral IL-1 receptor signaling, activation of the central IL-1RI

restrains the peripheral immune system. Hence, because the osteoclast

is a hematopoietic cell that branches from the monocyte-macrophage

lineage, we assumed that the low-bone-mass phenotype and the impaired

bone growth in the IL-1rKO mice result from the absence of central

IL-1RI signaling and a consequent increase in bone resorption. "

To confirm this, they characterized the osteogenic phenotype of the

IL-1raTG mice, which have an overexpression of IL-1ra targeted to the

CNS. IL-1ra was expressed in the hypothalamus but not in the bone of

these mice. The femurs of these mice were almost 1 mm shorter than

those of wild-type mice, and the bone medullary cavity diameter was

significantly smaller. The researchers note that these differences

were not due to reduced body mass, since the IL-1raTG mice were

actually heavier than the wild-type mice.

Both of the engineered mouse strains had osteoclast numbers about two

times higher than the wild-type mice. Both types of mice had " a

striking increase in bone resorption, " the researchers say. " Although

the pathway connecting the central IL-1RI signaling to bone

remodeling remains unknown, the outburst of osteoclastogenesis in its

absence suggests that normally it controls bone growth and mass by

tonically restraining bone resorption. " 

Bab says: " A major finding in our paper is the opposite effects of

peripheral and central IL-1 signaling. Our current understanding is

that at the local level IL-1 acts directly via receptors expressed by

both osteoblasts and osteoclasts. Moreover, it has no known

physiologic role in bone and is mainly involved in mediating bone

loss triggered by sex-hormone deficiency and TNF [tumor necrosis

factor] (as in rheumatoid arthritis). In contrast, central IL-1 has

several physiologic functions in the control of sleep and memory. Our

findings suggest that central IL-1 is important in maintaining bone

mass under physiologic conditions and that it does so by regulating

the nervous system(s) that innervate(s) bone. "

These researchers are now in the process of identifying and

characterizing that nervous system. " We believe that understanding

the pathway connecting the central IL-1 system with bone will

identify specific neural transmitters that can be modulated to

restrain bone resorption, thus preventing bone loss, " Bab says.

Bajayo A, Goshen I, Feldman S, et al. Central IL-1 receptor signaling

regulates bone growth and mass. Proc Natl Acad Sci 2005;

102:12956-12961. 16126903 Takeda S. Central control of bone

remodeling. Biochem Biophys Res Commun 2005; 328:697-699. 15694403

Baldock PA, Sainsbury A, Couzens M, et al. Hypothalamic Y2 receptors

regulate bone formation. J Clin Invest 2002; 14:1908-1916. 11927618

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