Osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF) is a recently identified cytokine that belongs to the tumor necrosis factor receptor superfamily and regulates bone mass by inhibiting osteoclastic bone resorption. The present study was undertaken to determine whether OPG/OCIF is produced in bone microenvironment and how the expression is regulated. These results suggest that TGF-␤1 negatively regulates osteoclastogenesis, at least in part, through the induction of OPG/OCIF by bone marrow stromal cells and that the balance between OPG/OCIF and TRANCE/ RANKL in local environment may be an important determinant of osteoclastic bone resorption.

Transforming growth factor-␤ (TGF-␤) is both abundant in bone and an important regulator of bone metabolism. A T3 C transition at nucleotide 29 in the signal sequence region of the TGF-␤1 gene results in a Leu3 Pro substitution at amino acid position 10. The possible association of this polymorphism with bone mass and the prevalence of osteoporosis has now been investigated in a total of 287 postmenopausal women from two regions (Obu City, Aichi Prefecture, and Sanda City, Hyogo Prefecture) of Japan. A significant association of TGF-␤1 genotype with bone mass was detected in both populations; bone mineral density (BMD) at the lumbar spine was greater in individuals with the CC genotype than in those with the TT or TC genotype. The frequency of vertebral fractures was significantly lower in individuals with the CC genotype than in those with the TC or TT genotypes. For each region, multivariable logistic regression analysis revealed that the frequency of the T allele was significantly higher in subjects with osteoporosis than in controls. Also, the serum concentration of TGF-␤1 in individuals with the CC genotype was significantly higher than that in age-matched subjects with the TC or TT genotype in osteoporotic or osteopenic as well as healthy control groups. These results suggest that the T/C polymorphism of the TGF-␤1 gene is one of the genetic determinants of bone mass and that the T allele is an independent risk factor for the genetic susceptibility to osteoporosis in postmenopausal Japanese women. Thus, analysis of the TGF-␤1 genotype may be useful in the prevention and management of osteoporosis. (J Bone Miner Res 1998;13:1569-1576)

Estrogen deficiency causes bone loss as a result of accelerated osteoclastic bone resorption. It also has been reported that estrogen deficiency is associated with an increase in the number of pre-B cells in mouse bone marrow. The present study was undertaken to clarify the role of altered B lymphopoiesis and of the receptor activator of nuclear factor-B ligand (RANKL), a key molecule in osteoclastogenesis, in the bone loss associated with estrogen deficiency. In the presence of prostaglandin E 2 (PGE 2 ), the activity to form tartrate-resistant acid phosphatase (

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Interleukin 1 (IL-1) and tumor necrosis factor ␣ (TNF-␣) have been implicated in the pathogenesis of osteoporosis. These proinflammatory cytokines induce both cyclooxygenase (COX) and nitric oxide synthase (NOS) with the release of prostaglandin (PG) and NO, respectively. The present study was undertaken to examine the interaction between COX and NOS pathways and their role in the regulation of osteoblastic function in MC3T3-E1 cells. Addition of IL-1␣ and TNF-␣ induced a marked increase in the production of both NO and PGE 2 . Reverse transcription-polymerase chain reaction analysis showed that the increase in NO production was preceded by the expression of inducible NOS mRNA. The temporal profile of PGE 2 production revealed a biphasic pattern: the first small peak at 3 h was caused by de novo synthesis of PGE 2 through inducible COX (COX-2) mRNA, while the subsequent progressive accumulation of PGE 2 was mediated through the activation of COX pathway by NO since (1) aminoguanidine (AG), a selective inhibitor of inducible NOS, significantly suppressed the PGE 2 production by IL-1␣ and TNF-␣, (2) NOC-18, an NO donor, reversed this suppression, and (3) NOC-18 increased PGE 2 production by itself. The increase in NO production in response to IL-1␣ and TNF-␣ was further stimulated by aspirin and inhibited by exogenous addition of PGE 2 , suggesting that PGE 2 produced by the cytokines, in turn, negatively modulates NO production. IL-1␣ and TNF-␣ inhibited alkaline phosphatase (ALP) activity, which was significantly reversed by AG. NOC-18 not only suppressed ALP activity by itself but also blocked the effect of AG, suggesting the role of NO in the inhibition of ALP activity. PGE 2 decreased ALP activity, and the inhibitory effect of NOC-18 was attenuated in the presence of aspirin, suggesting the involvement of PGE 2 in the negative modulation of ALP activity by NO. These results suggest that NO produced in response to proinflammatory cytokines participates in the modulation of ALP activity via the activation of COX pathway. The interaction between NO and the COX pathways may play an important role in the regulation of osteoblastic functions under physiologic as well as pathologic

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This study investigated the recruitment of different types of intrafusal fibers during prolonged swimming at 60-75% of VO2max. We used 56 male adult mice and examined depletion of glycogen in soleus (Sol) and extensor digitorum longus (EDL) muscle spindles by visual inspection and a newly developed optical scanning method. More than 80% of all spindles from six mice consisted of four fibers: one type I nuclear bag (bag1) fiber, one type II nuclear bag (bag2) fiber, and two nuclear chain fibers. Glycogen content was estimated in muscle fibers from groups of six mice that had rested or swum for either 0.5, 1, 2, 4, or 8 h. The optical scanning intensity of periodic acid Schiff (PAS)-stained sections was correlated with their biochemically determined glycogen content (r = 0.93). Both methods showed fundamentally the same result: each type of intrafusal fiber has its own typical recruitment pattern during exercise. In the initial phase (0-0.5 h), glycogen depletion was largest in nuclear bag1 fibers and insignificant in the bag2 and chain fibers. With the bag1 fibers having become fatigued, nuclear bag2 fibers mainly took over during the middle phase (2-4 h). During the last phase (4-8 h), only the glycogen content of chain fibers decreased significantly (4-8 h). There were significant correlations between the recruitment pattern of bag1 and extrafusal type I fibers in both Sol and EDL, between nuclear bag2 and type IIa fibers in Sol, and between nuclear chain and type IIb fibers in EDL. This suggests that, during moderately intense exercise, glycogen depletion occurs first in the slow, then the intermediate, and, finally, the fast intrafusal fibers.

This study demonstrated the feasibility of evaluating the effect of the antiosteoporotic agents within 2 weeks after ovariectomy in mice. The muCT analysis may serve as a valuable tool, specifically in a high-throughput pharmacological screening test, offering useful information regarding the effects of test compounds on both bone resorption and formation.