Physiological Paradigms Research Articles

Beyond the Ligament: A Whole-Bone Periodontal View of Dentofacial Orthopedics and Falsification of Universal Alveolar Immutability

When a theoretical basis for manifestly successful clinical outcomes cannot be fortified by traditional orthodontic tooth movement (OTM) biology that focuses solely on the periodontal ligament as the operant organ, a new hypothesis should be built on the old concepts by synthesizing new biological data with it. This article presents a modest synthesis of contemporary theories in cell biology to explain ostensible osteogenic activity and alveolar phenotype alterations by ultra-low orthopedic force from an alveolar development appliance (ADA). Histological appearance of biopsy specimens demonstrate a "reactive" woven bone pattern, dramatically illustrated under polarized light, where the alveolar development appliance puts labial forces on the palatal alveolus via acrylic panels and 300 <i>g</i> of force induced by coiled nickel titanium springs. "Internal control" biopsy specimens taken from nontreated alveoli show normal lamellar pattern in histological sections. The behavior of the bone cannot be explained totally with a periodontal pressure-tension model. Molecular biological concepts and the Utah Paradigm of Bone Physiology are recruited to explain how ultra-light forces applied to the palatal alveolus might stimulate "compensatory periosteal apposition" on the labial alveolus, thus developing a new alveolar phenotype through bony developmental "drift."

Extreme endurance flights by landbirds crossing the Pacific Ocean: ecological corridor rather than barrier?

Mountain ranges, deserts, ice fields and oceans generally act as barriers to the movement of land-dependent animals, often profoundly shaping migration routes. We used satellite telemetry to track the southward flights of bar-tailed godwits (Limosa lapponica baueri), shorebirds whose breeding and non-breeding areas are separated by the vast central Pacific Ocean. Seven females with surgically implanted transmitters flew non-stop 8117–11 680 km (10 153±1043 s.d.) directly across the Pacific Ocean; two males with external transmitters flew non-stop along the same corridor for 7008–7390 km. Flight duration ranged from 6.0 to 9.4 days (7.8±1.3 s.d.) for birds with implants and 5.0 to 6.6 days for birds with externally attached transmitters. These extraordinary non-stop flights establish new extremes for avian flight performance, have profound implications for understanding the physiological capabilities of vertebrates and how birds navigate, and challenge current physiological paradigms on topics such as sleep, dehydration and phenotypic flexibility. Predicted changes in climatic systems may affect survival rates if weather conditions at their departure hub or along the migration corridor should change. We propose that this transoceanic route may function as an ecological corridor rather than a barrier, providing a wind-assisted passage relatively free of pathogens and predators.

Conceitos fisiológicos do treinamento físico-esportivo: estresse, homeostase e alostase

The objective of this review article is to discuss the concepts of stress and homeostasis (homeos = equal; stasis = stable) and to expose their limitations on the basis of recent evidence demonstrating that the supposed internal stability of living organisms is merely apparent, and is even independent of environmental factors. This internal instability is often observed by researchers investigating circadian rhythms (hormone secretion), temporal series (heart rate) and behavior (hunger and satiety), who argue in favor of substituting the theory of homeostasis by the concept of allostasis (allo = different; stasis = stable). Indeed, these researchers suggest that the objective of regulation and control is not stability. There are two consequences for Physical Education and Sport if allostasis is accepted as a physiological paradigm: 1. Selye’s concept of stress requires a new defi nition and interpretation, with a clear impact on the concept of load and overload; 2. Noakes’ central governor hypothesis to explain the fatigue resulting from intense physical exercise loses its relevance, as will be discussed in this paper. Furthermore, it is very diffi cult for the model of stability by staying the same to explain why performance is improved by physical training or why we have a predisposition for this type of recognizedly anti-homeostatic activity. We intend to demonstrate the possibility that the allostatic concept of stability through change can explain these contradictions.

Role of Low Energy Expenditure and Sitting in Obesity, Metabolic Syndrome, Type 2 Diabetes, and Cardiovascular Disease

It is not uncommon for people to spend one-half of their waking day sitting, with relatively idle muscles. The other half of the day includes the often large volume of nonexercise physical activity. Given the increasing pace of technological change in domestic, community, and workplace environments, modern humans may still not have reached the historical pinnacle of physical inactivity, even in cohorts where people already do not perform exercise. Our purpose here is to examine the role of sedentary behaviors, especially sitting, on mortality, cardiovascular disease, type 2 diabetes, metabolic syndrome risk factors, and obesity. Recent observational epidemiological studies strongly suggest that daily sitting time or low nonexercise activity levels may have a significant direct relationship with each of these medical concerns. There is now a need for studies to differentiate between the potentially unique molecular, physiologic, and clinical effects of too much sitting (inactivity physiology) separate from the responses caused by structured exercise (exercise physiology). In theory, this may be in part because nonexercise activity thermogenesis is generally a much greater component of total energy expenditure than exercise or because any type of brief, yet frequent, muscular contraction throughout the day may be necessary to short-circuit unhealthy molecular signals causing metabolic diseases. One of the first series of controlled laboratory studies providing translational evidence for a molecular reason to maintain high levels of daily low-intensity and intermittent activity came from examinations of the cellular regulation of skeletal muscle lipoprotein lipase (LPL) (a protein important for controlling plasma triglyceride catabolism, HDL cholesterol, and other metabolic risk factors). Experimentally reducing normal spontaneous standing and ambulatory time had a much greater effect on LPL regulation than adding vigorous exercise training on top of the normal level of nonexercise activity. Those studies also found that inactivity initiated unique cellular processes that were qualitatively different from the exercise responses. In summary, there is an emergence of inactivity physiology studies. These are beginning to raise a new concern with potentially major clinical and public health significance: the average nonexercising person may become even more metabolically unfit in the coming years if they sit too much, thereby limiting the normally high volume of intermittent nonexercise physical activity in everyday life. Thus, if the inactivity physiology paradigm is proven to be true, the dire concern for the future may rest with growing numbers of people unaware of the potential insidious dangers of sitting too much and who are not taking advantage of the benefits of maintaining nonexercise activity throughout much of the day.

Recording of focal direct current (DC) changes in the human cerebral cortex using refined non-invasive DC-EEG methodology

A non-invasive DC electroencephalographic (DC-EEG) method was developed to record and analyze focal low-frequency (<0.1 Hz) DC changes in the human cerebral cortex. A simple repetitive finger-movement task was used as a physiological activation paradigm. DC-EEG amplitudes were recorded using a custom-made DC amplifier with automatic offset correction. A total of 16 standard Ag/AgCl electrodes covered the left primary motor cortex. In three of six subjects, reliable focal motor-related DC-EEG shifts over the hand cortex were monitored. This study demonstrates that refined DC-EEG recording and data analysis procedures allow non-invasive recording of low-frequency and low-amplitude focal cortical changes in humans. An important clinical perspective of this technology is the detection of stroke-associated cortical DC activity.

A role of the molecular structure of phytoregulators in chemical signal perception by receptors of plant hormonal systems

The role of the molecular structure of phytoregulators in chemical signal perception by receptors of plant hormonal systems and the character of complementarity of a phytoregulator to a receptor have been considered on the basis of (1) the mechanism of signal perception and transduction in a plant cell and (2) the postulates of the physiological paradigm, which lies at the heart of the strategy of chemical design of phytoregulators with specified properties. For regulatory interaction, as distinct from interactions of enzymes with their substrates, topochemical, rather than geometric (a key in a lock), complementarity of a bioregulator to a biotarget is of crucial importance. The action of a bioregulator on a receptor is assumed to be cooperative and quantized. It is shown that molecular parameters of quaternary ammonium salts that determine their antigibberellin (retardant) activity can be used as a measure of topochemical complementarity to a receptor if physiological activities are compared for compounds of the same series (cluster). Submolecular consideration of the physiological activity of a molecule as the sum of the activities of its constituting effector moieties, with taking into account the effect of the moieties that determine polar and hydrophobic binding to a receptor, is suggested as a possible means for developing the QSAR method to make it heuristic.

Demonstration of an Anterior Diffusional Pathway for Solutes in the Normal Human Eye with High Spatial Resolution Contrast-Enhanced Dynamic MR Imaging

The present studies were conducted to determine whether a diffusional pathway for solutes exists from the ciliary body stroma to the anterior chamber of the human eye. The existence of such a pathway has been demonstrated in rabbits and monkeys, but such a pathway in humans would necessitate a shift in the physiological paradigm of the blood-aqueous barrier. Seven normal human volunteers (five men, two women; age range, 27 to 59 years) underwent nine dynamic T1-weighted, spin-echo MR imaging studies, using intravenous, gadolinium-based contrast agents. In all cases, signal intensity rose rapidly in the ciliary body. In all subjects, there was a measurable latent rise in signal strength (enhancement) in the anterior chamber. Signal enhancement typically occurred in the angle of the anterior chamber earlier, and to a greater degree, than within the center of the chamber. Increased signal within the posterior chamber was significantly less than in the anterior chamber, with measured increases probably attributable to volume averaging. These findings are consistent with the existence of an anterior diffusional pathway in the human eye. The model warrants further testing.

Anatomical Profiling of Nuclear Receptor Expression Reveals a Hierarchical Transcriptional Network

In multicellular organisms, the ability to regulate reproduction, development, and nutrient utilization coincided with the evolution of nuclear receptors (NRs), transcription factors that utilize lipophilic ligands to mediate their function. Studying the expression profile of NRs offers a simple, powerful way to obtain highly relational information about their physiologic functions as individual proteins and as a superfamily. We surveyed the expression of all 49 mouse NR mRNAs in 39 tissues, representing diverse anatomical systems. The resulting data set uncovers several NR clades whose patterns of expression indicate their ability to coordinate the transcriptional programs necessary to affect distinct physiologic pathways. Remarkably, this regulatory network divides along the following two physiologic paradigms: (1) reproduction, development, and growth and (2) nutrient uptake, metabolism, and excretion. These data reveal a hierarchical transcriptional circuitry that extends beyond individual tissues to form a meganetwork governing physiology on an organismal scale.

Bone Mass Increase in Puberty: What Makes It Happen?

It is now thought that the critical property of bone is strength rather than weight, and that control of bone strength is mainly exercised through the effect of the mechanical loads brought to bear on bone. Muscle contraction places the greatest physiological load on bone, and so the strength of bone must be adapted to muscle strength (the functional muscle-bone unit). The Utah paradigm of skeletal physiology [J Hum Biol 1998;10:599–605] provides a model of bone development that describes how bone structure is regulated by local mechanical effects that can be adjusted by the effects of hormones. The DONALD (Dortmund Nutritional and Anthropometric Longitudinally Designed) study analysed the interaction between the muscle and bone systems in males and females before and during puberty. This study found that differences between the genders in bone adaptation during puberty are at least partly driven by the influence of oestrogen in females. Testosterone seems to have no direct relevant effect on bone during puberty, but may be implicated in the greater amount of muscle mass achieved in boys compared with girls.

GABAB Receptor Isoforms Caught in Action at the Scene

The metabotropic GABAB receptors mediate slow synaptic inhibition and consist of heterodimers of GABAB1 and GABAB2 subunits. The only known molecular diversity of the GABAB receptors arises from the two GABAB1 isoforms, but its functional significance has been unclear. Two studies in this issue of Neuron now demonstrate that GABAB1a and GABAB1b show strategically distinct subcellular localization and physiological action.

The past, present, and future of bone morphometry: its contribution to an improved understanding of bone biology.

It was not until the 1950s that a better paradigm for bone biology evolved, which led to the birth of bone histomorphometry. Two clinicians, Harold Frost (1958-1964) and Lent Johnson (1964), were responsible for the paradigm stating that the primary function of bone is mechanical load bearing with subsidiary function to participate in plasma calcium homeostasis to support hematopoesis. Dynamic bone histomorphometry was born when Milch et al. (1958) discovered bone localization of tetracycline and Frost generated the methodology to study tetracycline-based dynamic histological analysis of cortical bone remodeling (1961-1965). Dynamic bone histomorphometry did not blossom until Frost, while a Sun Valley Workshop participant, developed it to address trabecular bone dynamics. The combination of Arnold (1948) producing thin sections of plastic-embedded undecalcified bone and Frost's (1977-1983) modification of dynamic cortical bone histology for cancellous bone made it possible to study tetracycline-based dynamic histomorphometry of cancellous bone. It led to the better understanding of basic metabolic unit (BMU) remodelling and to Frost's mechanostat hypothesis, and characterized the rat model to accelerate the development of several drugs in the treatment of bone diseases. Currently, dynamic bone histomorphometry has contributed to studies in bone's mechanical usage windows, mechanical usage setpoint hypothesis, muscle-bone relations, marrow-bone relations, the Utah paradigm of musculoskeletal physiology, apoptosis, genetics (transgenic mice) and bone structure, bone quality, the lacunocanalicular network and bone modelling, and remodeling hypothesis, osteocyte role as mechanosensory, chemosensory, and regulatory in bone maintenance, targeted and untargeted remodeling, the role of permissive agents, etc., items in bone biology expounded briefly by Lent Johnson (1965) and continuously by Harold Frost at the Sun Valley Workshop (1965-2003). Finally, "What's next?" covers how to improve and perpetuate the employing of qualitative histomorphometry in research opportunities in hard tissue research.

The Evolution of Concepts on the Evolution of Endothermy in Birds and Mammals

Warm-blooded animals, mammals and birds, are unique not because they are endothermic in the strict sense of the term but because they use an extravagant economy: they have high energy budgets and spend a large part of their energy resources on basic maintenance. Although several advantages of endothermy are easy to indicate, mechanisms behind evolution of such a wasteful life strategy remain unclear and have been subject to intensive debate. For two decades, the aerobic capacity model has been widely recognized as a promising hypothesis and has catalyzed a new direction in ecological and evolutionary physiology--the study of correlated evolution of behavioral and morphophysiological traits. Recently, two alternative models have been proposed, both of which see evolution of high metabolic rates in birds and mammals as an element in evolution of intensive parental care. Unlike previous models, which treated individuals as static objects of fixed properties, the parental care models explicitly incorporate life histories into a evolutionary-physiology research program. The aim of this article was to outline the process of evolution of major concepts in the field, which reflects development of the paradigm of modern evolutionary physiology.

Commentary

HIGHLIGHTED TOPICSSkeletal and Cardiac Muscle Blood FlowCommentaryGary C. SieckGary C. SieckJournal of Applied Physiology September 2004, Volume 97Published Online:01 Sep 2004https://doi.org/10.1152/japplphysiol.00635.2004MoreSectionsPDF (9 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Reactive oxygen species are generally thought to play a role only in pathological conditions. However, recent studies have suggested that reactive oxygen species may play a physiological role in the modulation of vascular tone. In the first featured article, entitled “Biphasic effect of hydrogen peroxide on skeletal muscle arteriolar tone via activation of endothelial and smooth muscle signaling pathways,” Dr. C. Cseko and colleagues (1) examined the role of H2O2 in local regulation of skeletal muscle blood flow. These investigators provide further evidence supporting concentration-dependent effects of H2O2 on vasomotor tone of arterioles mediated by prostanoids, nitric oxide, and potassium channels. The findings of this study are important because in various physiological and/or pathological conditions, endothelial or smooth muscle cells may release H2O2 during increased oxidative metabolism. Under physiological conditions, H2O2 may provide a feedback signal to locally couple tissue metabolism to blood supply. Under pathological conditions, circulating leukocytes or macrophages that are in or near the vascular wall may produce significant amounts of H2O2, which may then modulate arteriolar diameter and locally increase blood flow, thereby ensuring that all necessary components of inflammation are present in the microcirculation. Together, these findings emphasize that the role of reactive oxygen species, such as H2O2, should be considered when attempting to explain the multifactorial nature of local regulation of blood flow.In the second featured article, entitled “Downhill running: a model of exercise hyperemia in the rat spinotrapezius muscle,” Dr. Y. Kano and colleagues (2) hypothesized that downhill treadmill running recruits the spinotrapezius muscle, as evidenced by the exercise hyperemia. Investigating the processes of blood-muscle exchange requires in vivo observations of capillary hemodynamics via intravital microscopy techniques. Visualization with transmission light microscopy requires that muscle tissue possess excellent optical properties and can be accessed without disturbing neural or vascular supplies. These criteria limit the selection of candidate muscles and impose a difficult challenge to investigation of microvascular adaptations to exercise training. The validity of swimming and uphill and flat running protocols used to train the cremaster and spinotrapezius muscles, respectively, has been questioned on the basis of their effectiveness in inducing physiological hyperemia. In a rat model, these investigators used radioactive microsphere techniques and demonstrated an approximate threefold increase in spinotrapezius blood flow during downhill running. These findings provide a physiological paradigm for the investigation of the microcirculatory basis of enhanced blood-muscle exchange and muscle performance after training.REFERENCES1 Cseko C, Bagi Z, and Koller A. Biphasic effect of hydrogen peroxide on skeletal muscle arteriolar tone via activation of endothelial and smooth muscle signaling pathways. J Appl Physiol 97: 1130–1137, 2004.Google Scholar2 Kano Y, Padilla D, Hageman KS, Poole DC, and Musch TI. Downhill running: a model of exercise hyperemia in the rat spinotrapezius muscle. J Appl Physiol 97: 1138–1142, 2004.Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 97Issue 3September 2004Pages 1129-1129 Copyright & PermissionsCopyright © 2004 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00635.2004History Published online 1 September 2004 Published in print 1 September 2004 Metrics

Modulation of cardiac contraction, relaxation and rate by the endothelial nitric oxide synthase (eNOS): lessons from genetically modified mice.

The modulatory role of endothelial nitric oxide synthase (eNOS) on heart contraction, relaxation and rate is examined in light of recent studies using genetic deletion or overexpression in mice under specific conditions. Unstressed eNOS-/- hearts in basal conditions exhibit a normal inotropic and lusitropic function, with either decreased or unchanged heart rate. Under stimulation with catecholamines, eNOS-/- mice predominantly show a potentiation in their beta-adrenergic inotropic and lusitropic responsiveness. A similar phenotype is observed in beta 3-adrenoceptor deficient mice, pointing to a key role of this receptor subtype for eNOS coupling. The effect of eNOS on the muscarinic cholinergic modulation of cardiac function probably operates in conjunction with other NO-independent mechanisms, the persistence of which may explain the apparent dispensability of this isoform for the effect of acetylcholine in some eNOS-/- mouse strains. eNOS-/- hearts submitted to short term ischaemia-reperfusion exhibit variable alterations in systolic and diastolic function and infarct size, while those submitted to myocardial infarction present a worsened ventricular remodelling, increased 1 month mortality and loss of benefit from ACE inhibitor or angiotensin II type I receptor antagonist therapy. Although non-conditional eNOS gene deletion may engender phenotypic adaptations (e.g. ventricular hypertrophy resulting from chronic hypertension, or upregulation of the other NOS isoforms) potentially confounding the interpretation of comparative studies, the use of eNOS-/- mice has undoubtedly advanced (and will probably continue to improve) our understanding of the complex role of eNOS (in conjunction with the other NOSs) in the regulation of cardiac function. The challenge is now to confirm the emerging paradigms in human cardiac physiology and hopefully translate them into therapy.

Cell and molecular cell biology of melanin-concentrating hormone

Recent advances in the study of melanin-concentrating hormone (MCH) have depended largely on molecular biological techniques. In mammals, which have attracted the most attention, novel findings concern (i) the MCH gene, which can yield several peptides by either posttranslational cleavage or alternative splicing, as well as bidirectional transcription; (ii) the identification of two G protein-coupled MCH receptors in the brain and peripheral tissues; and (iii) the evidence for subpopulations of MCH neurons in the central nervous system, characterized by their chemical phenotypes, connections, and individual physiological responses to different physiological paradigms. The involvement of central MCH in various functions, including feeding, reproduction, stress, and behavior patterns, is reviewed. The stage during evolution at which MCH may have acquired hypophysiotrophic and hormonal functions in lower vertebrates is considered in light of morphological data. Evidence that MCH also has peripheral paracrine/autocrine effects in mammals is provided.

Seeking genetic causes of “osteoporosis:” insights of the Utah paradigm of skeletal physiology

This article investigates: (1) the criteria used to select cohorts of patients for study when seeking genetic causes of “osteoporosis;” (2) the possibilities, genetic and otherwise, that might cause or help to cause this disorder; and (3) how one should define this disorder and bone health. Patients selected for such a study because current World Health Organization (WHO) absorptiometric criteria diagnosed them with “osteoporosis,” or because they had extremity bone fractures, could possibly include people with biologically different disorders, in addition to those with healthy or diseased bones. Seeking a common genetic cause of “osteoporosis” in such inhomogeneous cohorts may be like seeking a common genetic cause of “anemia” in a cohort that contained iron deficiency and pernicious anemias, thalassemia, sickle-cell disease, anemias due to blood loss, malnutrition, malaria, metastatic disease, etc. The Utah paradigm’s insights suggest how to select more homogeneous cohorts for such studies. This would require defining bone health in a way that acknowledges the main purpose of load-bearing bones, which the WHO criteria do not do. The present understanding of bone physiology indicates that many biologic mechanisms and features could cause or help to cause an osteopenia or osteoporosis. This study identifies 30 such mechanisms, some osseous and some extraosseous, and even this number seems conservative. Because each such mechanism could depend on any number of genes, when a strong genetic association with some kind of osteopenia or osteoporosis is found it could be difficult to determine which mechanism(s) it perturbed. This article summarizes the evidence and ideas on which these suggestions depend.

From Wolff's law to the Utah paradigm: insights about bone physiology and its clinical applications.

Efforts to understand our anatomy and physiology can involve four often overlapping phases. We study what occurs, then how, then ask why, and then seek clinical applications. In that regard, in 1960 views, bone's effector cells (osteoblasts and osteoclasts) worked chiefly to maintain homeostasis under the control of nonmechanical agents, and that physiology had little to do with anatomy, biomechanics, tissue-level things, muscle, and other clinical applications. But it seems later-discovered tissue-level mechanisms and functions (including biomechanical ones, plus muscle) are the true key players in bone physiology, and homeostasis ranks below the mechanical functions. Adding that information to earlier views led to the Utah paradigm of skeletal physiology that combines varied anatomical, clinical, pathological, and basic science evidence and ideas. While it explains in a general way how strong muscles make strong bones and chronically weak muscles make weak ones, and while many anatomists know about the physiology that fact depends on, poor interdisciplinary communication left people in many other specialties unaware of it and its applications. Those applications concern 1.) healing of fractures, osteotomies, and arthrodeses; 2.) criteria that distinguish mechanically competent from incompetent bones; 3.) design criteria that should let load-bearing implants endure; 4.) how to increase bone strength during growth, and how to maintain it afterwards on earth and in microgravity situations in space; 5.) how and why healthy women only lose bone next to marrow during menopause; 6.) why normal bone functions can cause osteopenias; 7.) why whole-bone strength and bone health are different matters; 8.) why falls can cause metaphyseal and diaphyseal fractures of the radius in children, but mainly metaphyseal fractures of that bone in aged adults; 9.) which methods could best evaluate whole-bone strength, "osteopenias" and "osteoporoses"; 10.) and why most "osteoporoses" should not have bone-genetic causes and some could have extraosseous genetic causes. Clinical specialties that currently require this information include orthopaedics, endocrinology, radiology, rheumatology, pediatrics, neurology, nutrition, dentistry, and physical, space and sports medicine. Basic science specialties include absorptiometry, anatomy, anthropology, biochemistry, biomechanics, biophysics, genetics, histology, pathology, pharmacology, and cell and molecular biology. This article reviews our present general understanding of this new bone physiology and some of its clinical applications and implications. It must leave to other times, places, and people the resolution of questions about that new physiology, and to understand the many devils that should lie in its details. (Thompson D'Arcy, 1917).

"OSTEOPOROSIS" IN 2000 AD: QUO VADIS?

Here, we suggest that new ideas and knowledge about "osteoporosis" reveal necessary new directions for future work. To explain, by 1999, five studies involving a total of 1827 healthy humans from two to over 80 years of age supported this proposal in the Utah paradigm of skeletal physiology: Momentary muscle strength strongly influences and may dominate control of the biologic mechanisms that determine the postnatal strength of load-bearing bones. That italicized proposal differed so much from former views that before 1999, few people thought it deserved testing in humans. The above five studies did finally test it, and they support it. If true, its implications would affect many things. In part, they include (A), genetic effects on bone strength and "mass", muscle and "osteoporosis"; (B) the pathogenesis, diagnosis, classification, prevention and management of "osteoporosis"; (C) the things osteoporosis-oriented basic, clinical and pharmaceutical research should study; (D) the absorptiometric methods and animal models used to study the disorder; (E) which research projects would receive preferred funding; (F) and the content of future texts, review articles, classroom lectures and many osteoporosis-oriented meetings. Many might find some of those implications dubious. While we will respect such doubts, this article describes some of those implications so others can exploit them and/or help to resolve any disagreements they may cause. Because they depend on the Utah paradigm of skeletal physiology, some of its pertinent features must be summarized.

“Osteoporosis” in 2000 Ad Quo Vadis?

Here, we suggest that new ideas and knowledge about osteoporosis reveal necessary new directions for future work. To explain, by 1999, five studies involving a total of 1827 healthy humans from two to over 80 years of age supported this proposal in the Utah paradigm of skeletal physiology: Momentary muscle strength strongly influences and may dominate control of the biologic mechanisms that determine the postnatal strength of load-bearing bones. That italicized proposal differed so much from former views that before 1999, few people thought it deserved testing in humans. The above five studies did finally test it, and they support it. If true, its implications would affect many things. In part, they include (A), genetic effects on bone strength and mass, muscle and osteoporosis; (B) the pathogenesis, diagnosis, classification, prevention and management of osteoporosis; (C) the things osteoporosis-oriented basic, clinical and pharmaceutical research should study; (D) the absorptiometric methods and animal models used to study the disorder; (E) which research projects would receive preferred funding; (F) and the content of future texts, review articles, classroom lectures and many osteoporosis-oriented meetings. Many might find some of those implications dubious. While we will respect such doubts, this article describes some of those implications so others can exploit them and/or help to resolve any disagreements they may cause. Because they depend on the Utah paradigm of skeletal physiology, some of its pertinent features must be summarized.

Activin Modulates Differential Effects of Estradiol on Synthesis and Secretion of Follicle-Stimulating Hormone in Ovine Pituitary Cells1

In several physiological paradigms, secretion of FSH and LH are not coordinately regulated. Because these hormones appear to be produced by a single cell type in the anterior pituitary gland, their discordant regulation must be related to differential intracellular responses to various stimuli. Estradiol-17beta (estradiol) has been shown to influence secretion of both FSH and LH and some of its effects are mediated directly on the gonadotrope. Changes in expression of intrapituitary factors such as activin and follistatin may mediate effects of estradiol and account for discordant patterns of FSH and LH. The aims of this study were 1) to determine if estradiol alters expression of genes encoding activin, follistatin, or both in ovine pituitary cells; and 2) to observe the effects of immunoneutralizing activin B in vitro on gonadotropin secretion. Pituitary cells from five ewes in the anestrous season were cultured for 24 h with estradiol (0.01 or 1.0 nM). Estradiol reduced basal secretion of FSH in a dose-dependent manner (P: < 0.001) and simultaneously increased basal secretion of LH (P: < 0.001). Decreased secretion of FSH in estradiol-treated cultures was accompanied by suppressed levels of FSHbeta subunit mRNA (P: < 0.001). Amounts of mRNA for activin beta(B) were reduced in a dose-dependent manner by estradiol (27% +/- 4.9% at 0.01 nM, P: < 0.02; and 46% +/- 3.9% at 1.0 nM, P: < 0.002). In contrast, mRNA for follistatin was not affected by treatment with estradiol. Treatment of pituitary cells with an antibody to activin B reduced secretion of FSH by 50% (P: < 0.01) without influencing secretion of LH. These data lead us to conclude that discordant secretion of gonadotropins can be induced by estradiol acting directly at the pituitary level. The inhibitory effect of estradiol on FSH secretion may be mediated indirectly through decreased pituitary expression of the activin gene.