A hypothesis for the local control of osteoclast function by Ca2+, nitric oxide and free radicals

Several important conclusions have recently emerged fromin vitro studies on the resorptive cell of bone, the osteoclast. First, it has been established that osteoclast function is modulated locally, by changes in the local concentration of Ca²⁺ caused by hydroxyapatite dissolution. It is thought that activation by Ca²⁺ of a surface membrane Ca²⁺ receptor mediates these effects, hence providing a feedback control. Second, a number of molecules produced locally by the endothelial cell, with which the osteoclast is in intimate contact, have been found to affect bone resorption profoundly. For instance, the autocoid nitric oxide strongly inhibits bone resorption. Finally, reactive oxygen species have been found to aid bone resorption and enhance osteoclastic activity directly. Here, we will attempt to integrate these control mechanisms into a unified hypothesis for the local control of bone resorption.     

Local Mechanical Stimuli Regulate Bone Formation and Resorption in Mice at the Tissue Level

Bone is able to react to changing mechanical demands by adapting its internal microstructure through bone forming and resorbing cells. This process is called bone modeling and remodeling. It is evident that changes in mechanical demands at the organ level must be interpreted at the tissue level where bone (re)modeling takes place. Although assumed for a long time, the relationship between the locations of bone formation and resorption and the local mechanical environment is still under debate. The lack of suitable imaging modalities for measuring bone formation and resorption in vivo has made it difficult to assess the mechanoregulation of bone three-dimensionally by experiment. Using in vivo micro-computed tomography and high resolution finite element analysis in living mice, we show that bone formation most likely occurs at sites of high local mechanical strain (p<0.0001) and resorption at sites of low local mechanical strain (p<0.0001). Furthermore, the probability of bone resorption decreases exponentially with increasing mechanical stimulus (R² = 0.99) whereas the probability of bone formation follows an exponential growth function to a maximum value (R² = 0.99). Moreover, resorption is more strictly controlled than formation in loaded animals, and ovariectomy increases the amount of non-targeted resorption. Our experimental assessment of mechanoregulation at the tissue level does not show any evidence of a lazy zone and suggests that around 80% of all (re)modeling can be linked to the mechanical micro-environment. These findings disclose how mechanical stimuli at the tissue level contribute to the regulation of bone adaptation at the organ level.     

Blood coagulation and bone metabolism: some characteristics of the bone resorptive effect of thrombin in mouse calvarial bones in vitro

Chronic inflammatory processes are often associated with bone resorption. Stimulated by the current great interest in the role of coagulation factors in inflammation and immune injury, we have studied the effect of thrombin on mouse calvarial bones in vitro. Thrombin caused a dose-dependent (0.1-7 U/ml) stimulation of 45Ca release from neonatal mouse calvarial bones. Thrombin also stimulated the mobilization of stable calcium and inorganic phosphate, the release of 3H from [3H]proline-labelled calvaria, the production of lactate and the release of the lysosomal enzymes, beta-glucuronidase and beta-N-acetylglucosaminidase. Thrombin also enhanced 45Ca release from fetal rat long bones, although this bone resorption assay was less sensitive to thrombin than the mouse calvarial system. The bone resorption stimulatory activity of thrombin in mouse calvaria could be inhibited by calcitonin and an increased concentration of phosphate in the culture medium. Thrombin-induced 45Ca release in mouse calvaria was sensitive to inhibition by hydrocortisone and dexamethasone. By contrast, 45Ca release response to parathyroid hormone was insensitive to corticosteroids. The prostaglandin synthetase inhibitors indomethacin, meclofenamic acid and naproxen and 5,8,11,14-eicosatetraynoic acid reduced 45Ca release from thrombin-stimulated calvaria. However, significant stimulation by thrombin could be achieved also in bones treated with inhibitors of arachidonate metabolism. The results obtained suggest that thrombin can stimulate cell-mediated bone resorption by an osteoclast-dependent mechanism. The mechanism of action may involve both prostaglandin-dependent and prostaglandin-independent pathways. Our findings indicate that thrombin may contribute to the bone resorptive processes seen in periodontal disease and rheumatoid arthritis.     

Aryl hydrocarbon receptor catabolic activity in bone metabolism is osteoclast dependent in vivo

Bone mass is regulated by various molecules including endogenous factors as well as exogenous factors, such as nutrients and pollutants. Aryl hydrocarbon receptor (AhR) is known as a dioxin receptor and is responsible for various pathological and physiological processes. However, the role of AhR in bone homeostasis remains elusive because the cell type specific direct function of AhR has never been explored in vivo. Here, we show the cell type specific function of AhR in vivo in bone homeostasis. Systemic AhR knockout (AhRKO) mice exhibit increased bone mass with decreased resorption and decreased formation. Meanwhile, osteoclast specific AhRKO (AhR^ΔOc/ΔOc) mice have increased bone mass with reduced bone resorption, although the mice lacking AhR in osteoblasts have a normal bone phenotype. Even under pathological conditions, AhR^ΔOc/ΔOc mice are resistant to sex hormone deficiency-induced bone loss resulting from increased bone resorption. Furthermore, 3-methylcholanthrene, an AhR agonist, induces low bone mass with increased bone resorption in control mice, but not in AhR^ΔOc/ΔOc mice. Taken together, cell type specific in vivo evidence for AhR functions indicates that osteoclastic AhR plays a significant role in maintenance of bone homeostasis, suggesting that inhibition of AhR in osteoclasts can be beneficial in the treatment of osteoporosis.     

Osteoclast activation: Potent inhibition by the bisphosphonate alendronate through a nonresorptive mechanism

Alendronate, an aminobisphosphonate used in the treatment of osteoporosis, is a potent inhibitor of bone resorption. Its mechanism of action is unknown. Because it localizes to bone surfaces, we compared the sensitivity of components of the resorptive process to incubation on alendronate-coated bone surfaces. We found that bone resorption by osteoclasts isolated from neonatal rat bone was unaffected by alendronate (10^-4 M). Osteoclast production in bone marrow cultures, as assessed by the production of calcitonin-receptor positive cells, was observed even at 10^-4 M, but bone resorption in these cultures was almost completely abolished by 10^-6 M alendronate. The greater sensitivity of osteoclast activation to inhibition by alendronate that these results suggest was supported by similar inhibition of osteoblast-mediated activation of osteoclasts from neonatal rat bone. Thus, activation of osteoclasts by osteoblastic/stromal cells is apparently the most sensitive component of the pathway whereby bone resorption is affected. Moreover, the ability of alendronate to suppress osteoclastic activation does not depend on resorption-mediated release of alendronate from bone surfaces. This ability extends the range of cell types and processes that might be affected by alendronate, beyond those in the immediate vicinity of resorbing cells, to include any cell that comes into contact with alendronate-coated bone surfaces. J. Cell. Physiol. 172:79–86, 1997. © 1997 Wiley-Liss, Inc.     

Dexamethasone inhibits bone resorption by indirectly inducing apoptosis of the bone-resorbing osteoclasts via the action of osteoblastic cells

Although glucocorticoids (GCs) are physiologically essentialfor bone metabolism, it is generally accepted that high dosesof GCs cause bone loss through a combination of decreased boneformation and increased bone resorption. However, the actionof GCs on mature osteoclasts remains contradictory. In thisstudy, we have examined the effect of GCs on osteoclasticbone-resorbing activity and osteoclast apoptosis, by using twodifferent cell types, rabbit unfractionated bone cells andhighly enriched mature osteoclasts (>95% of purity).Dexamethasone (Dex, 10^-10–10^-7 M) inhibited resorption pit formation on a dentine slice by the unfractionated bone cells in a dose- and time-dependent manner.However, Dex had no effect on the bone-resorbing activity of the isolated mature osteoclasts. When the isolated osteoclastswere co-cultured with rabbit osteoblastic cells, the osteoclastic bone resorption decreased in response to Dex,dependent on the number of osteoblastic cells. Like the effecton the bone resorption, Dex induced osteoclast apoptosis in cultures of the unfractionated bone cells, whereas it did not promote the apoptosis of the isolated osteoclasts. An inhibitorof caspases, Z-Asp-CH2-DCB attenuated both the inhibitory effecton osteoclastic bone resorption and the stimulatory effect onthe osteoclast apoptosis. In addition, the osteoblastic cellswere required for the osteoclast apoptosis induced by Dex. These findings indicate that the main target cells of GCs arenon-osteoclastic cells such as osteoblasts and that GCsindirectly inhibit bone resorption by inducing apoptosis ofthe mature osteoclasts through the action of non-osteoclasticcells. This study expands our knowledge about the multifunctional roles of GCs in bone metabolism.     

Bradykinin stimulates bone resorption and lysosomal-enzyme release in cultured mouse calvaria.

The effect of bradykinin on bone resorption was studied in cultures of newborn-mouse calvaria. Bradykinin (0.03 microM, 1 microM) stimulated the release of 45Ca2+ from bones dissected out from mice prelabelled in vivo with 45Ca. Bradykinin (1 microM) also augmented the release of stable calcium ( 40Ca ), Pi and the lysosomal enzyme beta-glucuronidase. The stimulatory effect of bradykinin on mineral mobilization and lysosmal -enzyme release could be blocked by indomethacin. It is speculated that concomitant generation of thrombin and bradykinin in areas of trauma and inflammation may induce resorption of nearby bone tissue.     

The effect of resorption cavities on bone stiffness is site dependent

Resorption cavities formed during the bone remodelling cycle change the structure and thus the mechanical properties of trabecular bone. We tested the hypotheses that bone stiffness loss due to resorption cavities depends on anatomical location, and that for identical eroded bone volumes, cavities would cause more stiffness loss than homogeneous erosion. For this purpose, we used beam–shell finite element models. This new approach was validated against voxel-based FE models. We found an excellent agreement for the elastic stiffness behaviour of individual trabeculae in axial compression (R² = 1.00) and in bending (R²>0.98), as well as for entire trabecular bone samples to which resorption cavities were digitally added (R² = 0.96, RMSE = 5.2%). After validation, this new method was used to model discrete cavities, with dimensions taken from a statistical distribution, on a dataset of 120 trabecular bone samples from three anatomical sites (4th lumbar vertebra, femoral head, iliac crest). Resorption cavities led to significant reductions in bone stiffness. The largest stiffness loss was found for samples from the 4th lumbar vertebra, the lowest for femoral head samples. For all anatomical sites, resorption cavities caused significantly more stiffness loss than homogeneous erosion did. This novel technique can be used further to evaluate the impact of resorption cavities, which are known to change in several metabolic bone diseases and due to treatment, on bone competence.     

Dissociation of organic acid secretion from macrophage mediated bone resorption

A prevailing concept in the literature on bone resorption suggests that the removal of calcium crystals from the bone matrix is the result of the secretion of lactic and/or citric acid. In the present study, we have reassessed this concept using an in vitro bone resorption system consisting of thioglycolate elicited rat peritoneal macrophages co-cultured, for up to 96 hours, with devitalized ⁴⁵Ca-labeled bone particles. In these combined cultures, medium lactate concentration increased linearly for the first 48 hours of culture and remained at a plateau thereafter. Medium citrate concentration, on the other hand, remained constant and at very low levels throughout incubation. In contrast to both citrate and lactate, bone resorption, measured as ⁴⁵Ca release, began a few hours after the onset of culture and increased at a constant rate for the balance of the 96-hour culture period. Alteration of resorptive activity by the addition of 10^?6M cortisol (which stimulates ⁴⁵Ca release) or the interposition of a filter between cells and bone (which inhibits resorption) was not paralleled by similar shifts in lactate or citrate concentration. These experiments indicate that mobilization of the bone mineral can occur in the absence of a concurrent, generalized release of lactic and citric acid by sesorbing cells. On the other hand, the data do not exclude a possible role for these compounds under circumstances where they are secreteo into a “closed” compartment at the cell-bone interface or, in the case of lactate, during the initial period of resorptive activity.     

Control of bone resorption by semaphorin 4D is dependent on ovarian function

Osteoporosis is one of the most common bone pathologies, which are characterized by a decrease in bone mass. It is well established that bone mass, which results from a balanced bone formation and bone resorption, is regulated by many hormonal, environmental and genetic factors. Here we report that the immune semaphorin 4D (Sema4D) is a novel factor controlling bone resorption. Sema4D-deficient primary osteoclasts showed impaired spreading, adhesion, migration and resorption due to altered ß3 integrin sub-unit downstream signaling. In apparent accordance with these in vitro results, Sema4D deletion in sexually mature female mice led to a high bone mass phenotype due to defective bone resorption by osteoclasts. Mutant males, however, displayed normal bone mass and the female osteopetrotic phenotype was only detected at the onset of sexual maturity, indicating that, in vivo, this intrinsic osteoclast defect might be overcome in these mice. Using bone marrow cross transplantation, we confirmed that Sema4D controls bone resorption through an indirect mechanism. In addition, we show that Sema4D −/− mice were less fertile than their WT littermates. A decrease in Gnrh1 hypothalamic expression and a reduced number of ovarian follicles can explain this attenuated fertility. Interestingly, ovariectomy abrogated the bone resorption phenotype in Sema4D −/− mice, providing the evidence that the observed high bone mass phenotype is strictly dependent on ovarian function. Altogether, this study reveals that, in vivo, Sema4D is an indirect regulator of bone resorption, which acts via its effect on reproductive function.     

Epidermal growth factor stimulates prostaglandin production and bone resorption in cultured mouse calvaria.

Murine epidermal growth factor (EGF) stimulated the production of prostaglandin E₂ (PGE₂) and bone resorption in neonatal mouse calvaria in organ culture. The effect of EGF on bone resorption occurred at low concentrations of the polypeptide (half-max stimulation = 0.4 ng/ml, 6.6 × 10^?11 M). All concentrations of EGF which stimulated resorption also stimulated the production of PGE₂ by bone; concentrations of EGF which did not stimulate resorption did not enhance PGE₂ production. EGF-induced formation of PGE₂ and bone resorption were inhibited completely by indomethacin (200 ng/ml) and hydrocortisone (3 × 10^?6 M). Indomethacin did not inhibit the bone resorption-stimulating activity of exogenous PGE₂. The time courses of action of EGF, parathyroid hormone and exogenous PGE₂ on bone resorption were similar. Brief exposure (15 or 60 min) to EGF (10 ng/ml) did not cause bone resorption or an increase in PGE₂ accumulation in a subsequent 48-h incubation in the absence of EGF. High concentrations (30 to 100 ng/ml) of bovine fibroblast growth factor (FGF) also stimulated the production of PGE₂ and bone resorption. We conclude that concentrations of EGF equal to or less than those present in mouse plasma stimulate the resorption of mouse bone in organ culture by a mechanism that involves the enhanced local production of PGE₂.     

Variation of resorption rates in vivo of various bones in immature rats

The ³H-tetracycline method of measuring bone resorption in vivo was applied to the comparison of various whole bones in rats of two different ages. The rat was chosen because it grows via modelling processes and contains little, if any, cortical remodelling except for a small amount of trabecular remodelling. It was found that resorption rates in vivo are high and similar in almost all of the 18 bones measured between birth and 2 weeks of age. However, in weanling rats studied at 4–6 weeks of age, resorption rates in the skull and in the long bones had decreased significantly while remaining high in the vertebrae, scapula, sternum and pelvis. Bones of neonatal rats were quite alike in their rates of bone resorption, but the bones of the weanlings manifested significant heterogeneity in their rates.It is known that anatomic heterogeneity of metabolic turnover of various bones characterizes the mature state in humans and dogs as well. The present data are unique in that they reflect absolute resorption rates in vivo uncomplicated by the extensive re-utilization of calcium inherent in other isotopic or non-isotopic protocols.     

RANKL from bone marrow adipose lineage cells promotes osteoclast formation and bone loss

Receptor activator of NF‐κB ligand (RANKL) is essential for osteoclast formation and bone remodeling. Nevertheless, the cellular source of RANKL for osteoclastogenesis has not been fully uncovered. Different from peripheral adipose tissue, bone marrow (BM) adipose lineage cells originate from bone marrow mesenchymal stromal cells (BMSCs). Here, we demonstrate that adiponectin promoter‐driven Cre expression (Adipoq^Cre ) can target bone marrow adipose lineage cells. We cross the Adipoq^Cre mice with rankl^fl/fl mice to conditionally delete RANKL from BM adipose lineage cells. Conditional deletion of RANKL increases cancellous bone mass of long bones in mice by reducing the formation of trabecular osteoclasts and inhibiting bone resorption but does not affect cortical bone thickness or resorption of calcified cartilage. Adipoq^Cre; rankl^fl/fl mice exhibit resistance to estrogen deficiency and rosiglitazone (ROS)‐induced trabecular bone loss but show bone loss induced by unloading. BM adipose lineage cells therefore represent an essential source of RANKL for the formation of trabecula osteoclasts and resorption of cancellous bone during remodeling under physiological and pathological conditions. Targeting bone marrow adiposity is a promising way of preventing pathological bone loss.     

Aryl Hydrocarbon Receptors in Osteoclast Lineage Cells Are a Negative Regulator of Bone Mass

Aryl hydrocarbon receptors (AhRs) play a critical role in various pathological and physiological processes. Although recent research has identified AhRs as a key contributor to bone metabolism following studies in systemic AhR knockout (KO) or transgenic mice, the cellular and molecular mechanism(s) in this process remain unclear. In this study, we explored the function of AhR in bone metabolism using AhR^{RANKΔOc/ΔOc} (RANK^Cre/+;AhR^flox/flox) mice. We observed enhanced bone mass together with decreased resorption in both male and female 12 and 24-week-old AhR^{RANKΔOc/ΔOc} mice. Control mice treated with 3-methylcholanthrene (3MC), an AhR agonist, exhibited decreased bone mass and increased bone resorption, whereas AhR^{CtskΔOc/ΔOc} (Ctsk^Cre/+;AhR^flox/flox) mice injected with 3MC appeared to have a normal bone phenotype. In vitro, bone marrow-derived macrophages (BMDMs) from AhR^{RANKΔOc/ΔOc} mice exhibited impaired osteoclastogenesis and repressed differentiation with downregulated expression of B lymphocyte-induced maturation protein 1 (Blimp1), and cytochrome P450 genes Cyp1b1 and Cyp1a2. Collectively, our results not only demonstrated that AhR in osteoclast lineage cells is a physiologically relevant regulator of bone resorption, but also highlighted the need for further studies on the skeletal actions of AhR inhibitors in osteoclast lineage cells commonly associated with bone diseases, especially diseases linked to environmental pollutants known to induce bone loss.     

In vitro effect of KCA-098, a derivative of coumestrol,on bone resorption of fetal rat femurs

The effects of 3,9-bis(N,N-dimethylcarbamoyloxy)-5H-benzofuro[3,2-c]quinoline-6-one (KCA-098), a derivative of coumestrol, on bone resorption was studied in organ cultures of 20-day fetal rat femora. KCA-098 increased the length, dry weight, and calcium and phosphorus contents of parathyroid hormone (PTH)-treated fetal rat femur. As PTH significantly reduced the calcium and phosphorus contents of the femora, probably by stimulating bone resorption, KCA-098 seems to inhibit bone resorption. In fact, KCA-098 inhibited the PTH-induced release of ⁴⁵Ca from pre-labeled fetal rat femora into the medium in organ culture. Coumestrol also inhibited the release of ⁴⁵Ca from bone into the medium. However, KCA-098 did not increase the uterine weight of ovariectomized rats, whereas coumestrol did so. Thus KCA-098 is a unique, new inhibitor of bone resorption that has no estrogenic activity.     

COLLAGENOLYTIC ACTIVITY IN RAT BONE CELLS : Characteristics and Intracellular Location

An assay system for estimating quantitatively collagenase-like activity present in bone cells has been developed as part of a more general investigation of mechanisms of bone resorption. Methods are described for preparing from bone a C¹⁴-labeled collagen which is relatively pure and highly resistant to degradation by trypsin although readily broken down by bacterial collagenase. Collagenolytic activity in homogenates of bone cells harvested from rat metaphyseal bone was measured as the number of counts per minute released in ultrafiltrable form from the C¹⁴-labeled collagen substrate after 40 minutes' incubation at 37°C and pH 7.3. Using these techniques, the presence of collagenase-like activity in whole bone cell homogenates was confirmed and the heat lability, partial cation dependence, pH optimum, and some other characteristics of the crude material were determined. Moreover, the major portion of the homogenate activity was found in a particulate fraction sedimenting in a centrifugal field between 700 and 15,000 g. The marked enhancement and solubilization of this activity by surface-active agents or freeze-thawing, together with the presence of considerable acid phosphatase activity in the same fraction and its sedimentation characteristics, suggested that it might be contained in lysosomes or similar bodies. The implications of these observations with respect to the physiology of collagen resorption in general and bone resorption in particular are discussed.     

Effects of electromagnetic stimulation on the functional responsiveness of isolated rat osteoclasts

We report the effects of pulsed electromagnetic fields (PEMFs) on the responsiveness of osteoclasts to cellular, hormonal, and ionic signals. Osteoclasts isolated from neonatal rat long bones were dispersed onto either slices of devitalised cortical bone (for the measurement of resorptive activity) or glass coverslips (for the determination of the cytosolic free Ca²⁺ concentration, [Ca²⁺]). Osteoclasts were also cocultured on bone with osteoblastlike, UMR-106 cells. Bone resorption was quantitated by scanning electron microscopy and computer-assisted morphometry. PEMF application to osteoblast–osteoclast cocultures for 18 hr resulted in a twofold stimulation of bone resorption. In contrast, resorption by isolated osteoclasts remained unchanged in the presence of PEMFs, suggesting that osteoblasts were necessary for the PEMF-induced resorption simulation seen in osteoblast–osteoclast cocultures. Furthermore, the potent inhibitory action of the hormone calcitonin on bone resorption was unaffected by PEMF application. However, PEMFs completely reversed another quite distinct action of calcitonin on the osteoclast: its potent inhibitory effect on the activation of the divalent cation-sensing (or Ca²⁺) receptor. For these experiments, we made fura 2-based measurements of cytosolic [Ca²⁺] in single osteoclasts in response to the application of a known Ca²⁺ receptor agonist, Ni²⁺. We first confirmed that activation of the osteoclast Ca²⁺ receptor by Ni²⁺ (5 mM) resulted in a characteristic monophasic elevation of cytosolic [Ca²⁺]. As shown previously, this response was attenuated strongly by calcitonin at concentrations between 0.03 and 3 nM but remained intact in response to PEMFs. PEMF application, however, prevented the inhibitory effect of calcitonin on Ni²⁺-induced cytosolic Ca²⁺ elevation. This suggested that the fields disrupted the interaction between the calcitonin and Ca²⁺ receptor systems. In conclusion, we have shown that electromagnetic fields stimulate bone resorption through an action on the osteoblast and, by abolishing the inhibitory effects of calcitonin, also restore the responsiveness of osteoclasts to divalent cations. J. Cell. Physiol. 176:537–544, 1998. © 1998 Wiley-Liss, Inc.     

Stimulation of prostaglandin production in bone by phorbol diesters and melittin

The production of prostaglandin E₂ (PGE₂) and bone resorption were studied in neonatal mouse calvaria in organ culture. Two tumor promoters 12- -tetradecanoyl-phorbol-13-acetate (TPA) and phorbol-12, 13-di-decanoate, but not the non-tumor promoters 4α-phorbol-12,13-didecanoate and phorbol, stimulated both PGE₂ synthesis in bone and bone resorption. The effect of TPA was maximum at about 25 ng/ml, and half-maximum stimulation occurred at about 8 ng/ml TPA. The effects of TPA on the production of PGE₂ and bone resorption were inhibited completely by indomethacin (5.6 × 10⁻⁸ to 5.6 × 10⁻⁷ M). The bee venom toxin, melittin, was also a potent stimulator of prostaglandin synthesis in bone and bone resorption. The effect of melittin was maximum at about 25 ng/ml, and the dose-response curve was biphasic. The effects of melittin on the production of PGE₂ and bone resorption were also inhibited by indomethacin. Indomethacin did not inhibit the bone resorption-stimulating activity of exogenously added PGE₂. We conclude that phorbol diesters, which have irritant and tumor-promoting activity in mouse skin, and the polypeptide melittin can act directly on bone to stimulate resorption by a mechanism involving the local production of PGE₂ or possibly other indomethacin-inhibited metabolites of arachidonic acid.     

Impaired bone formation and osteopenia in heterozygous β<Superscript>IVSII-654</Superscript> knockin thalassemic mice

β-thalassemia caused by the C→T mutation at nucleotide 654 of the intron 2 (β^IVSII-654) results in aberrant splicing of β-globin RNA, leading to an almost absence of β-globin synthesis. Although trabecular and cortical bone loss was previously reported in β-thalassemic mice with deletion of β-globin gene, the microscopic changes in trabecular structure in β^IVSII-654 thalassemic mice remained elusive. Here, we investigated the macroscopic and microscopic bone changes in 12-week-old β^IVSII-654 knockin thalassemic mice by dual-energy X-ray absorptiometry (DXA) and histomorphometric analysis, respectively. DXA revealed a decrease in bone mineral density in the lumbar vertebrae and tibial metaphysis, but not in the femoral diaphysis, suggesting that β^IVSII-654 thalassemia predominantly led to osteopenia at the trabecular site, but not the cortical site. Further histomorphometric analysis of the tibial secondary spongiosa showed that trabecular bone volume was significantly decreased with the expansion of marrow cavity. Decreases in osteoblast surface, osteoid surface, mineral apposition rate, mineralizing surface, and mineralized volume were also observed. Moreover, trabecular bone resorption was markedly enhanced as indicated by increases in the osteoclast surface and eroded surface. It could be concluded that β^IVSII-654 thalassemia impaired bone formation and enhanced bone resorption, thereby leading to osteopenia especially at the trabecular sites, such as the tibial metaphysis.     

Does the cortical bone resorption rate change due to <Superscript>90</Superscript>Sr-radiation exposure? Analysis of data from Techa Riverside residents

The Mayak Production Association released large amounts of ⁹⁰Sr into the Techa River (Southern Urals, Russia) with peak amounts in 1950–1951. Techa Riverside residents ingested an average of about 3,000 kBq of ⁹⁰Sr. The ⁹⁰Sr-body burden of approximately 15,000 individuals has been measured in the Urals Research Center for Radiation Medicine in 1974–1997 with use of a special whole-body counter (WBC). Strontium-90 had mainly deposited in the cortical part of the skeleton by 25 years following intake, and ⁹⁰Sr elimination occurs as a result of cortical bone resorption. The effect of ⁹⁰Sr-radiation exposure on the rate of cortical bone resorption was studied. Data on 2,022 WBC measurements were selected for 207 adult persons, who were measured three or more times before they were 50–55 years old. The individual-resorption rates were calculated with the rate of strontium recirculation evaluated as 0.0018 year⁻¹. Individual absorbed doses in red bone marrow (RBM) and bone surface (BS) were also calculated. Statistically significant negative relationships of cortical bone resorption rate were discovered related to ⁹⁰Sr-body burden and dose absorbed in the RBM or the BS. The response appears to have a threshold of about 1.5-Gy RBM dose. The radiation-induced decrease in bone resorption rate may not be significant in terms of health. However, a decrease in bone remodeling rate can be among several causes of an increased level of degenerative dystrophic bone pathology in exposed persons.