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Studies of a number of mouse mutations with skeletal defects have contributed significantly to the understanding of bone development and homeostasis. In many cases, such mutants are also genetic models of disorders in humans, characterized by reduced bone mass (osteoporosis), increased bone mass (osteopetrosis), or abnormalities in endochondral ossification (chondrodysplasias).
Renal transplant recipients are at risk of developing bone abnormalities that result in bone loss and bone fractures. These are related to underlying renal osteodystrophy, hypophosphatemia, and immunosuppressive treatment regimen. Although bisphosphonates are useful in ameliorating bone mineral loss after transplantation, it is not known whether their use in renal transplant patients leads to excessive suppression of bone turnover and increased incidence of adynamic bone disease. A randomized, prospective, controlled, clinical trial was conducted using the bisphosphonate pamidronate intravenously in patients with new renal transplants. Treatment subjects (PAM) received pamidronate with vitamin D and calcium at baseline and at months 1, 2, 3, and 6. Control (CON) subjects received vitamin D and calcium only. During months 6 to 12, the subjects were observed without pamidronate treatment. Biochemical parameters of bone turnover were obtained monthly and, bone mineral density (BMD) was obtained at baseline and months 6 and 12. Bone biopsies for mineralized bone histology were obtained at baseline and at 6 mo in a subgroup of subjects who underwent scheduled living donor transplantation. PAM preserved bone mass at 6 and 12 mo as measured by bone densitometry and histomorphometry. CON had decreased vertebral BMD at 6 and 12 mo (4.8 +/- 0.08 and 6.1 +/- 0.09%, respectively). Biochemical parameters of bone turnover were similar in both groups at 6 and 12 mo. Bone histology revealed low turnover bone disease in 50% of the patients at baseline. At 6 mo, all of PAM had adynamic bone disease, whereas 50% of CON continued to have or developed decreased bone turnover. Pamidronate preserved vertebral BMD during treatment and 6 mo after cessation of treatment. Pamidronate treatment was associated with development of adynamic bone histology. Whether an improved BMD with adynamic bone histology is useful in maintaining long-term bone health in renal transplant recipients requires further study.
Beagle dogs exposed to 238PuO2 aerosols (136 dogs, 13-22 per group, mean initial lung depositions of 0.0, 0.13, 0.68, 3.1, 13, 52 and 210 kBq) were observed throughout life to determine tissues at risk and dose-effect relationships. The pulmonary retention of 238Pu was represented by the sum of two exponentially decreasing components of the initial lung deposition; about 84% cleared with a 174-day half-time; the half-time of the remainder was 908 days. The average percentages of final body burden found in lung, skeleton, liver and thoracic lymph nodes in the 30 longest-surviving dogs (mean survival 14 years) were 1, 46, 42 and 6%, respectively. Of 116 beagles exposed to plutonium, 34 (29%) developed bone tumors, 31 (27%) developed lung tumors, and 8 (7%) developed liver tumors. Although lungs accumulated a higher average radiation dose than skeleton, more deaths were due to bone tumors than to lung tumors. Deterministic effects included radiation pneumonitis, osteodystrophy, hepatic nodular hyperplasia, lymphopenia, neutropenia and sclerosing tracheobronchial lymphadenitis. Hypoadrenocorticism was also observed in a few dogs. Increased serum alanine aminotransferase, indicative of liver damage, was observed in groups with > or =3.1 kBq initial lung deposition. Estimates of cumulative tissue dose in a human exposed to airborne 238PuO2 for 50 years at a rate of one annual limit on intake each year were derived based on a comparison of the data on metabolism for humans and beagles. The 50-year dose estimates for humans are an order of magnitude lower than doses at which increased incidence of neoplasia was observed in these dogs, whereas the projected doses to humans from 50-year exposure at the annual limit of intake are of similar magnitude to those at which deterministic effects were seen in the beagles.
Thyroid hormone nuclear receptors (TRs) mediate the biological activities of the thyroid hormone (T3) in growth, development and differentiation and in the maintenance of metabolic homeostasis. They are derived from two separate genes to yield four major T3-binding isoforms: alpha1, beta1, beta2, and beta3. To understand whether TR isoforms mediate specific functions in vivo, PV mutation, identified from a patient with resistance to thyroid hormone (RTH), was targeted to the TRbeta (TRbetaPV mice) or TRalpha gene (TRalpha1PV mice). PV has a frame-shift mutation in the last 14 carboxyl-terminal amino acids of TRbeta1 or TRalpha1, resulting in the loss of T3-binding and transcriptional activities. TRbetaPV mice faithfully reproduce human RTH with dysfunction of the pituitary-thyroid axis, impairment in weight gain and accelerated bone development, hearing defects, abnormal regulation of serum cholesterol and increased physical activity reminiscent of attention deficit-hyperactivity disorder. In contrast, TRalpha1PV mice show no abnormalities in the pituitary-thyroid axis and other discernable RTH phenotypes. In addition, TRalpha1PV mice are dwarfs with high mortality, reduced fertility and survival, reduced glucose utilization in the brain and marked delay in bone development. These results clearly show that the molecular actions of TRalpha1PV are distinct from those of TRbetaPV in vivo. Further studies indicate that these contrasting phenotypes are mediated by distinct isoform-dependent abnormal regulation of T3-target genes in tissues. Thus, these two mutant mice provide a valuable tool for further dissecting the molecular bases of isoform-dependent actions of mutant TRs in vivo and their roles in disease.
Data obtained from studies in childhood-onset GH deficiency (CO-GHD) in adult life indicate differences in body composition in comparison with adult-onset GHD, but the response to GH replacement is qualitatively similar in terms of reduction in fat mass, serum cholesterol and LDL-cholesterol. However, because bone development is GH dependent and achievement of peak bone mass occurs some years later than completion of linear growth, continuing somatic development is a potentially important issue in the GHD adolescent. This issue has been examined in a United Kingdom multicentre study, in which patients with persisting severe GHD were randomised to continue or discontinue GH replacement at completion of linear growth. Over the course of one years, important differences were observed in bone mineral content with continued accrual in patients continuing GH therapy, in comparison with minimal change in those patients who had discontinued. A similar pattern was observed for lean body mass. Both groups demonstrated gain in fat mass, with a tendency for this to be greater in the GH discontinuation group. There were no changes observed in lipoprotein profiles. These observations and similar data from other groups have provided the basis for recommendations that young adults with CO-GHD should be offered continuing GH replacement in order to optimise bone development. Despite the wide applicability of this advice, it should be recognised that there are significant interindividual differences in clinical characteristics. Further studies are required to determine whether sabbatical periods off GH replacement are clinically appropriate and, if so, their reasonable duration.
Bone morphogenetic proteins (BMP) were identified in full-thickness autogeneic implants of the urinary bladder by monoclonal antibody BMP immunohistochemistry and by in situ hybridization of BMP-2, -4, and -5 mRNAs. Within the first week after transplantation, BMP mRNAs were expressed in uroepithelial cytoplasm and basement membranes of proliferating cells. About the second week, BMP-2, -4, and -5 mRNA expression and monoclonal antibody BMP-2 synthesis were colocalized in the sites of conversion of transitional to columnar epithelium. In close association with basement membrane, mesenchymal-type cells migrated, proliferated, and formed osteogenetic condensations. The areas of condensation were composed of densely packed cells with high nucleocytoplasmic ratios and high mitotic activity, and resembled periosteum of growing membrane bone. For the first 3 to 4 weeks, the bone deposits grew rapidly in size on surfaces of columnar uroepithelial basement membrane. After 4 to 5 weeks, the growth was constrained by enclosure in a thick, dense, periosteum-like fibrous tissue, completely separated from basement membrane. Serial observations are submitted herewith as circumstantial evidence that bone development is a product of mutual interaction of uroepithelium and mesenchymal-type cells across basement membranes in response to endogenous BMP-2, -4, and -5. Neither BMP-2, -4, -5 mRNA nor monoclonal antibody BMP-2 was detected in the lamina propria, smooth muscle, or fibrous tissue.
The core binding factor beta gene (CBFB), essential to bone morphogenesis, is located at 16q22.1. Homozygous deficiency of CBFB leads to ossification defects in mice. CBFB forms a heterodimer with RUNX2 (CBFA1) during embryonic bone development. RUNX2 mutations lead to cleidocranial dysplasia in humans. We describe an infant boy with an interstitial deletion of 16q21q22, delayed skull ossification, cleft palate, and heart anomalies who had a difficult course in infancy but eventually improved and is healthy. He was found to have CBFB haploinsufficiency, but did not have mutations in RUNX2. We suggest that 16q21q22 deletion be considered when there are antenatal or postnatal findings of enlarged cranial sutures with or without cleft palate. The finding of CBFB haploinsufficiency in our case and the similarity of cranial ossification defects with a mouse model of CBFB deletion suggest a role for CBFB in cranial bone development in humans.
Thyroid hormone (T3) and the T3 receptor (TR) alpha gene are essential for bone development whereas adult hyperthyroidism increases the risk of osteoporotic fracture. We isolated fibroblast growth factor receptor-1 (FGFR1) as a T3-target gene in osteoblasts by subtraction hybridization. FGFR1 mRNA was induced 2- to 3-fold in osteoblasts treated with T3 for 6-48 h, and FGFR1 protein was stimulated 2- to 4-fold. Induction of FGFR1 was independent of mRNA half-life and abolished by actinomycin D and cycloheximide, indicating the involvement of an intermediary protein. Fibroblast growth factor 2 (FGF2) stimulated MAPK in osteoblasts, and pretreatment with T3 for 6 h induced a more rapid response to FGF that was increased in magnitude by 2- to 3-fold. Similarly, T3 enhanced FGF2-activated autophosphorylation of FGFR1, but did not modify FGF2-induced phosphorylation of the docking protein FRS2. These effects were abolished by the FGFR-selective inhibitors PD166866 and PD161570. In situ hybridization analyses of TRalpha-knockout mice, which have impaired ossification and skeletal mineralization, revealed reduced FGFR1 mRNA expression in osteoblasts and osteocytes, whereas T3 failed to stimulate FGFR1 mRNA or enhance FGF2-activated MAPK signaling in TRalpha-null osteoblasts. These findings implicate FGFR1 signaling in T3-dependent bone development and the pathogenesis of skeletal disorders resulting from thyroid disease.
Bone morphogenetic proteins (BMPs) are a group of peptide growth factors closely related to transforming growth factors-beta. The BMPs are suggested to play an essential role in bone development and they are strong candidate molecules to be used clinically to improve fracture healing. BMPs are also involved in the differentiation of several other tissues during embryogenesis. Here, we show that human recombinant BMP-2 regulates cell-matrix interactions by modifying the expression of integrin-type receptors. The synthesis of alpha3 integrin was down-regulated by BMP-2 in two osteogenic sarcoma-derived cell lines, Saos-2 and HOS, and also in human fetal chondrocytes. BMP-2 had no effect on the expression of alpha1, alpha2, alpha5, alpha6, and alphaV integrins. BMP-2 reduced the expression of alpha3 integrin subunit at mRNA level. Laminin-5 was shown to be the ligand for alpha3beta1 integrin on Saos cells and BMP-2 decreased the ability of Saos cells to attach to it. These results suggest that BMP-2 has a specific effect on the alpha3beta1 integrin-mediated cell adhesion to laminin-5. Given the fact that BMP-2 is expressed in osteosarcomas, in addition to in bone, this mechanism is putatively important especially in bone development and tumors. We also studied the effect of BMP-2 on a human keratinocyte cell line, HaCaT. In HaCaT cells, the expression of alpha2 integrin was strongly down-regulated by BMP-2, whereas its effect on the expression of alpha3 integrin was smaller. We suggest that the effects of BMP-2 may be partially mediated by specifically altered cell adhesion.
A recent study using the photon absorption technique has revealed a high frequency of significant bone loss in diabetic adults regardless of age or duration of diabetes. In this study 107 diabetic children age 4-18 were studied using cortical bone thickness and skeletal maturation as indicators of bone development. Overall, 25% of all diabetic children had cortical thickness values below the five percent limit for normal children. This was more common in boys than girls and was unrelated to duration of diabetes. A modest increase in delayed skeletal maturation did not account for the cortical thinning and osteopenia observed. The cause of the osteopenia of diabetic children remains an enigma.
The data presented here were obtained from a series of experiments designed to determine 1) whether normal growth and bone development could be maintained in young, growing rats (3-9 weeks of age) on a diet containing 0.1% Ca, and 2) whether Ca presented in a bolus would be utilized as effectively as the same amount of Ca distributed throughout the diet. Weanling female rats were raised to 9 weeks of age on diets containing 0.4% P and either 0.5% or 0.1% Ca. One group of animals on the 0.1% Ca diet was given oral supplements of CaCO3 twice each day to supply the same amount of Ca consumed by age-matched animals on the 0.5% Ca diet. We found that animals consuming diet containing 0.1% Ca grew at the same rate as animals receiving 0.5% Ca, or 0.1% Ca + supplement for up to 9 weeks of age when the experiment was terminated. Measurement of femur length indicated that long bone length was the same for all animals. However, the 0.1% Ca group exhibited mild hypocalcemia (9.1 mg/dl vs 10.4 for controls), a 2.6-fold elevation in immunoreactive parathyroid hormone, and an increase of similar magnitude in circulating levels of 1,25-dihydroxyvitamin D. Bones from the 0.1% Ca group contained less than half as much Ca as bones from the 0.5% Ca group, and exhibited significant decreases in mid-shaft diaphyseal thickness, % trabecular volume of the distal metaphysis and breaking strength (torsion testing). These results suggest that while a diet containing 0.1% Ca is able to maintain normal growth, bone mineralization is compromised.(ABSTRACT TRUNCATED AT 250 WORDS)
Despite the molecular and histological similarities between fetal bone development and fracture healing, inflammation is an early phase of fracture healing that does not occur during development. Cyclo-oxygenase 2 (COX-2) is induced at inflammation sites and produces proinflammatory prostaglandins. To determine if COX-2 functions in fracture healing, rats were treated with COX-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) to stop COX-2-dependent prostaglandin production. Radiographic, histological, and mechanical testing determined that fracture healing failed in rats treated with COX-2-selective NSAIDs (celecoxib and rofecoxib). Normal fracture healing also failed in mice homozygous for a null mutation in the COX-2 gene. This shows that COX-2 activity is necessary for normal fracture healing and confirms that the effects of COX-2-selective NSAIDs on fracture healing is caused by inhibition of COX-2 activity and not from a drug side effect. Histological observations suggest that COX-2 is required for normal endochondral ossification during fracture healing. Because mice lacking Cox2 form normal skeletons, our observations indicate that fetal bone development and fracture healing are different and that COX-2 function is specifically essential for fracture healing.
Developing neutrophil granulocytes of normal human bone marrow were investigated with the diaminobenzidine technique to determine the ultrastructural localization of peroxidase activity. Neutrophil granulocytes have three types of granule: nucleated, azurophil, and specific granules. These granules are produced consecutively during the eomyelocyte stage, the promyelocyte stage, and the myelocyte stage, respectively. The organelles involved in the production of granules, i.e., the nuclear envelope, rough endoplasmic reticulum, and Golgi apparatus, are peroxidase positive during the eomyelocyte and promyelocyte stages and peroxidase negative thereafter. This pattern differs for the granules themselves: nucleated granules are negative in the eomyelocyte and become positive in the promyelocyte. Azurophil granules become positive in the promyelocyte. Specific granules are negative. Our observations highly suggest that small Golgi-derived peroxidase-positive vesicles are involved in the maturation of both nucleated granules and azurophil granules.
Teleost fish develop bones directly from mesenchymal condensations and from cartilage precursors. At the cellular level, the involved cell populations share many features with their mammalian counterparts. In addition, several genes are already described in fish showing high homology in amino acid sequence and expression with the corresponding genes of tetrapods that are involved in bone metabolism. Therefore, analysis of the underlying molecular mechanism in fish, in particular zebrafish and medaka, will increase the knowledge in teleosts. Furthermore, it will help to identify novel genes and regulatory pathways of bone homeostasis and skeletal disorders also in higher vertebrates, including disorders caused by altered gravity.
Chicks and turkey poults were fed for 3 weeks on low-zinc diets, prepared from purified ingredients, supplemented with zinc oxide at graded levels. Birds of both species given the unsupplemented basal diets grew poorly, with high mortality rates. All had severe hyperkeratosis but bone development was normal. Only when birds received diets with low concentrations of added Zn were leg abnormalities observed. Zn requirements were assessed visually from dose-response graphs. The chick required 18 mg Zn/kg diet for maximal live weight and 24 mg Zn/kg for maximal Zn concentration in blood serum. The responses of tibial Zn and net retention of Zn did not reach plateaux within the range of dietary Zn concentrations studied. The turkey poult's Zn requirement for maximal live weight was 25 and 28-29 mg/kg for net retention of Zn and for maximal concentration of Zn in blood plasma and in the tibia; 41 mg Zn/kg diet was required for maximal Zn in blood serum. Liver Zn was not correlated with dietary Zn in either species.
Connexin43 (Cx43) is involved in bone development, but its role in adult bone homeostasis remains unknown. To overcome the postnatal lethality of Cx43 null mutation, we generated mice with selective osteoblast ablation of Cx43, obtained using a Cx43fl allele and a 2.3-kb fragment of the alpha1(I) collagen promoter to drive Cre in osteoblasts (ColCre). Conditionally osteoblast-deleted ColCre;Cx43-/fl mice show no malformations at birth, but develop low peak bone mass and remain osteopenic with age, exhibiting reduced bone formation and defective osteoblast function. By both radiodensitometry and histology, bone mineral content increased rapidly and progressively in adult Cx43+/fl mice after subcutaneous injection of parathyroid hormone (PTH), an effect significantly attenuated in ColCre;Cx43-/fl mice, with Cx43-/fl exhibiting an intermediate response. Attenuation of PTH anabolic action was associated with failure to increase mineral apposition rate in response to PTH in ColCre;Cx43-/fl, despite an increased osteoblast number, suggesting a functional defect in Cx43-deficient bone-forming cells. In conclusion, lack of Cx43 in osteoblasts leads to suboptimal acquisition of peak bone mass, and hinders the bone anabolic effect of PTH. Cx43 represents a potential target for modulation of bone anabolism.
The bone morphogenetic proteins (BMPs) are a family of pleiotropic morphogens isolated and cloned from the demineralized extracellular matrix of bone. BMPs and related cartilage-derived morphogenetic proteins (CDMPs) initiate, promote and maintain bone and cartilage. The pleiotropic effects of BMPs are based on concentration-dependent thresholds. Targeted disruption of gene action by homologous recombination has demonstrated the role of BMP 7 in kidney, eye and skeletal development. BMP 7 is critical for kidney tubulogenesis, retinal pigmented epithelium differentiation and skeletal pattern. BMP 7 is also synthesized by the kidney and is detectable in serum; hence BMP 7 is both an autocrine and endocrine morphogen. It is likely renal BMP 7 may influence skeletal development and growth in children although there may be sources of other BMPs with skeletogenic actions. In conclusion, we are beginning to unravel the mysteries of kidney-bone connection with special reference to pediatric nephrology.
OBJECTIVE: To determine the incidence and etiology of dehiscences of bone overlying the superior semicircular canal in a temporal bone archive. DESIGN: A microscopic study was performed of 1000 temporal bones from 596 adults in a university hospital registry. Specimens were sectioned vertically in the plane of the superior semicircular canal. Measurements of minimum bone thickness over the superior canal were made in a subset of 108 randomly chosen specimens. All bones were examined for thinning or dehiscence relative to these norms. Clinical histories, when available, were reviewed. RESULTS: Complete dehiscence of the superior canal was identified in 5 specimens (0.5%), at the middle fossa floor (n = 1) and where the superior petrosal sinus was in contact with the canal (n = 4). In 14 other specimens (1.4%), the bone at the middle fossa floor (n = 8) or superior petrosal sinus (n = 6) was no thicker than 0.1 mm, significantly less than values measured in the control specimens (P<.001). Abnormalities were typically bilateral. Specimens from infants demonstrated uniformly thin bone over the superior canal in the middle fossa at birth, with gradual thickening until 3 years of age. CONCLUSIONS: Dehiscence of bone overlying the superior canal occurred in approximately 0.5% of temporal bone specimens (0.7% of individuals). In an additional 1.4% of specimens (1.3% of individuals), the bone was markedly thin (< or =0.1 mm), such that it might appear dehiscent even on ultra-high-resolution computed tomography of the temporal bone. Sites affected were in the middle fossa floor or a deep groove for the superior petrosal sinus, often bilaterally. These abnormalities may arise from failure of postnatal bone development. Thin areas of bone over the superior canal may be predisposed to disruption by trauma.