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PubMed2004

Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survival.

VEGF is crucial for metaphyseal bone vascularization. In contrast, the angiogenic factors required for vascularization of epiphyseal cartilage are unknown, although this represents a developmentally and clinically important aspect of bone growth. The VEGF gene is alternatively transcribed into VEGF(120), VEGF(164), and VEGF(188) isoforms that differ in matrix association and receptor binding. Their role in bone development was studied in mice expressing single isoforms. Here we report that expression of only VEGF(164) or only VEGF(188) (in VEGF(188/188) mice) was sufficient for metaphyseal development. VEGF(188/188) mice, however, showed dwarfism, disrupted development of growth plates and secondary ossification centers, and knee joint dysplasia. This phenotype was at least partly due to impaired vascularization surrounding the epiphysis, resulting in ectopically increased hypoxia and massive chondrocyte apoptosis in the interior of the epiphyseal cartilage. In addition to the vascular defect, we provide in vitro evidence that the VEGF(188) isoform alone is also insufficient to regulate chondrocyte proliferation and survival responses to hypoxia. Consistent herewith, chondrocytes in or close to the hypoxic zone in VEGF(188/188) mice showed increased proliferation and decreased differentiation. These findings indicate that the insoluble VEGF(188) isoform is insufficient for establishing epiphyseal vascularization and regulating cartilage development during endochondral bone formation.

Angiography↗

PubMed2000

Functional adaptation of bone to exercise and injury.

Bone adapts to altered physical stimuli, dietary changes, or injury. Dietary calcium and vitamins play important roles in maintaining skeletal health, but high-fat diets are pervasive in western cultures and may contribute to the increasing prevalence of osteoporosis and incidence of related hip fractures. Exercise helps maintain bone mass and counter osteoporosis, but exercise can also have detrimental effects-particularly for immature bone. Some negative exercise effects may also be linked to diet. For example, insufficient dietary protein during exercise can impair bone development and remodeling. Bone remodeling is a potent example of tissue repair. Chronically altered loading after a joint injury, however, can result in remodeling processes that can be detrimental to the joint. Anterior cruciate ligament injury, for example, commonly leads to osteoarthritis. Early changes in the periarticular cancellous bone may play a role in the development of knee osteoarthritis. Although these factors influence skeletal health, the mechanisms remain unclear by which bone interprets its environment and responds to mechanical stimuli or injury. To understand why different levels of exercise are beneficial or detrimental or why altered joint loading leads to changes in periarticular bone structure, underlying mechanisms must be understood by which bone interprets its mechanical environment.

Adaptation, Physiological↗

PubMed1983

The vitamin D endocrine system, calcium metabolism, and osteoporosis.

Although the nutritional aspects related to bone development and subsequent bone loss have been appreciated for many years, they are now being reemphasized in view of current information concerning the vitamin D endocrine system, the development of new assay procedures and more sensitive radiologic techniques to assess changes in bone mass, and the realization that clinical problems related to bone loss will increase as individuals live longer. The vitamin D endocrine system is complex, involving the skin, liver, and kidney for synthesis of the vitamin D metabolites and, primarily, the intestine and bone for biologic expression. Numerous factors and disorders affecting the skin, gastrointestinal tract, and kidney will adversely affect vitamin D metabolism. Vitamin D deficiency is common in elderly individuals, especially those who are chronically ill, house-bound, and poorly nourished. Subclinical vitamin D deficiency and osteomalacia may also be complicating problems in elderly patients with osteoporosis and hip fractures. At present the role of the vitamin D endocrine system in the pathogenesis and treatment of osteoporosis is unclear. There is little evidence that vitamin D or its metabolites are helpful in osteoporosis, except perhaps to heal osteomalacia which may be present. It is hoped that encouraging results will follow the use of more potent vitamin D metabolites, either alone or in combination with other agents. Calcium homeostasis is affected by numerous dietary factors (including protein, phosphorus, fiber, and lactose) and drugs (including alcohol, diuretics, and antacids), and calcium absorption in the intestine and the ability to adapt to low-calcium diets will decrease with advancing age. There are conflicting reports concerning the relation between low-calcium intake and osteoporosis, and about the role of calcium intake in the development and then maintenance of bone mass. There is little doubt that many older individuals ingest less calcium than is recommended, especially at a time when even more may be required to maintain bone mass. Several studies show that calcium supplementation producing a total calcium intake of 1,200-1,500 mg/day can slow the rate of bone loss. When the high doses of calcium are given along with vitamin D, periodic monitoring of blood and urine calcium is necessary to avoid hypercalcemia and hypercalciuria.

Aged↗

PubMed2003

Developmental regulation of the growth plate.

Vertebrates do not look like jellyfish because the bones of their skeletons are levers that allow movement and protect vital organs. Bones come in an enormous variety of shapes and sizes to accomplish these goals, but, with few exceptions, use one process--endochondral bone formation--to generate the skeleton. The past few years have seen an enormous increase in understanding of the signalling pathways and the transcription factors that control endochondral bone development.

Animals↗

PubMed1997

OP-1 (BMP-7) affects mRNA expression of type I, II, X collagen, and matrix Gla protein in ossifying long bones in vitro.

In long bone development, a regulating role of OP-1 is suggested by the local correlated expression of both OP-1 ligand and OP-1 binding receptors in developing mouse hind limbs. OP-1 is expressed in the interdigital mesenchyme, whereas OP-1 binding receptors are found in the bordering perichondrium, and both OP-1 ligand and receptors are present in the zone of (pre)hypertrophic chondrocytes. We investigated the role of OP-1 in long bone development experimentally by treating organ cultures of embryonic mouse metatarsals with rhOP-1. The mRNA expression patterns of type I, II, X collagen, and matrix Gla protein (MGP) were studied using in situ hybridization and cell proliferation using [3H]thymidine and BrdU labeling. In the epiphyseal perichondrium, treatment with 40 ng/ml OP-1 enhanced cell proliferation after day 2, while 6-day treatment caused a shift in expression from type I collagen to type II collagen mRNA. This supports previous histochemical findings that OP-1 induced the transition of perichondrium into cartilage. In the center of the rudiment, OP-1 inhibited the expression of type X collagen mRNA, indicating inhibition of chondrocyte hypertrophy. An arrest of differentiation at the (pre)hypertrophic chondrocyte stage was also indicated by the large area of cells expressing MGP mRNA in the OP-1-treated rudiments. We conclude that OP-1 affected the expression of marker genes of chondrocyte differentiation by acting on two steps in endochondral ossification. First, cell proliferation was enhanced, particularly so in the perichondrium where cells started to express the chondrocyte phenotype. Second, the terminal differentiation of mature chondrocytes into hypertrophic chondrocytes was inhibited. These results, combined with the known pattern of OP-1 ligand and BMP receptor expression in the embryo, suggest that OP-1 plays a local role in the cascade of events during endochondral ossification.

Animals↗

PubMedDate not supplied

The development of bone mineral density and the occurrence of osteoporosis from 15 to 20 years of disease onset in patients with rheumatoid arthritis.

OBJECTIVE: To ascertain the occurrence of osteoporosis and the development of central bone mineral density (BMD) in long-term rheumatoid arthritis (RA) METHODS: BMD of the lumbar spine (L2-L4) and the femoral neck were measured by dual-energy X-ray absorptiometry in a cohort of 59 patients (49 women and 10 men) with rheumatoid factor-positive RA followed up for 20 years. BMD measurements were obtained at the 15- and 20-year follow-up visits. RESULTS: At the 15-year check-up the mean age was 61 (SD 13)for men and 54 (SD 11) years for women. Bone densitometry of these patients revealed decreased BMD at both lumbar spine and femoral neck, the mean T-scores being -1.1 [95%CI: -1.6 to -0.6] and -1.3 [95%CI: -1.6 to -1], respectively). Eighteen (31 %) patients thus had osteoporosis (BMD T -score < or = -2.5) and 32 (54%) patients were osteopenic (BMD T-score -1.0 to -2.5). However, when compared with reference values, the decreases in central bone mineral in this patient group were of low degree; the mean Z-score -0.2 [95%CI: -0.7 to 0.2] at the lumbar spine and -0.5 [95%CI: -0.8 to -0.3] at the femoral neck, respectively. After the subsequent five years the mean Z-score increased 0.45 [95%CI: 0.32 to 0.58] at the lumbar spine and the mean T-score decreased -0.20 [95%CI: -0.32 to -0.08] at the femoral neck. ESR, Larsen score, gender and cumulative dose of prednisolone during the 5 year follow-up and HAQ-index were used as explanatory parameters of BMD change between the 15- and 20-year follow-ups. None of these parameters explained the BMD change. CONCLUSION: We conclude that in long-term RA central bone densities seemed to be only moderately decreased after 15 years from eruption of RA. No essential change in central BMD was found after the consecutive 5 years.

Absorptiometry, Photon↗

PubMed1990

Effect of calcium citrate-malate on skeletal development in young, growing rats.

It has been previously demonstrated that calcium from calcium citrate-malate (CCM), a mixture of calcium, citric acid and malic acid, is better-absorbed than calcium from calcium carbonate (CaCO3) in humans and in rats. It was of interest to determine if this differential in absorption would result in differences in bone development under chronic feeding conditions. The present study was designed to compare CCM with CaCO3 for effects on bone development in weanling female C/D rats fed either CCM or CaCO3 at 0.3 or 0.6% dietary Ca for 4 or 12 wk. There was a nonsignificant trend for rats fed CCM to weigh more and have larger bones than rats fed CaCO3. Histologic evaluation of cortical and trabecular bone revealed normal bone formation in all rats. Trabecular bone was significantly affected by calcium level and source. The 0.3% Ca diets (either source) resulted in reduced trabecular bone volumes in tibias. After 4 wk, rats fed CCM had 23-25% more trabecular bone than rats fed CaCO3. By 12 wk, the difference was even greater; rats fed CCM had 44-47% more trabecular bone than rats fed CaCO3. Dietary calcium source did not affect cortical bone. It is concluded that because of its positive effects on bone, CCM is a more bioavailable calcium source than CaCO3.

Animals↗

PubMed1997

Mutation associated with Crouzon syndrome causes ligand-independent dimerization and activation of FGF receptor-2.

FGF signaling is clearly important for proper bone development, and several autosomally dominant forms of genetic bone disorders have been mapped to FGF receptors 1, 2, and 3. We have studied the biological effects of the most commonly mutated cysteine residue in FGFR-2 which is detected in individuals with Crouzon syndrome, an autosomally dominant trait which causes premature fusion of the skull bones (craniosynostosis). This Crouzon mutation replaces the cysteine at position 342 with tyrosine, thus disrupting the formation of the third immunoglobulin (Ig)-like loop in the extracellular portion of the receptor. By transfecting mutated and wild-type receptors into a variety of cell lines, we have shown that the C342Y mutation in FGFR-2 produces a receptor which is constitutively activated and capable of transforming NIH3T3 cells and preventing the differentiation of C2 myoblasts in the absence of ligand. Constitutive activation appears to result from the ability of this receptor to form stable interreceptor dimers which involve disulfide bonds between the remaining free cysteine in the mutant receptor. The altered conformation of the third Ig-like domain in the mutated receptor also results in a drastically reduced ability to bind FGF-1 or FGF-2 and in a reduced level of receptor glycosylation. Thus it appears that Crouzon syndrome results from constitutive activation of FGFR-2 and that uncontrolled FGF signaling produces alterations of intramembranous bone development and premature closing of cranial sutures.

3T3 Cells↗

PubMed2006

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.

Bone Density↗

PubMed1988

The demonstration of bone and cartilage remodelling using alcian blue and hematoxylin.

A new staining technique based on alcian blue and hematoxylin was used during the study of experimentally produced fractures in long bone. The distinction between cartilage, woven bone, mature bone and necrotic bone during successive stages of the fracture healing process was particularly remarkable. This method was found also to be very useful in the study of general tissue morphology. It is suggested that this postdecalcification light microscopy staining method is suitable for studies of cartilage and bone development with particular reference to ossification, remodelling and bone pathology.

Alcian Blue↗

PubMed2006

Identification of differentially expressed genes in the developing antler of red deer Cervus elaphus.

Understanding the molecular mechanisms underlying bone development is a fundamental and fascinating problem in developmental biology, with significant medical implications. Here, we have identified the expression patterns for 36 genes that were characteristic or dominant in the consecutive cell differentiation zones (mesenchyme, precartilage, cartilage) of the tip section of the developing velvet antler of red deer Cervus elaphus. Two major functional groups of these genes clearly outlined: six genes linked to high metabolic demand and other five to tumor biology. Our study demonstrates the advantages of the antler as a source of mesenchymal markers, for distinguishing precartilage and cartilage by different gene expression patterns and for identifying genes involved in the robust bone development, a striking feature of the growing antler. Putative roles for "antler" genes that encode alpha-tropomyosine (tpm1), transgelin (tagln), annexin 2 (anxa2), phosphatidylethanolamine-binding protein (pebp) and apolipoprotein D (apoD) in intense but still controlled tissue proliferation are discussed.

Animals↗

PubMed2006

Parents' knowledge and behaviour concerning sunning their babies; a cross-sectional, descriptive study.

BACKGROUND: For centuries, sunlight has been used for therapeutic purposes. Parents still sun their infants to treat neonatal jaundice, nappy rash or mostly to supply vitamin D for bone development as a consequence of health beliefs. In this study we aimed to assess knowledge and behaviour of parents about benefits of sunlight and sun protection. METHODS: In this study, parents attending to governmental primary healthcare units for their children's routine vaccinations, upon their informed consent, were consecutively enrolled during one month. Data were collected by a semi-structured questionnaire. RESULTS: The mean age of 118 enrolled parents and their babies were 27.9 +/- 6.5 years and 8.3 +/- 5.8 months, respectively. Most of the participants were mothers (93.2%), housewives (81.4%) with an educational level of > or =6 years (71.2%). Sunlight was considered beneficial for bone development (86.4%), diaper rash (5.9%) and neonatal jaundice (12.7%). In case of neonatal jaundice 72.0% of the participants reported that they would consult a physician. Most of the participants (82.2%) were sunning their babies outdoors. Nearly half (49.7%) of them got this information from medical staff. Fifty two percent of the parents were sunning their babies before 10-11 a.m. and/or after 3 p.m. Only 13.6% of parents reported using sunscreen for their babies, and the majority of them were using sun protecting factor > or = 15. One forth of the sunscreen users was using sunscreen according to their physicians' advice. CONCLUSION: Most of the participants were aware of the benefits of sunlight; especially for bone development. However they were displaying inappropriate behaviour while sunning their babies for health reasons. More education should be given to parents about the danger of sunlight at primary health care units while advising to sun their babies, if any.

Adult↗

PubMed2001

T lymphocytes promote the development of bone marrow-derived APC in the central nervous system.

Certain cells within the CNS, microglial cells and perivascular macrophages, develop from hemopoietic myelomonocytic lineage progenitors in the bone marrow (BM). Such BM-derived cells function as CNS APC during the development of T cell-mediated paralytic inflammation in diseases such as experimental autoimmune encephalomyelitis and multiple sclerosis. We used a novel, interspecies, rat-into-mouse T cell and/or BM cell-transfer method to examine the development and function of BM-derived APC in the CNS. Activated rat T cells, specific for either myelin or nonmyelin Ag, entered the SCID mouse CNS within 3-5 days of cell transfer and caused an accelerated recruitment of BM-derived APC into the CNS. Rat APC in the mouse CNS developed from transferred rat BM within an 8-day period and were entirely sufficient for induction of CNS inflammation and paralysis mediated by myelin-specific rat T cells. The results demonstrate that T cells modulate the development of BM-derived CNS APC in an Ag-independent fashion. This previously unrecognized regulatory pathway, governing the presence of functional APC in the CNS, may be relevant to pathogenesis in experimental autoimmune encephalomyelitis, multiple sclerosis, and/or other CNS diseases involving myelomonocytic lineage cells.

Animals↗

PubMed1982

Mechanisms of lytic and blastic metastatic disease of bone.

In the majority of skeletal metastases, new bone develops simultaneously with bone destruction. The roentgenogram indicates the net effect of these two processes. Where the bone formation predominates, the lesion appears sclerotic. Where bone destruction predominates, it appears lytic. Mixed lesions may also occur. There are two main mechanisms for the new bone formation. Those tumors associated with a suitable fibrous stroma develop islands of intramembranous ossification within the stroma, e.g., metastases from prostatic carcinoma. In the vast majority of metastases bone destruction is associated with reactive new bone formation. The latter is similar to callus associated with fracture repair. Myelomata and lymphomata are not associated with this reactive new bone formation. There are at least two main mechanisms for the bone destruction. The earlier and quantitatively more important phase is mediated via osteoclasts, neoplasms secreting a variety of osteoclast stimulating factors. The main humoral factor in myeloma and the lymphomata is probably osteoclast activating factor (OAF), whereas in the carcinomata it may be prostaglandin. Two thirds of human mammary carcinomata are osteolytically active in vitro. In a co-culture model, the osteolysis can be significantly reduced by prostaglandin inhibitors, diphosphonates and particularly, their combination. At a late stage, neoplastic or monocytic cells are directly responsible for the continuing bone destruction.

Animals↗

PubMed2001

Asymmetrical development of bones and soft tissues during eye migration of metamorphosing Japanese flounder, Paralichthys olivaceus.

The symmetrical body of flatfish larvae dramatically changes into an asymmetrical form after metamorphosis. Eye migration results in the most significant asymmetrical development seen in any vertebrate. To understand the mechanisms involved in eye migration, bone and cartilage formation was observed during metamorphosis in laboratory-reared Japanese flounder, Paralichthys olivaceus, by using whole-body samples and histological sections. Most of the hard tissues of the cranium (parasphenoid, trabecular cartilage, supraorbital canal, and supraorbital bar) exist symmetrically in the larval period before metamorphosis and develop by twisting in the same direction as that in which the eye migrates. An increase in skin thickness beneath the eye was observed only on the blind side at the beginning of eye migration; this was the first definitive difference between the right and left sides of the body. The pseudomesial bar, a peculiar bone present only in flatfishes, developed from this thick skin and grew dorsad. Novel sac-like structures were found and named retrorbital vesicles. The retrorbital vesicle of the blind side grew larger and faster than that of the ocular side when the right eye moved most dramatically, whereas no difference was observed between the volume of right and left connective tissue in the head. The asymmetrical presence and growth of the pseudomesial bar together with inflation of the retrorbital vesicle on the blind side may be responsible for right eye migration during metamorphosis in the Japanese flounder.

Animals↗

PubMed1994

Alterations in the expression of osteonectin, osteopontin and osteocalcin mRNAs during the development of skeletal tissues in vivo.

Heterogeneity in the expression of three members of non-collagenous matrix proteins in osteogenic and chondrogenic development in vivo were investigated by in situ hybridization. Sections of several skeletal tissues from mice at various stages of development were hybridized with digoxigenin-labeled complementary RNA probes encoding osteonectin (Osn), osteopontin (Osp) and osteocalcin (Osc). In calvariae and mandibulae, Osn messenger RNA (mRNA) was detected in cells in pre-osseous and osseous tissues before mineralization. Osp mRNA was found in cells attached to the mineralized bone matrix together with Osn mRNA followed by the expression Osc mRNA. In long bones, mRNAs for Osn, Osp and Osc were sequentially expressed with bone development from primary spongiosa to diaphyseal bone. In growth cartilage, Osn mRNA was observed in chondrocytes in non-mineralized cartilage, whereas Osp mRNA was detected in hypertrophic chondrocytes in mineralized cartilage matrix with a characteristic switch in expression. Osc mRNA was not detected in any chondrocytes. These results indicate that osteogenic differentiation in bone development in vivo is characterized by the sequential expression of these three genes, and suggest that these genes are expressed differentially and specifically, in association with extra-cellular matrix mineralization.

Animals↗

PubMed2001

Pubertal maturation characteristics and the rate of bone mass development longitudinally toward menarche.

To assess risks for osteoporosis and to compare bone mass in different groups of healthy children or children with diseases, it is important to have knowledge of their sexual maturation status during puberty. The aim of our study was to evaluate bone mass formation longitudinally in relation to pubertal maturation characteristics in healthy white girls. We investigated the bone mineral content (BMC) and the bone mineral density (BMD) at different skeletal sites in 151 girls with increasing pubertal stages in relation with their chronological age and with an early or late onset of puberty or menarche and with a slow or fast maturation. Bone mass was measured at the onset of puberty, during puberty, and at menarche. We conclude the following: (1) from midpuberty to menarche, the increase in bone mass formation is highest at all skeletal sites in white girls; (2) early mature girls at the onset of puberty have slightly but definitely lower bone masses at all skeletal sites and at all pubertal stages than late mature girls, whereas the average bone mass formation from the onset of puberty to menarche is similar in both groups; (3) girls with a slow rate of pubertal maturation have lower bone mass values 2 years after the onset of puberty, but at menarche bone mass is similar compared with fast maturers; and (4) it cannot be confirmed that there is an effect of menarcheal age on bone mass values at menarche.

Absorptiometry, Photon↗

PubMed2002

Allergy development after bone marrow transplantation from a non-atopic donor.

BACKGROUND: Transfer of allergy from atopic bone marrow donors to recipients is known to occur. Development of allergy in a non-atopic patient transplanted from a non-atopic donor is an unfamiliar phenomenon in clinical practice. OBJECTIVES: To clarify the course of events causing a bone marrow recipient to acquire an allergic disease in such non-conducive circumstances. METHODS: Full medical history, prick and intradermal skin tests, and serum IgE levels were obtained from both donor and recipient patients. DNA and red blood cell phenotype analyses were used to detect the degree of chimerism. RESULTS: Only the recipient patient showed positive specific IgE antibodies and skin tests to house dust mite. The recipient patient displayed 100% donor chimera, based on all engraftment markers sought. CONCLUSION: Full engraftment after allogeneic bone marrow transplantation may be associated with modulation of T and B cell function, which in turn could cause the onset of allergic disease after bone marrow transplantation.

Adult↗