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PubMed1996

Recombinant human bone morphogenetic protein (rhBMP) induced heterotopic bone development in vivo and in vitro.

In vivo, recombinant human bone morphogenetic protein (rhBMP-2) with deactivated bone matrix as a carrier, implanted in muscle in adult rates, induced development of heterotopic bone, including bone marrow. The volume of bone was proportional to the dose of rhBMP-2 in a range of 0.2-150 microg. In vitro, in response to 50-microgram dose range, subcutis- and brain-derived outgrowths differentiated into loosely woven connective tissues composed of spindle-shaped fibroblasts, adipocytes, and cartilage. Muscle-derived connective tissues cultivated first in culture media supplemented with 50 microgram of rhBMP-2 for 72 hr, then enclosed in a diffusion chamber, and immediately transplanted into a rectus abdominous muscle pouch in an autogenic rat for 28 days, induced cartilage development on the inside and transmembrane hetertoptic bone development including bone marrow on the outside. These experiments are interpreted to show that muscle derived connective tissue cells have the competence of embryonic cells to develop de novo in response to BMP in postfetal life.

Animals↗
PubMedDate not supplied

Cellular interactions during cartilage and bone development.

Both interactions between like cells, as between chondrogenic cells in a developing cartilaginous rudiment, and between unlike cells, as in epithelial-mesenchymal interactions, are dealt with in this review. Such interactions may involve direct apposition of cell membranes or may be mediated via interaction with peri- or extracellular matrices. An ontogenetic approach is taken in which cellular interactions involved in five processes of the development of cartilage and bone are discussed, the five being (1) origin of the cells, (2) migration of the cells within the embryo, (3) localization of the cells at their final embryonic site, (4) differentiation, and (5) morphogenesis. Some emphasis is placed on interactions affecting neural crest-derived cells both before and during their migration and on interactions, especially epithelial-mesenchymal interactions, that precede cytodifferentiation of chondroblasts or osteoblasts. Whether epithelial or mesenchymal specificity is required for such interactions to occur is discussed with reference to the otic vesicle-otic mesenchyme interaction that leads to differentiation and morphogenesis of the cartilaginous otic capsule.

Animals↗
PubMed1996

Parathyroid hormone-related peptide delays terminal differentiation of chondrocytes during endochondral bone development.

To test the hypothesis that PTH-related peptide (PTHrP) is a paracrine regulator of endochondral bone development, we localized PTHrP and its cognate receptor during normal skeletal development at both messenger RNA (mRNA) and protein levels and compared the growth plate phenotypes of PTHrP-deficient [(PTHrP(-/-)] mice to those of normal littermates [PTHrP(+/+]. PTHrP mRNA was expressed adjacent to uncavitated joints, in the perichondrium of long bones and to a lower level in proliferating chondrocytes. In contrast, PTHrP protein was most evident at the interface of proliferating and hypertrophic zones, where it colocalized with PTH/PTHrP receptor mRNA and protein. Most strikingly, the proliferating zone was dramatically shorter in PTHrP(-/-) cartilage, although the percentage of cells in S-phase of the cell cycle in the proliferating zone was indistinguishable between PTHrP(+/+) and PTHrP(-/-) mice. Terminal differentiation of chondrocytes, which was characterized by cell hypertrophy, apoptosis (DNA fragmentation and decreased bcl-2 mRNA expression), and matrix mineralization, was more advanced in growth cartilage of PTHrP(-/-), compared with PTHrP(+/+) animals. These data demonstrate that PTHrP acts principally as a paracrine factor, which promotes elongation of endochondral bone by restraining or delaying the pace of chondrocytic development and terminal differentiation of growth-plate chondrocytes.

Animals↗
PubMed2001

Expression and localization of activin receptors during endochondral bone development.

The expression and localization of activins (dimeric protein of inhibin beta subunit) and activin receptors in skeletal tissue were examined. RT-PCR revealed that cultured chondrocytes expressed mRNAs of inhibin/activin betaA and four activin receptors (two type I (ActRI and ActRIB) and two type II (ActRII and ActRIIB)). Immunohistochemical analyses showed that activin betaA, ActRI and ActRII were localized in proliferating chondrocytes and osteoblasts in tibiae of neonatal rats, and in implants of demineralized bone matrix, a well-established model of ectopic bone formation. The immunoreactivities of osteoblasts were decreased with aging in the tibiae and with progressing endochondral bone development in the implants. The strong expression of ActRI was also detected in hypertrophic chondrocytes both in the tibial growth plate and in the implants, whereas immunoreactive ActRII was lower in hypertrophic chondrocytes. Western blot analysis also showed that immunoreactive ActRI, migrating at 52 kDa, was detected only in the implants on days 9 and 11, the period of conversion from cartilage to bone. In view of the sharing of type II receptors between activins and bone morphogenetic proteins (BMPs), our findings suggest that activin/BMP activity involves in bone modeling, especially during active chondro- and osteogenesis and during the conversion from cartilage to bone.

Activin Receptors↗
PubMed2002

Effects of targeted overexpression of pleiotrophin on postnatal bone development.

Pleiotrophin (PTN) is an extracellular matrix-associated growth/differentiation factor that, in post-natal life, is found mainly in bone and brain. Bone development was investigated in ptn-overexpressing mice between 1 and 30 weeks. In transgenics and controls, PTN (and its receptor syndecan-3) was synthesized by osteoblasts and was present in striated muscle. ptn over-expression enhanced intramembranous bone formation and had multiple effects on long-term bone growth. The pubertal growth spurt did not take place in transgenic mice, in which the growth trajectory was steady and continuous until 25 weeks. By 30 weeks, transgenic and control mice were of the same size, but the calcium content/mg bone was approximately 10% higher in the transgenics. PTN was also localized in growth plate and articular chondrocytes, but only in transgenic mice. In these, synthesis of type I collagen by articular chondrocytes was observed, as well as an encroachment of subchondral bone into the articular cartilage. The results suggest that PTN has multiple roles during in vivo bone formation and remodeling, probably acting as a co-factor or accessory protein that modulates the effects of primary signaling molecules.

Animals↗
PubMed1984

Effects of vitamin D3, calcium, and phosphorus on growth and bone development of market turkeys.

A study was undertaken to determine the effects of maternal and poult nutrition on poult growth and bone development through to market age. Nicholas Large White turkey hens (200) were fed diets with 300, 900, or 2700 IU vitamin D3/kg from day-old to 37 weeks of age. Male poults (649 from Hatch 1 and 555 from Hatch 2) were fed diets containing .6 or 1.2% Ca; .4 or .8% available P; and 300, 900, or 2700 IU vitamin D3/kg to 4 weeks (Hatch 1) or 2 weeks of age (Hatch 2) in a complete factorial design. All Hatch 2 poults were given a "therapeutic" diet from 2 to 4 weeks, followed by normal grower diets from 4 to 24 weeks of age. Increasing the level of vitamin D3 in the hen diet increased weight at hatching and at 2 and 4 weeks, decreased mortality from 0 to 2 weeks, and increased bone ash percent and breaking strength and decreased the severity of rickets score at 2 weeks. Increasing the levels of Ca, P, and vitamin D3 in the poult diet gave reduced mortality from 0 to 2 weeks, increased weight at 2 and 4 weeks, increased bone ash percent and breaking strength, and decreased severity of rickets score at 2 and 4 weeks. Carcass fleshing score at 24 weeks was improved with 1.2% Ca. Conformation score and percent grade A carcasses increased linearly with level of vitamin D3 in the starter diet and were also improved by increasing the vitamin D3 in the breeder diet.

Animals↗
PubMed2005

Abnormalities in cartilage and bone development in the Apert syndrome FGFR2(+/S252W) mouse.

Apert syndrome is an autosomal dominant disorder characterized by malformations of the skull, limbs and viscera. Two-thirds of affected individuals have a S252W mutation in fibroblast growth factor receptor 2 (FGFR2). To study the pathogenesis of this condition, we generated a knock-in mouse model with this mutation. The Fgfr2(+/S252W) mutant mice have abnormalities of the skeleton, as well as of other organs including the brain, thymus, lungs, heart and intestines. In the mutant neurocranium, we found a midline sutural defect and craniosynostosis with abnormal osteoblastic proliferation and differentiation. We noted ectopic cartilage at the midline sagittal suture, and cartilage abnormalities in the basicranium, nasal turbinates and trachea. In addition, from the mutant long bones, in vitro cell cultures grown in osteogenic medium revealed chondrocytes, which were absent in the controls. Our results suggest that altered cartilage and bone development play a significant role in the pathogenesis of the Apert syndrome phenotype.

Acrocephalosyndactylia↗
PubMed1993

Inhibition of induced endochondral bone development in caffeine-treated rats.

We have addressed questions raised by the observation in fetal rats of delayed ossification induced by caffeine at maternal doses above 80 mg/kg body weight per day. The effect of caffeine on endochondral bone development and mineralization has been studied in an experimental model system of bone formation which involves implantation of demineralized bone particles (DBP) in subcutaneous pockets of young growing rats. Caffeine's effects on cellular events associated with endochondral ossification were examined directly by quantitating cellular mRNA levels of chondrocyte and osteoblast growth and differentiation markers in DBP implants from caffeine-treated rats harvested at specific stages of development (day 7 through day 15). Oral caffeine administration to rats implanted with DBP resulted in a dose dependent inhibition of the formation of cartilage tissue in the implants. Histologic examination of the implants revealed a decrease in the number of cells which were transformed to chondrocytes compared to control implants. Those cartilaginous areas that did form, however, proceeded through the normal sequelae of calcified cartilage and bone formation. At the 100 mg/kg dose, cellular levels of mRNA for histone, collagen type II, and TGF beta were all reduced by greater than 40% of control implants consistent with the histological findings. Alkaline phosphatase activity in the implants and mRNA levels for proteins reflecting the hypertrophic chondrocyte and bone phenotype, collagen type I and osteocalcin were markedly decreased compared to controls. Lower doses of 50 and 12.5 mg/kg caffeine also resulted in decreased cellular proliferation and transformation to cartilage histologically and reflected by significant inhibition of type II collagen mRNA levels (day 7). The effects of caffeine on gene expression observed in vivo during the period of bone formation (day 11 to day 15) in the DBP model were similar to the inhibited expression of H4, alkaline phosphatase, osteocalcin, and osteopontin found in fetal rat calvarial derived osteoblast cultures following 24 hour exposure of the cultures to 0.4 mM caffeine. Thus the observed delayed mineralization in the fetal skeleton associated with caffeine appears to be related to an inhibition of endochondral bone formation at the early stages of proliferation of undifferentiated mesenchymal cells to cartilage specific cells as well as at later stages of bone formation.

Administration, Oral↗
PubMed2004

Impaired endochondral bone development and osteopenia in Gli2-deficient mice.

Mice homozygous for targeted disruption of the zinc finger domain of Gli2 (Gli2(zfd/zfd)) die at birth with developmental defects in several organ systems including the skeleton. The current studies were undertaken to define the role of Gli2 in endochondral bone development by characterizing the molecular defects in the limbs and vertebrae of Gli2(zfd/zfd) mice. The bones of mutant mice removed by cesarian section at E16.5 and E18.5 demonstrated delayed endochondral ossification. This was accompanied by an increase in the length of cartilaginous growth plates, reduced bone tissue in the femur and tibia and by failure to develop the primary ossification centre in vertebral bodies. The growth plates of tibiae and vertebrae exhibited increased numbers of proliferating and hypertrophic chondrocytes with no apparent alteration in matrix mineralisation. The changes in growth plate morphology were accompanied by an increase in expression of FGF2 in proliferating chondrocytes and decreased expression of Indian hedgehog (Ihh), patched (Ptc) and parathyroid-hormone-related protein (PTHrP) in prehypertrophic cells. Furthermore, there was a reduction in expression of angiogenic molecules in hypertrophic chondrocytes, which was accompanied by a decrease in chondroclasts at the cartilage bone interface, fewer osteoblasts lining trabecular surfaces and a reduced volume of metaphyseal bone. These results indicate that functional Gli2 is necessary for normal endochondral bone development and that its absence results in increased proliferation of immature chondrocytes and decreased resorption of mineralised cartilage and bone formation.

Animals↗
PubMed2001

A molecular analysis of matrix remodeling and angiogenesis during long bone development.

The replacement of cartilage by bone is the net result of genetic programs that control chondrocyte differentiation, matrix degradation, and bone formation. Disruptions in the rate, timing, or duration of chondrocyte proliferation and differentiation result in shortened, misshapen skeletal elements. In the majority of these skeletal disruptions, vascular invasion of the elements is also perturbed. Our hypothesis is that the processes involved in endochondral ossification are synchronized via the vasculature. The purpose of this study was to examine carefully the events of vascular invasion and matrix degradation in the context of chondrocyte differentiation and bone formation. Here, we have produced a 'molecular map' of the initial vascularization of the developing skeleton that provides a framework in which to interpret a wide range of fetal skeletal malformations, disruptions, and dysplasias.

Animals↗
PubMed2003

Fgfr mRNA isoforms in craniofacial bone development.

Mutations in genes encoding for fibroblast growth factor receptors (FGFRs) have been identified as causes of both chondrodysplasias and craniosynostoses, both of which cause abnormalities in the growth and development of the craniofacial region. FGFRs form mRNA splicing isoforms, each with distinct ligand binding specificity and tissue distribution. These confer specific biological functions on these isoforms. Although it is known that FGFRs are expressed at numerous locations during early mouse development, including the craniofacial area, relatively little is known about the expression of the splicing isoforms during craniofacial bone development. To address this, we have performed a detailed survey to detect these genes in the developing mouse craniofacial region. We have analyzed the developing mouse mandible, calvaria, and cranial base, in particular the spheno-occipital synchondrosis, a key centre of craniofacial growth. Fgfr1c was detected weakly in osteoblastic cells in both the developing calvarial and mandibular bones. Fgfr3b and Fgfr3c were found chiefly in proliferating chondrocytes of the cranial base synchondroses and the mandibular condyle. Fgfr2b transcripts were most notably detected in the perichondria of the mandibular condyle and the cranial base. Fgfr2c transcripts were detected with high intensity in differentiating osteoblasts at the sutural osteogenic fronts of the calvarial bones. In addition, Fgfr2c was also expressed in the perichondria of the mandibular condyle and the cranial base. These expression patterns suggest both differing and similar functions for -b and -c isoforms. The former is exemplified by Fgfr1 transcripts, which show distinct differences in their distribution, being mutually exclusive. Similar functions are suggested by the overlapping expression patterns of the -b and -c isoforms of both Fgfr2 and Fgfr3. Fgfr4 transcripts were found in developing muscles. These data help to explain the disturbances in craniofacial growth exhibited by both patients and the growing number of transgenic mice carrying mutations in genes encoding FGFRs/Fgfrs.

Animals↗
PubMed2006

Hearts and bones: shared regulatory mechanisms in heart valve, cartilage, tendon, and bone development.

The mature heart valves are dynamic structures composed of highly organized cell lineages and extracellular matrices. The discrete architecture of connective tissue within valve leaflets and supporting structures allows the valve to withstand life-long functional demands and changes in hemodynamic forces and load. The dysregulation of ECM organization is a common feature of heart valve disease and can often be linked to genetic defects in matrix protein structure or developmental regulation. Recent studies have identified specific regulatory pathways that are active in the developing valve structures and also control cartilage, tendon, and bone development. This review will focus on the regulatory hierarchies that control normal and abnormal heart valve development in parallel with other connective tissue cell types.

Aggrecans↗
PubMed1993

Whole body irradiation does not affect induction of new bone development.

The effect of whole body irradiation given either beforehand to the donor or after implantation to the recipient rats on the inductive capacity of decalcified bone grafts was studied. In examining the effect of advance whole body irradiation of the donor animal, the grafts were harvested five days after the irradiation, non-irradiated rats serving as control donors. Error! Reference source not found-irradiation with doses of 800, 950 or 1100 rad was used. The grafts, implanted either alone or in composite form in the muscle pouches of non-irradiated rats of an inbred strain, were removed four weeks after implantation and examined by measuring 45Ca uptake, ash weight and area of radio-opacity in roentgenographs. There were no differences in bone-inductive capacity between the grafts obtained after total body irradiation and the control grafts. In the other part of the study, decalcified bone grafts were implanted in the abdominal muscle pouches of the recipient rats, which were exposed to Error! Reference source not found.-radiation of 800 rad on either the second, 10th or 21st day after implantation. Four weeks after implantation the grafts were removed and examined. No differences in new bone formation were found between the groups subjected to irradiation at different times or between these and the non-irradiated controls. It is concluded that donor whole body irradiation of 800-1100 rad in rat has no significant effect on the properties of new bone developed in allogeneic decalcified bone grafts, neither does recipient 800 rad irradiation administered after implantation affect the bone induction activity.

Animals↗
PubMed1983

Proteoglycans of developing bone.

We purified and characterized the bone proteoglycans from fetal calves, growing rats, and human fetuses. The major proteoglycan is part of the mineralized tissue matrix and only 10-20% can be extracted prior to demineralization. This bone proteoglycan is a small glycoconjugate (Mr = 80,000-120,000) containing approximately 20-30% protein and either one or two chondroitin sulfate chains (Mr = 40,000) attached to a relatively monodisperse protein core (Mr = 38,000). "O"-linked and "N"-linked oligosaccharide units are also present. Antibodies directed against the protein core of calf bone proteoglycan do not cross-react with cartilage, skin, corneal, or basement membrane proteoglycans in immunoassays and have minimal cross-reactivity with scleral proteoglycans. Quantitative immunoassays and indirect immunofluorescence were used to show that the molecule is localized to forming bone trabeculae and dentin, but not to any other tissue. Osteoblasts and osteoprogenitor cells adjacent to areas undergoing rapid osteogenesis also contain this small proteoglycan. A second proteoglycan (Mr approximately equal to 1,000,000) was extracted from newly forming bone prior to demineralization. This large proteoglycan, which was isolated from the cartilage-free areas of developing intramembranous bone, has a protein core similar to that of the cartilage aggregating proteoglycan and cross-reacts with antisera raised against these cartilage proteoglycans but not with the small mineral-entrapped proteoglycan. It contains larger (Mr = 40,000) and fewer chondroitin sulfate chains than its cartilage-derived analogue, and is localized to the soft connective tissue mesenchyme lying between growing bone trabeculae. More fully formed compact bone did not contain detectable quantities of this proteoglycan.

Animals↗
PubMed1987

Effects of neonatal estrogenization on rat bone development: a histomorphometric study.

The effects of a single dose of 500 micrograms of estradiol benzoate, administered on the first day of life, on rat bone development have been histomorphometrically studied at 15 days of age. Estrogenized animals presented decreased total tibial length (16.55 +/- 0.50 vs. 17.84 +/- 0.73 mm, P less than 0.05) and increased thickness of the cartilage growth plate (528.92 +/- 13.30 vs. 382.77 +/- 37.85 micron, P less than 0.01). This increase was mostly due to the presence of a wider (P less than 0.01) layer of hypertrophic cartilage in the estrogenized rats than in control ones. It might be related to the decreased number of chondroclasts (0.20 +/- 0.01 vs. 0.36 +/- 0.06 mm-1, P less than 0.05) found in the resorption zone. Two metaphyseal zones have been considered. In the upper metaphyseal zone there was an increase in the surface density of the cartilaginous trabeculae (49.20 +/- 1.80 vs. 40.72 +/- 1.95 mm2/mm3, P less than 0.05), without changes in the volume density. It was related to the presence of thinner and more irregular trabeculae in the estrogenized animals. In the lower metaphyseal zone both the volume (0.19 +/- 0.01 vs. 0.14 +/- 0.01 mm3/mm3, P less than 0.01) and surface (34.83 +/- 3.01 vs. 26.52 +/- 2.46 mm2/mm3, P less than 0.05) densities of the osseous trabecular tissue were increased in estrogenized rats. No significant differences were found either in the number of osteocytes per area unit of osseous tissue or in the number of osteoclasts per unit length of trabecular osseous tissue.

Animals↗
PubMed2003

Absence of transcription factor c-maf causes abnormal terminal differentiation of hypertrophic chondrocytes during endochondral bone development.

In this study, we report that the transcription factor c-Maf is required for normal chondrocyte differentiation during endochondral bone development. c-maf is expressed in hypertrophic chondrocytes during fetal development (E14.5-E18.5), with maximal expression in the tibia occurring at E15.5 and E16.5, in terminally differentiated chondrocytes. In c-maf-null mice, fetal bone length is decreased approximately 10%, and hypertrophic chondrocyte differentiation is perturbed. There is an initial decrease in the number of mature hypertrophic chondrocytes at E15.5 in c-maf-null tibiae, with decreased expression domains of collagen X and osteopontin, markers of hypertrophic and terminal hypertrophic chondrocytes, respectively. By E16.5, there is an expanded domain of late hypertrophic, osteopontin-positive chondrocytes in the c-maf-/-. This accumulation of hypertrophic chondrocytes persists and is still observed at 4 weeks of age. These data suggest that c-Maf facilitates the initial chondrocyte terminal differentiation and influences the disappearance of hypertrophic chondrocytes. BrdU and TUNEL analyses show normal proliferation rate and apoptosis in the c-maf-null. There is a specific decrease in MMP-13 expression at E15.5 in the c-maf-null. MMP-13 is known to be regulated by AP-1 and may also be a target of c-Maf. Thus, cartilage is a novel system in which c-Maf acts during development, where c-Maf is required for normal chondrocyte differentiation.

Animals↗