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PubMed2000

Abnormal timing in the prenatal ossification of vertebral column and hand in Crouzon syndrome.

We report on a radiographically examined fetus (gestational age 13 weeks) with Crouzon syndrome caused by a mutation in the gene encoding the fibroblast growth factor 2 (FGFR2). We found an approximately 2-week delay in vertebral body and hand ossification with normal vertebral arch ossification, suggesting that regionally delayed skeletal maturation might be a manifestation of FGFR2 mutation syndromes. The findings support other studies indicating that different signaling pathways control skeletal maturation in vertebral bodies and vertebral arches.

Abnormalities, Multiple↗

PubMed1996

Restricted expression of a novel retinoic acid responsive gene during limb bud dorsoventral patterning and endochondral ossification.

Using a differential substractive hybridization cloning procedure we have recently identified Stra6 as a novel retinoic acid-induced gene in murine P19 embryonal carcinoma cells. The putative amino acid sequence of Stra6 shows no similarity with previously characterised proteins. We report here the pattern of expression of Stra6 transcripts during mouse limb development as revealed by in situ hybridization. In 8.5-9.0 days post-coitum (dpc) embryos, Stra6 was expressed in the lateral plate mesenchyme prior to limb bud outgrowth. By 9.5 dpc, expression was restricted to the proximal and dorsal forelimb bud mesoderm. Over the next 2 gestational days, Stra6 expression was specific of the dorsal mesoderm of the undifferentiated forelimb and hindlimb buds with the exception of their distal-most region or progress zone. A novel proximal-ventral expression domain appeared, however, by 11.0-11.5 dpc. Stra6 also remained expressed in the flank mesoderm. From 11.5-13.5 dpc, Stra6 expression was restricted to the superficial mesenchyme surrounding the chondrogenic blastemas, and progressively extended until the distal extremities of the limbs upon disappearance of the progress zone. Progressive restriction of Stra6 expression to perichondrium and developing muscles was seen at 13.5-14.5 dpc. Upon the initiation of endochondral ossification (15.5-16.5 dpc), Stra6 expression was limited to the area of perichondrium opposing cells of high metabolic and proliferative activity (the elongation zone). We suggest that Stra6 may play a role in early dorsoventral limb patterning and later in the control of endochondral ossification.

Animals↗

PubMed2000

Extent of ossification at the amputation plane is correlated with the decline of blastema formation and regeneration in Xenopus laevis hindlimbs.

Xenopus laevis larvae gradually lose the ability to regenerate lost hindlimb structures as they progress through metamorphosis. Previous studies have suggested that this loss of regenerative capacity occurs in a proximal-to-distal fashion. We assessed the quality of overall regeneration and early bud blastema formation in order to evaluate previous explanations for this loss of regenerative ability in Xenopus. We further examined the extent to which epidermis, basement membrane, dermis, cartilage, bone, periosteum, and accumulated mesenchyme within the blastema are involved in the decline of regenerative abilities during mid-metamorphic stages of development. Each tissue was scored based on its contributions to the regeneration blastema, in accordance with previously reported blastemal descriptions. Tadpoles amputated at the ankle and tarsal-metatarsal joints scored objectively higher within the overall regeneration and blastema quality rating systems. Both joint sites met more criteria associated with regeneration-capable blastemas than tadpoles amputated through the middle of the tarsus, especially at later stages of metamorphosis. The three amputation sites studied began to vary in their ability to regenerate skeletal elements and to generate productive blastemas during the same stages at which we initially observed ossification of the tarsus. These results suggest that the decline of Xenopus hindlimb regeneration does not occur in a strictly proximal-to-distal fashion but rather is dependent at later stages on the state of ossification of the structure through which amputation occurs. Our morphological and cellular observations reveal specific times and places during Xenopus hindlimb development at which further investigations into tissue-specific molecular events during early regeneration should be focused.

Amputation, Surgical↗

PubMed2003

A newly recognized autosomal recessive syndrome with abnormal vertebral ossification, rib abnormalities, and nephrogenic rests.

We describe three cases of a severe malformation syndrome in siblings of both sexes. The characteristic features observed were absent intrauterine ossification of an apparently normal cartilaginous spinal column; rib abnormalities, with unossified segments and posterior gaps; thoracic hypoplasia; and multiple intralobar nephrogenic rests in the kidneys. This syndrome can be identified in early pregnancy by ultrasound scans due to the lack of ossification of the thoraco-lumbar spine and its association with increased nuchal translucency thickness. We suggest that this is a newly recognized autosomal recessive syndrome.

Female↗

PubMed1975

Magnitude of sex differences in dichotomous ossification sequences of the hand and wrist.

Among the dichotomous (present/absent:absent/present) ossification sequences individually ascertained in 3059 boys and girls with at least one but not more than 27 ossification centers of the hand and wrist, 54 such sequences exhibit statistically-significant sex differences in frequency, 32 of them at the 1% confidence level or better. Analyzed by regions (rows and rays, epiphyses and round bones), ten centers, primarily distals and those of the first digit, account for the majority of the significant sex differences.

Age Factors↗

PubMed2007

Secondary centers of ossification of the human toes: exceptional polymorphism and evolutionary perspectives.

As great morphological variability characterizes the phalanges of the human toes in adults, we hypothesized for a possible variability in the presence or absence of their secondary (= epiphyseal) centers of ossification linked to the unique morphology of the human foot within primates. The aim of this study was thus to provide original and detailed data on the occurrence of these centers. Classically, the big toe or hallux (I) presents two secondary centers and the lateral toes (II-V) three centers, and consequently the five toes present a total of 14 secondary centers. The material studied consisted of 261 foot radiographs from 261 young individuals of European origin (202 males and 59 females; 6-16 years). The presence (or absence) of the secondary centers of the phalanges of the toes was assessed for each foot. Feet presenting a biphalangeal variant in one or more lateral toes were studied separately. The theoretical possibilities of association of the three secondary centers in a given lateral toe (II-V) are eight in number; these eight patterns were studied and coded in the present study by types A-H. An exceptional variability in the occurrence of the secondary centers in lateral toes (II-V) was observed, and the classic pattern of phalangeal ossification was never observed. The absence of one or more secondary centers seems to be observed only in the human species, and we suggest that this could be a derived pattern specific to the human species, i.e., autapomorphic pattern. These results are of interest in the characterization and understanding of the reduction in size of the lateral toes which characterizes the specific evolution of the human foot.

Adolescent↗

PubMed2001

Cellular origin of endochondral ossification from grafted periosteum.

Grafted periosteum is known to have potential for heterotopic bone formation by endochondral ossification. Although osteochondrogenic cells have been thought to originate from the osteogenic layer in grafted periosteum, no histological report has yet demonstrated this. The present study was designed to elucidate the origin of chondrogenesis preceding bone formation in grafted periosteum. Periostea harvested from young Japanese white rabbits' tibiae were grafted into suprahyoid muscles and examined radiographically and histologically at postoperative days 1, 7, 9, 14, 21, and 35. Normal periostea and tibial graft site were also examined. Surgical harvesting of the periosteum split and damaged its osteogenic layer but retained the fibrous layer intact. Most of the osteoblasts remained on the tibial bone surface, and only few cells of the osteogenic layer were present in grafted tissue. By the seventh day after grafting, the fibrous layer had thickened. The fibroblastic cells in the fibrous layer had significantly increased in number (P < 0.01) and were positively stained for proliferating cell nuclear antigen. These cells exhibited alkaline phosphatase activity at day 9. The differentiated chondrocytes had formed cartilage at postoperative day 14. Cells in the osteogenic layer appeared necrotic and subsequently disappeared. Following postoperative day 21, cartilage was replaced by trabecular bone. Bone formation was completed by 35 days. An X-ray analysis at this time also revealed new bone formation. These findings indicate that grafted periosteum forms bone by endochondral ossification and that the cells of the fibrous layer play essential roles in chondrogenesis that precedes such bone formation.

Alkaline Phosphatase↗

PubMed1982

A radiographic study of the longitudinal growth of primary ossification centers in limb long bones of the human fetus.

This paper describes an extensive study of the growth of ossification centers in limb long bones of the human fetus from 8 to 26 weeks of conceptual age. Longitudinal measurements were made of the femur, tibia, fibula, humerus, radius, and ulna. Comparisons were made between bones on the left and right sides of the body and between the sexes. Standards are presented for the growth of these centers. They compare well with previous studies, any differences being accounted for by different methods of aging and measurement. A complicated picture of growth of the two sides of the fetal body is presented. Growth of the humerus, tibia, and fibula appears to be dominant on the left side of the body while growth in the femur is dominant on the right. At present, no explanation is available, but it is possible that factors such as manual dominance may be related. Evidence also is presented which suggests that the female fetus is in advance of the male in terms of ossification but only ater 21 weeks gestation.

Bone and Bones↗

PubMed1976

Ossification centers as evidence of fetal lung maturity.

Fetal pulmonary maturity based on visualization of one or both fetal knee secondary centers of ossification was assessed in 84 gravidas. Amniotic fluid lecithin/sphingomyelin ration of 2:1 or greater was the criterion of fetal lung maturity. It was concluded that when antenatal radiographs reveal the presence of both centers of ossification, fetal lung maturity can be assured in 100% of the fetuses. When the distal femoral center along is seen, only 60% of the fetuses will have mature lungs.

Amniotic Fluid↗

PubMed1989

Stimulation of experimental endochondral ossification by low-energy pulsing electromagnetic fields.

Pulsed electromagnetic fields (PEMFs) of certain configuration have been shown to be effective clinically in promoting the healing of fracture nonunions and are believed to enhance calcification of extracellular matrix. In vitro studies have suggested that PEMFs may also have the effect of modifying the extracellular matrix by promoting the synthesis of matrix molecules. This study examines the effect of one PEMF upon the extracellular matrix and calcification of endochondral ossification in vivo. The synthesis of cartilage molecules is enhanced by PEMF, and subsequent endochondral calcification is stimulated. Histomorphometric studies indicate that the maturation of bone trabeculae is also promoted by PEMF stimulation. These results indicate that a specific PEMF can change the composition of cartilage extracellular matrix in vivo and raises the possibility that the effects on other processes of endochondral ossification (e.g., fracture healing and growth plates) may occur through a similar mechanism.

Animals↗

PubMed1992

Adhesion molecules in skeletogenesis: I. Transient expression of neural cell adhesion molecules (NCAM) in osteoblasts during endochondral and intramembranous ossification.

We report that neural cell adhesion molecules (NCAM) are expressed transiently in developing chicken osteoblasts during osteogenesis using immunostaining on cryostat sections. NCAM is strongly expressed in most osteoblasts along bone trabeculae that coincide with the presence of collagen I and alkaline phosphatase activity. In endochondral ossification, NCAM is highly expressed in osteogenic buds as seen in the epiphysis and diaphysis of tibia and vertebrae. In intramembranous ossification, NCAM is seen in osteogenic condensation of calvaria and in the periosteum of tibial diaphysis. The expression is transient because NCAM is not expressed in mesenchymal cells before osteogenic condensation and NCAM expression is lost in osteocytes in later stages. The staining pattern suggests that NCAM is present on the cell membrane of osteoblasts. Using a specific monoclonal antibody, the osteoblast NCAM is shown to contain polysialic acid, which is enriched in embryonic brain. Northern blot analysis using chicken brain NCAM cDNA as probes showed two major sizes of mRNA at 6.4 and 4.2 kb in calvarial mRNA as opposed to bands at 7.2, 6.4, and 4.2 kb in the brain. An immunoblot showed major proteins at Mr 165 and 110 kd, unlike brain NCAM, which are 180, 140, and 120 kD. That NCAM is involved in bone morphogenesis is consistent with the general hypothesis that NCAM plays pivotal roles in mesenchymal condensation, as shown in the formation of muscle, kidney, skin, and cartilage. The results establish NCAM as a cell surface molecule expressed transiently during osteoblast lineage. The implication that NCAM may mediate osteoblast interaction and regulate skeletal morphogenesis is discussed.

Animals↗

PubMed1996

A new role for the chondrocyte in fracture repair: endochondral ossification includes direct bone formation by former chondrocytes.

We studied the endochondral ossification that occurs during the transition of soft to hard callus during fracture healing in the rabbit. During this process, parts of the cartilaginous soft callus are invaded by capillaries, and new bone is laid down onto the central unresorbed cartilage struts. We found that the chondrocytes within these cartilage struts changed phenotype and became bone-forming cells which directly replaced the central cartilage core with bone matrix. We have termed this bone "lacunar" bone to distinguish it from the "vascular" bone laid down by osteoblasts. With time the lacunar bone spread beyond the confines of the lacunae and gradually replaced all the cartilage matrix that was originally present in the early endochondral spicules. The lacunar bone could still be distinguished from the vascular bone as follows: (1) it was woven bone, whereas vascular bone was lamellar bone; (2) it contained acid phosphatase activity, whereas vascular bone did not; and (3) it had strong antigenicity for bone sialoprotein, whereas this noncollagenous protein was undetectable in vascular bone. Eventually the hard callus was resorbed and remodeled, but at an interim period of endochondral ossification the direct replacement of cartilaginous callus by the formation of lacunar bone is a rapid mechanism by which the mechanical strength of fracture callus is increased.

Acid Phosphatase↗

PubMed2007

Hyaline cartilage formation and enchondral ossification modeled with KUM5 and OP9 chondroblasts.

What is it that defines a bone marrow-derived chondrocyte? We attempted to identify marrow-derived cells with chondrogenic nature and immortality without transformation, defining "immortality" simply as indefinite cell division. KUM5 mesenchymal cells, a marrow stromal cell line, generated hyaline cartilage in vivo and exhibited enchondral ossification at a later stage after implantation. Selection of KUM5 chondroblasts based on the activity of the chondrocyte-specific cis-regulatory element of the collagen alpha2(XI) gene resulted in enhancement of their chondrogenic nature. Gene chip analysis revealed that OP9 cells, another marrow stromal cell line, derived from macrophage colony-stimulating factor-deficient osteopetrotic mice and also known to be niche-constituting cells for hematopoietic stem cells expressed chondrocyte-specific or -associated genes such as type II collagen alpha1, Sox9, and cartilage oligomeric matrix protein at an extremely high level, as did KUM5 cells. After cultured OP9 micromasses exposed to TGF-beta3 and BMP2 were implanted in mice, they produced abundant metachromatic matrix with the toluidine blue stain and formed type II collagen-positive hyaline cartilage within 2 weeks in vivo. Hierarchical clustering and principal component analysis based on microarray data of the expression of cell surface markers and cell-type-specific genes resulted in grouping of KUM5 and OP9 cells into the same subcategory of "chondroblast," that is, a distinct cell type group. We here show that these two cell lines exhibit the unique characteristics of hyaline cartilage formation and enchondral ossification in vitro and in vivo.

Animals↗

PubMed2002

Dlx5 is a positive regulator of chondrocyte differentiation during endochondral ossification.

The process of endochondral ossification in which the bones of the limb are formed after generation of cartilage models is dependent on a precisely regulated program of chondrocyte maturation. Here, we show that the homeobox-containing gene Dlx5 is expressed at the onset of chondrocyte maturation during the conversion of immature proliferating chondrocytes into postmitotic hypertrophying chondrocytes, a critical step in the maturation process. Moreover, retroviral misexpression of Dlx5 during differentiation of the skeletal elements of the chick limb in vivo results in the formation of severely shortened skeletal elements that contain excessive numbers of hypertrophying chondrocytes which extend into ectopic regions, including sites normally occupied by immature chondrocytes. The expansion in the extent of hypertrophic maturation detectable histologically is accompanied by expanded and upregulated domains of expression of molecular markers of chondrocyte maturation, particularly type X collagen and osteopontin, and by expansion of mineralized cartilage matrix, which is characteristic of terminal hypertrophic differentiation. Furthermore, Dlx5 misexpression markedly reduces chondrocyte proliferation concomitant with promoting hypertrophic maturation. Taken together, these results indicate that Dlx5 is a positive regulator of chondrocyte maturation and suggest that it regulates the process at least in part by promoting conversion of immature proliferating chondrocytes into hypertrophying chondrocytes. Retroviral misexpression of Dlx5 also enhances formation of periosteal bone, which is derived from the Dlx5-expressing perichondrium that surrounds the diaphyses of the cartilage models. This suggests that Dlx5 may be involved in regulating osteoblast differentiation, as well as chondrocyte maturation, during endochondral ossification.

Animals↗

PubMed1996

Syndecan-3 and the control of chondrocyte proliferation during endochondral ossification.

During endochondral ossification, chondrocytes progress through several stages of maturation before they are replaced by bone cells. Chondrocyte proliferation, the first step in this complex multistage process, is strictly controlled both spatially and temporally but its underlying mechanisms of regulation remain unclear. In this study we asked whether chondrocytes produce syndecan-3, a cell surface receptor for growth factors such as fibroblast growth factor 2 (FGF-2), and whether syndecan-3 may play a role in proliferation during chondrocyte maturation. We found that proliferating immature cartilage from chick embryo tibia and sternum contained significant amounts of syndecan-3 mRNA, whereas mature hypertrophic cartilage contained markedly lower transcript levels. Immunohistochemical analyses on sections of Day 18 chick embryo tibia revealed that syndecan-3 was spatially restricted and indeed detectable only in immature proliferating chondrocytes in the top zone of growth plate. These syndecan-3-rich proliferating chondrocytes lay beneath developing articular chondrocytes rich in their typical matrix protein tenascin-C, resulting in a striking boundary between these two populations of chondrocytes. Immature proliferating chondrocyte populations reared in growth-promoting culture conditions displayed strong continuous syndecan-3 gene expression; upon induction of maturation by vitamin C treatment, syndecan-3 gene expression was markedly down-regulated. Treatment with FGF-2 for 24 h stimulated both syndecan-3 gene expression and chondrocyte proliferation; this growth stimulation was counteracted by cotreatment with heparinase I or III. The results of the study indicate that syndecan-3 participates in the maturation of chondrocytes during endochondral ossification and represents a regulator of the proliferative phase of this multistage process.

Animals↗

PubMed2000

Process heterochronies in endochondral ossification.

Heterochrony, evolutionary changes in developmental rates and timing, is a key concept in the construction of a synthesis of development and evolution. Heterochronic changes in vertebrate evolution have traditionally been identified through plesiomorphic-apomorphic comparisons of bone growth. This methodological framework assumes that observed heterochronies are the outcome of dissociations of developmental processes in time. Recent findings of non-heterochronic developmental changes underlying morphological heterochrony invalidate this assumption. In this paper, a function for bone growth (at the organ level) has been mathematically deduced from the underlying developmental mechanisms. The temporal domain of the model spans from the time at maximum growth rate, after the formation of growth plates, to the time at atrophy of the proliferating stratum of cells. Three organizational levels were considered: (a) cell kinetics of endochondral ossification, (b) variation of bone growth rates and (c) variation of accumulated bone growth with increasing age. This quantitative model provides an excellent tool to deal with the problem of the developmental basis of morphological change. I have modelled potential evolutionary changes on the system at different levels of biological organization. This new framework involves an epistemological shift in heterochronic analysis from a pattern-oriented inductive way to a process-oriented deductive way. The analysis of the relationships between the evolutionary alterations of endochondral ossification and the morphological expression of these changes reveals that observed pattern heterochronies can be the outcome of different process heterochronies. Moreover, I discuss at length the heteroposic hypothesis, that evolutionary changes in the tight regulation of the amount of protein synthesized by a cell population during development would underlie acceleration or deceleration in cases of evolutionary changes in the initial number of proliferating cells at growth plates. Future research on the genetic basis of process heterochronies and heteroposies will complete our understanding of these evolutionary phenomena.

Animals↗

PubMed1994

Meniscal ossification. II. The normal pattern in the tiger knee.

Examination of knee menisci of Bengal tigers revealed ossicles within the cartilaginous anterior horn of each medial meniscus. This ossification was not evident in the neonatal animal, but was present in animals aged 20 months or older. The ossicle appeared prior to the completion of skeletal maturation at the knee, and was composed of normal remodeling trabecular bone. While most animals had a single, variably sized ossicle, multiple ossicles also occurred. The meniscal cartilage apposed to the femoral articulation exhibited a distinct columnar pattern in the region of the ossicle, in contrast to the non-columnar pattern throughout the bulk of the meniscus, including the ossicle side apposed to the tibial plateau. In this particular large mammalian species medial meniscal ossification appears to be a normal anatomical variation that progressively develops following birth, and may serve as a model for the phylogenetic (developmental) theory of etiology.

Aging↗

PubMed1986

99mTc-methylene diphosphonate uptake by ossifications and calcifications of non-osseous metastatic tumors.

Two cases of extra-osseous uptake of 99mTc-methylene diphosphonate (MDP) by non-osseous metastatic tumors are reported. One was a metastasis with ossification in the abdominal wall from carcinoma of the sigmoid colon and the other was a metastasis with calcification from an ovarian carcinoma. The mechanism of extra-osseous uptake of 99mTc-MDP is discussed. Bone scintigraphy can be a potential means to assess tumor spread with ossifications and calcifications.

Abdominal Neoplasms↗