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PubMed1986

Relationship between ossification and body weight of the CD-1 mouse fetus exposed in utero to anticonvulsant drugs.

The anticonvulsant drugs carbamazepine, Na valproate, and phenytoin have been suspected as a cause of human congenital defects. The malformations produced may include cleft lip and/or palate, heart defects, skeletal defects, and low body weights. Since the toxic effects of these anticonvulsant drugs manifest themselves in terms of fetal growth retardation, evaluation of the state of ossification attained in the fetus is important. In the present study, pregnant CD-1 mice received on gestational days 8-16 an oral dose of 375, 563, 938 mg/kg of carbamazepine; or 225, 338, 563 mg/kg of Na valproate; or 50, 75, 125 mg/kg of phenytoin. These groups were compared to two control groups. On day 17, the dams were killed by cervical dislocation and one-third of the live fetuses were weighed and fixed for skeletal examination. Photographs were taken of the fore- and hindlimb skeletons. From these photographs, the length and width measurement of ossified regions of the humerus and femur were determined using a Zeiss Video-Plan Morphometrics Computer. Of the three anticonvulsant drugs studied, the greatest correlation between reduced fetal weights and retarded ossification of the long bones was phenytoin at the 125 mg/kg dosage. Our results also showed that long bone ossification, when compared to the fetal weight, indicated that 59-66% of variability in weight is predictable by bone measurements.

Animals↗
PubMed1980

A study of fetal growth retardation in teratological tests: an examination of the relationship between body weight and ossification of coccygeal vertebrae in mouse and rat fetuses.

We examined the relationship between body weight and ossification of coccygeal vertebrae in normal full-term fetuses of mice and rats to reliably evaluate fetal growth retardation in teratological tests. Correlation coefficients between body weight and number of ossified coccygeal vertebrae were positive in mice and rats. However, the coefficients were variable between groups and were not statistically significant in some groups. Averages of body weight and ossified coccygeal vertebrae were variable in the normal fetuses. However, the coefficient of variation in each group was nearly constant, and the component of variance between groups (sigma 1(2)) was small as compared with that within groups (sigma 0(2)). Therefore, the relationship between low body weight and retardation of ossification observed in teratological experiments may be evaluated by measuring relative differences of body weight and ossification between the treated group and the control group with the variance within groups (sigma 0) as a scale.

2-Methyl-4-chlorophenoxyacetic Acid↗
PubMed1998

Role of the subchondral vascular system in endochondral ossification: endothelial cells specifically derepress late differentiation in resting chondrocytes in vitro.

Endochondral ossification in growth plates proceeds through several consecutive steps of late cartilage differentiation leading to chondrocyte hypertrophy, vascular invasion, and, eventually, to replacement of the tissue by bone. It is well established that the subchondral vascular system is pivotal in the regulation of this process. Cells of subchondral blood vessels act as a source of vascular invasion and, in addition, release factors influencing growth and differentiation of chondrocytes in the avascular growth plate. To elucidate the paracrine contribution of endothelial cells we studied the hypertrophic development of resting chondrocytes from the caudal third of chick embryo sterna in co-culture with endothelial cells. The design of the experiments prevented cell-to-cell contact but allowed paracrine communication between endothelial cells and chondrocytes. Under these conditions, chondrocytes rapidly became hypertrophied in vitro and expressed the stage-specific markers collagen X and alkaline phosphatase. This development also required signaling by thyroid hormone in synergy. Conditioned media could replace the endothelial cells, indicating that diffusible factors mediated this process. By contrast, smooth muscle cells, fibroblasts, or hypertrophic chondrocytes did not secrete this activity, suggesting that the factors were specific for endothelial cells. We conclude that endochondral ossification is under the control of a mutual communication between chondrocytes and endothelial cells. A finely tuned balance between chondrocyte-derived signals repressing cartilage maturation and endothelial signals promoting late differentiation of chondrocytes is essential for normal endochondral ossification during development, growth, and repair of bone. A dysregulation of this balance in permanent joint cartilage also may be responsible for the initiation of pathological cartilage degeneration in joint diseases.

Alkaline Phosphatase↗
PubMed1995

Transient local presence of nerve fibers at onset of secondary ossification in the rat knee joint.

In view of recent evidence that nerves may be involved in bone formation, the present study examines the local occurrence of axons at the onset of secondary ossification center formation in the knee region of developing rats. Radiographic and histological examination showed that secondary ossification center formation commenced at day 10. At day 15 the epiphyseal ossification had reached a relatively mature state. As seen by light microscopy, cartilage canals first appeared at day 5, reaching the epiphyseal center by day 9. Axons exhibiting a neurofilament-like immunoreactivity emerged from the perichondrial plexa into the cartilage canals. Many calcitonin gene-related peptide (CGRP)-immunoreactive axons were found in the canals, as well as in the perichondrium. Axons with tyrosine hydroxylase-like immunoreactivity were not found in the canals, but such fibers occurred in relation to blood vessels at other sites. The canal-related axons disappeared between days 13 and 15, and the canals themselves did not persist beyond bone formation. As seen in the electron microscope, an individual canal contained 3-10 unmyelinated Schwann cell-enclosed axons with diameters of 0.1-2.0 microM. These observations show that putative sensory unmyelinated axons with CGRP-and SP-like immunoreactivity are transiently present during initiation of bone formation in developing epiphyses. Whether there is a causal relation between transient innervation and osteogenesis remains to be determined.

Animals↗
PubMed1990

Transphyseal linear ossific striations of the distal radius and ulna.

Radiologic and histologic analysis of transphyseal linear ossific striations of the distal ulna and radius showed that these striations consist of trabecular bone extending from the metaphysis across all zones of the physis into a small focus of fibrous and necrotic tissue within the epiphyseal cartilage. The focus appears to be a discrete area of epiphyseal ischemia with subsequent necrosis within and around the vasculature of a cartilage canal and probably represents a microscopic response to antecedent trauma that was insufficient to cause macrofailure (fracture) of the physis. The striations did not continue into the epiphyseal ossification center. The consequence is partial osseous bridging across the physis. This bridging is unlikely to cause significant growth damage, since in most cases it does not appear to extend farther into the secondary ossification center.

Child↗
PubMed1992

The role of morphogens in endochondral ossification.

The formation of bone occurs normally by one of two developmental processes: intramembranous or endochondral ossification. Endochondral ossification occurs in the morphogenesis of the limb buds and growth plates, and in the regeneration of bone following injury (fracture callus). Two classes of diffusible morphogen-like molecules (MLMs) involved in limb development are the bone morphogenetic proteins (BMPs) and retinoic acid (RA). These MLMs are associated, respectively, with the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) of the primitive limb bud. They function as potent regulators of pattern formation and are involved in tissue proliferation and differentiation. The presence of endochondral ossification in fracture callus suggests a role for MLMs in that process as well. To date, virtually nothing is known about the role of morphogens in the regeneration of bone (fracture healing). In this article, we review the current knowledge of MLMs in bone formation and propose a theory on their role in fracture healing. We hypothesize that MLMs involved in fracture healing may also express spatial and temporal information. A more complete understanding of the role of morphogens in both limb development and fracture healing is of major importance to practicing orthopedists and their patients.

Animals↗
PubMed1994

Biochemical and histological study of the ossification in the early developing pedicle of the fallow deer (Dama dama).

To date, no histochemical data exist concerning the process of ossification of developing pedicles in deer. Four different zones of the growing pedicle (subcutaneous tissue; fibrous layer of the periosteum; cambial layer of the periosteum; woven bone of the primary spongiosa) were analysed in direct correlation to their histological appearance. The level of extractable specific alkaline phosphatase in the preosseous zones of the pedicle was 4-fold higher than levels in the epiphyseal growth plate previously reported. These results reflect that rapid bone formation takes place in the growing pedicle. Highest buffer-extractable alkaline phosphatase activity was found in the cambial layer directly in front of the mineralization area of the pedicle-bone, connected with maximal values for organically bound phosphate and inorganic phosphate. Moreover, the values for buffer-extractable alkaline phosphatase, organically bound phosphate and inorganic phosphate decreased with increasing mineralization in the zone of the primary spongiosa. The present histological and biochemical findings on the process of ossification in the pedicle show similarities to typical endochondral ossification. The process of pedicle growth may serve as a new and important system for chondrogenic and osteogenic studies, including a better understanding of antler development.

Alkaline Phosphatase↗
PubMed1994

Occurrence of osteoblast necroses during ossification of long bone cortices in mouse fetuses.

Previous investigations concerned with in vitro osteogenesis and mineralization have revealed some indication of a participation of cell necroses in the course of calcification. These observations were confirmed by in vivo investigations on desmoid ossification in fetal mouse calvariae, where abundant necrotic osteoblasts were found at the mineralization border and in the osteoid. In the present study, ossification of long bone cortices from fetal mice was investigated by use of electron microscopy. Specimens obtained from the collection of the Institute of Anatomy, Free University of Berlin (mouse fetuses, forearm; rat fetuses, forearm) were reinvestigated for control purposes. In all cases, mineralization of osteoid was accompanied by cell necroses. Cell degeneration was characterized by swelling of the endoplasmic reticulum and loss of the plasma membrane resulting in freely distributed vesicular structures. Cell debris was incorporated within the mineral. Initially, cell necroses in the perichondrium occurred in the region surrounding the hypertrophic cartilage and the matrix of which showed spots of endochondral mineralization. Necrotic osteoblasts occurred simultaneously with mineralization of the osteoid. During further ossification of the long bone cortices, the number of necrotic cells increased markedly. In addition to necrotic cells, healthy osteoblasts, osteocytes and perichondral tissue were present, indicating that an artifact can be excluded. The importance of cell necroses in the process of mineralization is as yet unclear. Possibly, the cells act as calcium and/or phosphate stores, which are liberated by cell death to increase the amount of mineral constituents at sites of mineralization.

Animals↗
PubMed1983

The pattern of spinal and extraspinal hyperostosis in patients with ossification of the posterior longitudinal ligament and the ligamentum flavum causing myelopathy.

Thirty one patients suffering from myelopathy associated with ossification of the posterior longitudinal ligament and ligamentum flavum of the spine have been investigated. The pattern of spinal and peripheral hyperostosis was recorded in each case. Flowing anterior vertebral hyperostosis and ligamentous ossification at the enthesis around the pelvis and hips were the most frequent associations, occurring in approximately 86% of patients. The distribution and incidence of the spinal and extraspinal hyperostosis in this series corresponds closely to the findings in diffuse idiopathic skeletal hyperostosis (DISH). The present findings indicate that patients suffering from cervical myelopathy and ossification of the posterior longitudinal ligament should be regarded as manifesting focal features of a more generalised disorder producing skeletal hyperostosis.

Adult↗
PubMed1986

Development of heterotopic ossification around the hip. A long-term follow-up of patients who underwent surgery with two different types of endoprostheses.

Heterotopic ossification has been reported in many pathological situations, most important clinically as a sequel to hip arthroplasty and spinal trauma. The etiology of heterotopic ossification is yet not clear, but the disease is supposed to be connected with trauma. Heterotopic bone was found in 53% (1.2% with the severe form) of 623 patients operated on at the Orthopaedic Hospital of the Invalid Foundation, Helsinki, Finland; the operations included 849 arthroplasties. The rate of heterotopic ossification was higher after revision arthroplasty, following operation of the contralateral side, in men, and in primary coxarthrosis, and the incidence was higher with the Brunswik (metal-on-plastic) endoprosthesis than in the McKee-Farrar type (metal-on-metal). Heterotopic bone formation generally seemed to increase and to be more manifest during long-term observation.

Calcinosis↗
PubMed1993

Selenium deficiency and fulvic acid supplementation induces fibrosis of cartilage and disturbs subchondral ossification in knee joints of mice: an animal model study of Kashin-Beck disease.

Kashin-Beck disease is an acquired, chronic and degenerative osteoarticular disorder. Selenium deficiency and fulvic acid in drinking water have been implicated in the cause of this disease. Pathologically, chondronecrosis of the growth plate and articular cartilage and subconsequent disturbance of ossification were observed in the joints. In this animal model study, mice were fed with a selenium deficient diet and fulvic acid supplemented drinking water for two generations. In undecalcified histological preparations of bone we carried out histological staining to detect mineralized and unmineralized bone and cartilage. The results revealed that selenium deficiency and fulvic acid supplementation induced degeneration of the articular cartilage in the knee joints of mice. Dynamic fluorescent labelling of ossification, enzyme histochemical detection of alkaline phosphatase activity in osteoblasts and a typical immunohistochemical localization of collagens type I and II indicated the development of fibrocartilage at the articular surface of knee joints, resembling the early stages of osteoarthrosis. This became obvious by disturbed development of the articular space and meniscus, markedly impaired formation of subchondral bone and early differentiation failure during enchondral ossification. This animal model provides an approach to study the molecular pathogenesis of Kashin-Beck disease.

Animals↗
PubMed2002

Inhibition of growth plate angiogenesis and endochondral ossification with diminished expression of MMP-13 in hypertrophic chondrocytes in FGF-2-treated rats.

Fibroblast growth factors (FGFs)/fibroblast growth factor receptor-3 signaling interferes with endochondral bone growth. However, the exact mechanisms by which FGFs inhibit endochondral ossification remain to be elucidated. In the present study, we utilized immunohistochemical techniques to clarify the effects of FGF-2 on the proximal tibial growth plate cartilage, when injected systemically into growing rats. In the FGF-2-treated rats, the growth plate was obviously thickened and, in the lowermost part, the hypertrophic chondrocytes were flattened, with an irregular arrangement. The connection of the cartilage columns and trabecular bone was disrupted. FGF-2 treatment stimulated the proliferation of chondrocytes and permitted their differentiation, but inhibited vascular invasion and resorption of the cartilage matrix. Expression of matrix metalloproteinase-13 (MMP-13) was detected in the chondrocytes in the last row of the hypertrophic zone of the growth plate in control animals. The immunoreactivity of MMP-13 was diminished in the regions where endochondral ossification was disturbed in the FGF-2-treated rats. Because MMP-13 has potent proteolytic activity on cartilage components, the FGF-2 signal may inhibit angiogenesis and endochondral ossification of the growth plate by the suppression of MMP-13 expression in hypertrophic chondrocytes.

Animals↗
PubMed1990

A suitable culture medium for ossification of embryonic chick femur in organ culture.

To establish a culture medium which allows ossification in organ culture, 9-day-old embryonic chick femurs were cultured in variously supplemented BGJb-HW2 media. Changes of Ca and Pi concentrations in the BGJb-HW2 medium or the 10% addition of chick embryo extract (CEE) did not induce ossification. Furthermore, combinations of the 10% CEE with a high Ca x Pi product or with 5 mM beta-glycerophosphate (beta-GP) or with 10% horse serum plus a high Ca x Pi product often caused pathological abnormalities in the periosteum. On the other hand, BGJb-HW2 medium supplemented with 5 mM beta-GP induced development of ossification. The Ca content of femurs and the diaphysial hydroxyproline content were markedly increased. Histological observation showed a formation of a thick and active periosteum, numerous osteoblastic cells, a sufficient amount of osteoid tissue and well developed calcified trabeculae without any pathological changes. Thus, the organ culture system using this medium was considered to be an appropriate one for studies on osteogenesis in vitro.

Animals↗
PubMed1991

Interaction between cadmium and copper on ossification of embryonic chick bone in tissue culture.

To investigate the interaction between cadmium and copper in ossification, femurs from 9-day-old chick embryos were cultured for 6 days in the presence of 2 microM cadmium and/or 1 microM copper. It was found that cadmium + copper treatment caused interactively severe damage to osteogenic mesenchymal cells in the periosteum and a severe degenerative change in osteoblasts around the trabecula, resulting in severe impairment of ossification in the diaphysis. Cadmium content was increased by copper; however, copper content was unaffected by cadmium in the diaphysis. It was therefore considered that the copper-induced increase in cadmium content was a primary factor in the interactive toxic effect of the cadmium + copper treatment in ossification.

Animals↗
PubMed2005

Expression profile of Xenopus banded hedgehog, a homolog of mouse Indian hedgehog, is related to the late development of endochondral ossification in Xenopus laevis.

Late development of endochondral ossification occurs at the boundary between the growth cartilage and bone marrow during the formation of long bones in Xenopus laevis. Since the Indian hedgehog (Ihh) is involved in endochondral ossification in mouse, we investigated the expression of Xenopus banded hedgehog (X-bhh), which is a homolog of mouse Ihh. RT-PCR analysis demonstrated that the X-bhh mRNA was detected from an early stage of limb formation to formation of femurs in mature frogs, and it was associated with the expression of Xenopus-ptc1 (X-ptc1), Xenopus-gli1 (X-gli1), Xenopus-type II collagen (X-col II), Xenopus-runx2 (X-runx2), and Xenopus-osteocalcin (X-ocn) mRNAs. In situ hybridization revealed that chondrogenic cells observed at early limb development expressed X-bhh and X-gli1. At later stages of limb development, chondrocytes, located slightly away from the boundary between the cartilage and bone marrow, expressed the X-bhh, X-ptc1, and X-gli1 mRNAs; however, the mesenchymal cells at the boundary failed to express these mRNAs. The X-bhh, X-ptc1, and X-gli1 mRNAs as well as those of X-runx2 and X-ocn were expressed by the mesenchymal cells in the periosteal region at the tip of the cortical bone, indicating an intimate relationship between X-bhh expression and bone formation in this region. Considered collectively, the present study suggests that X-bhh evolutionally acquired the function to induce osteogenesis; however, the expression profile of X-bhh in epiphysis is closely related to the late development of endochondral ossification in X. laevis.

Animals↗
PubMed2006

Endochondral ossification in vitro is influenced by mechanical bending.

Bone development is influenced by the local mechanical environment. Experimental evidence suggests that altered loading can change cell proliferation and differentiation in chondro- and osteogenesis during endochondral ossification. This study investigated the effects of three-point bending of murine fetal metatarsal bone anlagen in vitro on cartilage differentiation, matrix mineralization and bone collar formation. This is of special interest because endochondral ossification is also an important process in bone healing and regeneration. Metatarsal preparations of 15 mouse fetuses stage 17.5 dpc were dissected en bloc and cultured for 7 days. After 3 days in culture to allow adherence they were stimulated 4 days for 20 min twice daily by a controlled bending of approximately 1000-1500 microstrain at 1 Hz. The paraffin-embedded bone sections were analyzed using histological and histomorphometrical techniques. The stimulated group showed an elongated periosteal bone collar while the total bone length was not different from controls. The region of interest (ROI), comprising the two hypertrophic zones and the intermediate calcifying diaphyseal zone, was greater in the stimulated group. The mineralized fraction of the ROI was smaller in the stimulated group, while the absolute amount of mineralized area was not different. These results demonstrate that a new device developed to apply three-point bending to a mouse metatarsal bone culture model caused an elongation of the periosteal bone collar, but did not lead to a modification in cartilage differentiation and matrix mineralization. The results corroborate the influence of biophysical stimulation during endochondral bone development in vitro. Further experiments with an altered loading regime may lead to more pronounced effects on the process of endochondral ossification and may provide further insights into the underlying mechanisms of mechanoregulation which also play a role in bone regeneration.

Animals↗
PubMed2004

The role of osteogenic index, octahedral shear stress and dilatational stress in the ossification of a fracture callus.

The exact mechanism by which mechanical stimulus regulates the healing process of a bone fracture is not understood. This has led to the development of several hypotheses that predict the pattern of differentiation of tissue during healing that may arise from characteristic fields of stress or strain at the fracture. These have so far remained unproved because data on stress fields in actual fracture tissue have been unavailable until recently. Thus the present study examines the predictive performance of the hypothesis proposed in J Orthop Res 6 (1988) 736, against measured and calculated data reported in J Biomech 33 (2000) 415, using a 2D FEM of a clinical fracture. The hypothesis was used to predict the influence of stress fields present in the Gardner et al. tissues at four temporal stages during healing. These predictions were then correlated with callus-size, rate of endochondral ossification and ossification pattern subsequently observed by Gardner et al. in the clinical fracture. Results corroborate the hypothesis that high octahedral shear stresses may increase the size of the callus during the initial phase of healing, and they also suggest that this may be true during the later stages of the fracture fixation period. However, compressive dilatational stresses were not found to inhibit endochondral ossification, as suggested by the hypothesis. Although high shear stresses were found in regions indicative of fibrous tissue as postulated by the hypothesis, this was not found to be the case for high tensile dilatational stresses. Also, contour diagrams of Osteogenic index (I) indicated only limited correlation with callus maturation and the pattern of healing. Therefore, the hypothesis was not wholly successful in predicting healing pattern.

Adult↗