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PubMed1979

[Long-term follow-up of stress injuries to the metaphyses and apophyses of the spinous processes of juvenile thoracic spines (Schmitt's disease) (author's transl)].

Unlike the clay-shoveller's fracture in adults, stress injuries in juveniles trend to be localised at the tip of the spinous process, i.e. in the metaphysis, the apophyseal line and the apophysis. Characteristic changes are found only between 14 1/2 and 16 1/2 years, at, or immediately before, ossification of the tip of the apophysis. These fractures share with the corresponding fractures in adults similar occupational history, a similar clinical picture with a benign course of the disease. Healing is by the formation of a pseudo-arthrosis which may, however, consolidate after several months or years. Synonyms which have been used for the stress injury to the spinous process in the growing skeleton are: clay-shoveller's fractures in juveniles, apophysitis of the spinous process, aseptic necrosis of the spinous process, gross disturbance of the spinous process after chronic trauma or Schmitt's disease.

Adolescent↗

PubMed1999

Different effects of bone morphogenetic proteins 2, 4, 12, and 13 on the expression of cartilage and bone markers in the MC615 chondrocyte cell line.

In order to study the lineage leading to chondrocyte and osteoblast phenotype in vertebrate development, we examined the effect of recombinant human bone morphogenetic protein (BMP)-2, BMP-4, BMP-12 [or growth and differentiation factor (GDF)-7], and BMP-13 (or GDF-6) on the phenotypic expression of the mouse chondrocyte cell line MC615, grown for 1 or 2 weeks in monolayer. Protein synthesis rates were monitored after incubation with [(14)C]proline. BMP-2 and BMP-4 increased protein synthesis, in agreement with our observation by phase-contrast microscopy of a highly refractile matrix around MC615 cells treated with BMP-2 and -4. Markers of the chondrocytic and osteoblastic differentiation were analyzed at mRNA level. Expression of the type II collagen gene, a marker of the cartilage phenotype, was up-regulated in the presence of low concentration of BMP-2 or -4 (50 ng/ml) and down-regulated at higher concentrations (100-400 ng/ml). In parallel, this expression was stable in the presence of BMP-12 or -13 in the dose range tested (50-400 ng/ml). Expression of the matrix Gla protein (MGP) gene, another marker of cartilage, was also reduced in the presence of 100 ng/ml BMP-2 or -4, while it remained stable in the presence of BMP-12 or -13 at the same concentration. In contrast, expression of the bone Gla protein (BGP) gene, or osteocalcin, a marker of the bone phenotype, was induced when the cells were treated with BMP-2 or -4 but was not detected when the cells were treated with BMP-12 or -13. At the same time, BMP-2 or -4 markedly up-regulated expression of type X collagen mRNA, indicating that MC615 cells possess the ability to express traits associated with endochondral ossification, when exposed to specific BMPs. Furthermore, detailed analysis of type II collagen expression showed that the alternatively spliced transcript collagen IIB, specific for cartilage, is expressed concomitantly with BGP. Therefore, MC615 chondrocytes can simultaneously express chondrocytic and osteoblastic markers, in response to BMP-2 or -4, but show minimal response to BMP-12 (or GDF-7) or to BMP-13 (or GDF-6). These results raise the possibility that chondrocytes in vivo can express osteoblastic properties, provided they are induced by BMP-2 or -4.

Animals↗

PubMed1999

Histochemical and immunohistochemical analysis of the mechanism of calcification of Meckel's cartilage during mandible development in rodents.

It is widely accepted that Meckel's cartilage in mammals is uncalcified hyaline cartilage that is resorbed and is not involved in bone formation of the mandible. We examined the spatial and temporal characteristics of matrix calcification in Meckel's cartilage, using histochemical and immunocytochemical methods, electron microscopy and an electron probe microanalyser. The intramandibular portion of Meckel's cartilage could be divided schematically into anterior and posterior portions with respect to the site of initiation of ossification beneath the mental foramen. Calcification of the matrix occurred in areas in which alkaline phosphatase activity could be detected by light and electron microscopy and by immunohistochemical staining. The expression of type X collagen was restricted to the hypertrophic cells of intramandibular Meckel's cartilage, and staining with alizarin red and von Kossa stain revealed that calcification progressed in both posterior and anterior directions from the primary centre of ossification. After the active cellular resorption of calcified cartilage matrix, new osseous islands were formed by trabecular bone that intruded from the perichondrial bone collar. Evidence of such formation of bone was supported by results of double immunofluorescence staining specific for type I and type II collagens, in addition to results of immunostaining for osteopontin. Calcification of the posterior portion resembled that in the anterior portion of intramandibular Meckel's cartilage, and our findings indicate that the posterior portion also contributes to the bone formation of the mandible by an endochondral-type mechanism of calcification.

Alkaline Phosphatase↗

PubMed2006

Clinical biophysics: the promotion of skeletal repair by physical forces.

Skeletal tissues respond to the physical demands of their environment by altering the synthesis and organization of the extracellular matrix. These observations have major implications for how physical environmental demands result in the clinical observations of atrophy and hypertrophy, and how manipulation of the physical environment can be used therapeutically to stimulate repair. Electrical stimulation will be considered as a paradigm of how musculoskeletal tissues respond to physical stimuli. A model of demineralized bone matrix-induced endochondral ossification has been used because it epitomizes the cell biology of endochondral bone formation in a temporally consistent way. We have studied cartilage and bone matrix production, the temporal locus of cell responsiveness, signal dosimetry, and the synthesis of signaling cytokines (TGF-beta) using biochemical, immunohistochemical, and molecular techniques. Exposure to certain electrical environments enhances chondrocyte differentiation reflected as a temporal acceleration and quantitative increase of cartilage extracellular matrix, earlier onset of osteogenesis, and more mature trabecular bone. The cell pool competent to respond resides in the mesenchymal stage. The enhancement in chondrogenesis is associated with an increase in TGF-beta synthesis mediated at least in part by binding of the transcription factor AP-1 and may be modulated specifically by phosphorylation of JNK. The clinical practice of orthopedics has empirically created a variety of biophysical environments in attempts to optimize skeletal repair. We are beginning to understand the biological effects of biophysical stimulation and are now poised to replace empiricism with treatment paradigms based upon physiologic understandings of dose and biologic response.

Animals↗

PubMed1998

Initiation of the bony epiphysis in long bones: chronology of interactions between the vascular system and the chondrocytes.

Many events occur concurrently during the initiation of the secondary ossification center in the cartilaginous epiphyses of long bones. We have investigated the chronology of interactions between the vascular system and epiphyseal chondrocytes by culturing explanted heads of femurs and humeri from pre- and neonatal rabbits on the chorioallantoic membrane (CAM) of growing chick embryos. We confirmed that, on the whole, the epiphyseal cartilage was resistant to vascular invasion, whereas the physeal growth plate was resorbed. However, new CAM-derived cartilage canals occasionally penetrated through the articular surface. This caused death of those chondrocytes in the immediate vicinity of the canal but no further reaction. If explants already contained a bony epiphysis and were halved prior to culture, CAM-derived vessels were attracted to the spongiosa. From there they pushed into the uncalcified cartilage, indicating that calcification was not a prerequisite for vascular invasion. Where at least two vessels were in apposition, a new pseudo-ossification center was initiated: chondrocytes became hypertrophic and the matrix calcified. This suggests that cumulative release of diffusible factors from more than one vessel was the trigger for chondrocyte hypertrophy, which, in turn, led to the initiation of the bony epiphysis. CAM cultures thus provide an experimental model for both the quiescent angiogenesis of cartilage canal formation and the reactionary angiogenesis associated with chondrocyte hypertrophy. By exploiting the different anatomy of CAM-derived vascularity, events that occur concurrently in vivo can be specially separated in CAM culture.

Allantoin↗

PubMed2005

Articular / epiphyseal osteochondrosis in Thoroughbred foals at 5 months of age: influences of growth of the foal and prenatal copper supplementation of the dam.

AIMS: To determine the influence of copper (Cu) supplementation by injection of mares in late gestation on the frequency and severity of osteochondrosis (OC) lesions in their foals at around 160 days of age. To determine if there was any influence of the concentration of Cu in the liver, growth rate, birthweight, weight at 160 days of age, fatness, sex, or year of birth of the foal on the frequency and severity of OC lesions. To determine the influence of dam's age, and sex and birthweight of the foal on the growth rate from birth to 160 days of age, and weight at 160 days of age. METHODS: Thirty-three Thoroughbred foals, born in two consecutive years, were weighed every 2 weeks from birth. The dams had been supplemented with parenteral Cu or saline during late gestation, and the supplementation regimens were different in each year. Foals had liver biopsies harvested at birth for determination of Cu concentration. Pasture samples were collected every 4-8 weeks for analysis of concentration of Cu and zinc (Zn). At 160 days of age, articular cartilage of long bones was examined. Gross lesions were counted and scored, then sawn and radiographed, and processed for histopathology. Lesions were given radiographic scores and histopathological scores. Maximum scores for each lesion were combined to give a total OC score for each joint and each foal. The fatness of 20 foals (10 each from Years 1 and 2) at 160 days of age was determined chemically. RESULTS: Supplementation of dams with Cu had no significant effect on the concentration of Cu in the liver of foals at birth, or on the frequency or severity of lesions in articular cartilage at 160 days of age. The Cu and Zn concentrations of pasture were similar in Years 1 and 2, and were lower than current recommendations. All foals in Year 2, and 9/10 foals in Year 1 had irregularities in cartilage that was confirmed histologically to be indicative of OC. The average number of lesions per foal was 4.7 (SD 1.1) and 5.7 (SD 1.1) in Years 1 and 2, respectively. However, the severity of the lesions was considered mild, and no foals showed any clinical evidence of OC while alive. The number of lesions in the tarsocrural (TC) joint and the TC OC score at 160 days were positively associated with average daily weight gain (ADG) in the previous 4 weeks (p=0.005 and p=0.001, respectively). There was no significant effect of sex, fatness, birthweight, weight at 160 days of age, or year of birth of the foal on the frequency and severity of OC lesions. CONCLUSIONS: Many of the lesions classified as OC, using classification systems described by other authors, were likely to be normal variations of the process of endochondral ossification. Despite the high frequency of such lesions, they were considered to be of minor significance and none were clinically evident. The distribution of lesions was not typical, and most probably reflected the subtlety of the lesions. These results support the hypothesis that Cu is an over-emphasised factor in the aetiopathogenesis of OC. The relationship between subtle macroscopic lesions and lesions resulting in clinical signs of disease requires further investigation.

Aging↗

PubMed1996

Alterations of maternal estrogen levels during gestation affect the skeleton of female offspring.

Estrogens have important effects on bone turnover in both humans and experimental animals models. Moreover, the decreased level of estrogen after menopause appears to be one of the key factors in determining postmenopausal osteoporosis. The presence of estrogen receptor in both osteoblasts and osteoclasts has suggested a direct role of these steroid hormones on bone tissue. Thus, this tissue is now regarded as a specific estrogen target tissue. Exposure to estrogens during various stages of development has been shown to irreversibly influence responsive target organs. We have recently shown that transient developmental neonatal exposure (days 1-5 of life) of female mice to estrogen resulted in an augmented bone density in the adult animals. The aim of the present study was to evaluate whether short-term modification of maternal estrogen levels during pregnancy would induce changes in the skeleton of the developing fetuses and to identify any long-term alterations that may occur. Pregnant mice were injected with varying doses (0.1-100 micrograms/kg maternal BW) of the synthetic estrogen diethylstilbestrol (DES) from day 9-16 of pregnancy. Offspring were weaned at 21 days of age, and effects on bone tissue of the female mice were evaluated in adulthood (6-9 months of age). Prenatal DES treatment(s) did not significantly affect BW. However, a dose-dependent increase in bone mass, both in the trabecular and cortical compartments, was observed in the prenatal DES-exposed female offspring. Furthermore, long bones of DES-exposed females were shorter than controls. Normal skeletal mineralization accompanied these changes in the bone tissue, as shown by a parallel increase in skeletal calcium content. Double tetracycline labeling performed in 6-month-old DES-exposed animals showed an increase in mineral apposition rate in adult DES-exposed mice as compared with untreated control animals, although no significant difference in the circulating estrogen levels was found in animals of this age. Experiments were then performed to evaluate whether perturbation of the estrogen surge at puberty in these diethylstilbestrol (DES)-exposed mice could reverse the observed changes. Femur length was chosen as a marker of potential estrogenic effect. Prepubertal ovariectomy of the prenatally DES-treated animals could only partially reverse the effects observed in the skeleton of the DES-treated animals. Further experiments were performed to evaluate whether these changes could have occurred in utero. CD-1 pregnant female mice were injected with DES (100 micrograms/kg maternal BW) from days 9-15 of gestation. On day 16 of gestation, fetuses were examined and stained by a standard Alizarin Red S and Alcian Blue procedure to visualize calcified and uncalcified skeletal tissue. Estrogen treatment induced an increase in the amount of calcified skeleton as compared with untreated controls and also a decrease in the length of long bones, strongly suggesting a change in both endochondral ossification and endosteal and periosteal bone formation. In summary, these data show, for the first time, that alterations in the maternal estrogenic levels during pregnancy can influence early phases of fetal bone tissue development and subsequently result in permanent changes in the skeleton. Finally, the effect of this short-term estrogen treatment can be seen in the fetal skeleton, suggesting an estrogen-imprinting effect on bone cell-programming in fetal life because treatment effects on bone cell turnover can be observed later in adult life.

Animals↗

PubMed2000

Histological studies of pedicle skin formation and its transformation to antler velvet in red deer (Cervus elaphus).

Deer antlers and their antecedent pedicles are made up of two components, interior osseocartilage and exterior integument. In a previous study, we described that histogenesis of the interior osseocartilage proceeds through four ossification stages. These are intramembranous (IMO), transition (OPC), pedicle endochondral (pECO), and antler endochondral (aECO). In the present study, we used histological techniques to examine pedicle skin formation and its transformation to antler velvet. The results showed that pedicle skin initiated from the apex of a frontal lateral crest and was formed through three distinctive stages. These stages are 1) compression of the subcutaneous loose connective tissue at the OPC stage, 2) stretching of the undulated epidermis at the early pECO stage, and 3) neogenesis of the skin and its associated appendages at the mid pECO stage. Transformation into antler velvet, which occurs at the late pECO stage, is mainly associated with alteration in the skin appendages. This alteration includes the loss of arrector pili muscle and sweat glands, and the gain of the large bi- or multi-lobed sebaceous glands. These results suggest that pedicle skin expansion occurs to release the mechanical tension created by underlying forming antlerogenic tissue, initially in response to it by mechanical stretch, and then by neogenesis of skin. In turn, the stretched pedicle skin may exert mechanical pressure on the underlying antlerogenic tissue causing it to change in ossification type. Antler velvet generation may be accomplished by both mechanical stimulation and chemical induction from the underlying pECO stage antlerogenic tissue. If this hypothesis is correct it is likely that mechanical stimulation would drive skin formation and chemical induction then determine skin type. Furthermore, asynchronous transformation of the interior and exterior components during pedicle formation and antler generation may result from the delayed chemical induction and the way antler velvet initially generates. The results from both mitotic cell labelling of the basal layer and ultrastructure of the basement membrane of the apical skin in the study support these hypotheses.

Aging↗

PubMed2005

Comparison of biophysical stimuli for mechano-regulation of tissue differentiation during fracture healing.

Most long-bone fractures heal through indirect or secondary fracture healing, a complex process in which endochondral ossification is an essential part and bone is regenerated by tissue differentiation. This process is sensitive to the mechanical environment, and several authors have proposed mechano-regulation algorithms to describe it using strain, pore pressure and/or interstitial fluid velocity as biofeedback variables. The aim of this study was to compare various mechano-regulation algorithms' abilities to describe normal fracture healing in one computational model. Additionally, we hypothesized that tissue differentiation during normal fracture healing could be equally well regulated by the individual mechanical stimuli, e.g. deviatoric strain, pore pressure or fluid velocity. A biphasic finite element model of an ovine tibia with a 3mm fracture gap and callus was used to simulate the course of tissue differentiation during normal fracture healing. The load applied was regulated in a biofeedback loop, where the load magnitude was determined by the interfragmentary movement in the fracture gap. All the previously published mechano-regulation algorithms studied, simulated the course of normal fracture healing correctly. They predicted (1) intramembranous bone formation along the periosteum and callus tip, (2) endochondral ossification within the external callus and cortical gap, and (3) creeping substitution of bone towards the gap from the initial lateral osseous bridge. Some differences between the effects of the algorithms were seen, but they were not significant. None of the volumetric components, i.e. pore pressure or fluid velocity, alone were able to correctly predict spatial or temporal tissue distribution during fracture healing. However, simulation as a function of only deviatoric strain accurately predicted the course of normal fracture healing. This suggests that the deviatoric component may be the most significant mechanical parameter to guide tissue differentiation during indirect fracture healing.

Algorithms↗

PubMed1992

Nutritional status of children of urban leprosy patients staying at preventoria based on biochemical parameters.

Measurements of nutritionally relevant biochemical and endocrine variables were made on 60 apparently healthy children (group A) whose parents suffered from leprosy and who had been separated at the age of 4 years and brought up in preventoria. Most of the measurements were also made on a comparison group of healthy children from the same poor socio-economic class (group B). In both groups the serum concentrations of cholesterol and triglycerides were well below those found in Western populations. Almost all the children in both groups were anaemic, but serum iron and ferritin levels were satisfactory. Folate and vitamin B12 levels were measured in group A only and were low in a significant proportion. Deficiency of these water-soluble vitamins may be a cause of the anaemia. Low albumin levels were found in 40% of group A children, compared with 2% in group B. The concentrations of calcium and magnesium were lower and that of phosphate higher in group A than in B. In both groups one-third of the children had low levels of serum zinc. Fifteen per cent of group A children had biochemical evidence of vitamin A deficiency, but none were deficient in vitamin E. Levels of total T3 and total T4 were below the lower limit of normal in a substantial proportion of children in both groups. Concentrations of parathyroid hormone were increased in parallel with the low values for serum calcium. Radiological studies of ossification centres in 57 group A children showed delayed maturation in 11 cases. The relevance of these findings to previous studies of the children of lepers in India is discussed.

Adolescent↗

PubMed1995

Cranial sutures require tissue interactions with dura mater to resist osseous obliteration in vitro.

A chemically defined serum-free medium, which supports the development of bones and fibrous tissues of rat calvaria from nonmineralized mesenchymal precursor tissues, was employed to investigate tissue interactions between the dura matter and overlying tissues. Fetal calvarial rudiments from stages prior to bone and suture morphogenesis (fetal days 19 and 20) and neonatal calvarial rudiments with formed sutures (day 1) were cultured with and without associated dura mater. Removal of calvaria for in vitro culture allowed the examination of suture morphogenesis in the absence of tensional forces exerted on the sutures via fiber tracts in the dura mater originating in the cranial base. Ossification of frontal and parietal bones proceeded in a fashion comparable to development in vivo, but the cranial (coronal) sutures--primary sites for subsequent skull growth--were obliterated by osseous tissue union in the absence of dura mater. Bony fusion did not occur when rudiments were cocultured with dura mater on the opposite sides of 0.45 microns polycarbonate transwell filters, suggesting that the influence of dura mater on sutural obliteration was mediated by soluble factors rather than cell-cell or cell-matrix interactions. These results indicate that cell signaling mechanisms rather than biomechanical tensional forces are required for morphogenesis of the calvaria.

Animals↗

PubMed1992

Degeneration of osteoblasts involved in intramembranous ossification of fetal rat calvaria.

Ossification of calvariae from day-21 rat fetuses was reinvestigated by electron microscopy using different fixation techniques (glutaraldehyde/OsO4, tannic acid, ruthenium red, K-pyroantimonate). An osteoid layer with scattered mineral deposits was found at the mineralization front. Directly beyond this layer, a sheet of one to two layers of necrotic and degenerating osteoblasts was present. Above this sheet, normal and healthy cells were seen, formed by six to eight layers of flattened cells, embedded in a collagenous matrix. The osteoblasts on the less mineralizing opposite side of the calcified calvariae and the osteocytes embedded in the calcified calvariae appeared healthy. Closer inspection of the necrotic zone revealed apatite crystals in vesicles which most probably originated from mitochondria of the degenerated cells. Large K-pyroantimonate deposits were found throughout the osteoid and the necrotic zone, whereas only small granules were scattered in the cytoplasm and at the plasma membrane of the healthy cells directly adjacent to the necrotic zone. A concept of intramembranous mineralization is outlined, according to which osteoblasts store enormous amounts of calcium, which are liberated by physiological cell death in the vicinity of the mineralizing front.

Animals↗

PubMed1977

A functional analysis of fusion of the tibia and fibula in the rat and mouse.

The distal diaphyseal shafts of the rat tibia and fibula fuse postnatally, a process initiated by the seventh day with the formation of secondary cartilage that is subsequently replaced by endochondral ossification. The histological appearance of this fusion process is described. A homologous process occurs postnatally in the mouse. An analysis of some of the pertinent recent developmental, comparative and paleontological data indicated that extrinsic, biomechanical factors probably played a significant causal role in tibia-fibula fusions. The production of secondary cartilage is evoked by extrinsic forces, and these fusions were analyzed within the present concepts of intrinsic and extrinisic factors in skeletogenesis. It was concluded that the fusions currently reported fit well within the hypothesis of the functional matrix and that, such fusions between skeletal tissues are secondary, compensatory and mechanically obligatory responses to the prior demands of functionally related nonskeletal tissues and organs.

Animals↗

PubMed1997

Localization and quantification of proliferating cells during rat fracture repair: detection of proliferating cell nuclear antigen by immunohistochemistry.

Bilateral femurs of 12-week-old female Sprague-Dawley rats were fractured, and the fractured femurs were harvested 36 h, 3, 7, 10, and 14 days after the fracture. Localization of cell proliferation in the fracture calluses was investigated using immunohistochemistry with antiproliferating cell nuclear antigen (PCNA) monoclonal antibodies. Thirty-six hours after the fracture, many PCNA-positive cells were observed in the whole callus. The change was not limited to mesenchymal cells at the fracture site where the inflammatory reaction had occurred, but extended in the periosteum along almost the entire femoral diaphysis where intramembranous ossification was initiated. On day 3, periosteal cells or premature osteoblasts in the newly formed trabecular bone during intramembranous ossification still displayed intense staining. On day 7, many premature chondrocytes and proliferating chondrocytes were PCNA positive. Endochondral ossification appeared on days 10 and 14, and the premature osteoblasts and endothelial cells in the endochondral ossification front were stained with anti-PCNA antibodies. Quantification of PCNA-positive cells was carried out using an image analysis computer system, obtaining a PCNA score for each cellular event. The highest score was observed in the periosteum early after the fracture near the fracture site. Immunohistochemistry using anti-PCNA antibodies showed that the distribution of proliferating cells and the degree of cell proliferation varied according to the time lag after the fracture, suggesting the existence of local regulatory factors such as growth factors, and that significant cell proliferation was observed at the beginning of each cellular event.

Animals↗

PubMed1991

Osteochondrosis in the horse--searching for the key to pathogenesis.

This paper reviews current developments in equine osteochondrosis complex and the clinical syndromes associated with it. Although the primary lesion has been defined as a failure of endochondral ossification, its definitive cause is unknown and appears to involve heredity, growth rate, nutrition, mineral imbalance, endocrinological dysfunction and biomechanical trauma. Despite the international importance of osteochondrosis in horses, surprisingly few controlled investigations have been performed on its pathogenesis. The studies that have been conducted suggest that local effects on differentiating growth cartilage are the key to a more complete understanding of the problem. Gaps in the current knowledge include in-depth understanding of the life cycle of chondrocytes in growth cartilage, the process of mineralisation and the use of a standard experimental model for the induction of osteochondrosis. The ultimate goal of osteochondrosis research must be to prevent or reduce the incidence of the condition in horses.

Animal Nutritional Physiological Phenomena↗

PubMed1998

Mechanisms of anterior cruciate ligament neovascularization and ligamentization.

Columbia-Rambouillet cross-bred sheep were used to study the revascularization and ligamentization process of anterior cruciate ligament (ACL) reconstruction over a 6-month period using basic histology, immunohistochemistry, and electron microscopy. The reconstruction technique studied was a quadruple-hamstring, interference screw fixation technique. Further, these specimens, after retrieval at 6, 12, and 26 weeks, were compared with human arthroscopic 'second looks' and with 10 en bloc specimens obtained when a cruciate-sacrificing total knee replacement was performed. The study showed that, with this reconstruction technique, Sharpey's fibers were seen at 6 weeks in both sheep and human specimens. The intratunnel specimens showed proliferative chondrification, then ossification of the matrix. Intra-articular neovascularization, ligamentization, and junction ossification occurred. Myoblasts or smooth muscle cells appear to mediate the ligamentization as evidenced in electron microscopy by proliferate collagen manufacture. These myoblasts were seen in both the healing sheep and human second looks, but not seen in mature ACL grafts or in normal ACLs. At 6 months postoperatively, the sheep ACL reconstruction appeared clinically, histologically, and immunohistochemically indistinguishable from the normal sheep ACL. A correlation of this work with published animal studies in which biomechanical testing was performed and with human 'second looks' would imply that an ACL reconstruction may be vulnerable during this period of neovascularization and ligamentization.

Adult↗

PubMed2006

Insulin-like growth factor-I is essential for embryonic bone development.

Although IGF-I has been identified as an important growth factor for the skeleton, the role of IGF-I on embryonic bone development remains unknown. Here we show that, in IGF-I-deficient (IGF-I(-/-)) mice, skeletal malformations, including short-limbed dwarfism, were evident at days post coitus (dpc) 14.5 to 18.5, accompanied by delays of mineralization in the spinal column, sternum, and fore paws. Reduced chondrocyte proliferation and increased chondrocyte apoptosis were identified in both the spinal ossification center and the growth plate of long bones. Abnormal chondrocyte differentiation and delayed initiation of mineralization was characterized by small size and fewer numbers of type X collagen expressing hypertrophic chondrocytes and lower osteocalcin expression. The Indian hedgehog-PTHrP feedback loop was altered; expression of Indian hedgehog was reduced in IGF-I(-/-) mice in long bones and in the spine, whereas expression of PTHrP was increased. Our results indicate that IGF-I plays an important role in skeletal development by promoting chondrocyte proliferation and maturation while inhibiting apoptosis to form bones of appropriate size and strength.

Animals↗

PubMedDate not supplied

Influence of inoculation sites and tumor cell culture techniques on the phenotype of a mixed cartilage- and bone-producing mouse mammary tumor.

We have previously reported the characterization of an intraperitoneally (IP) transplantable bone-forming MXT tumor. However, the question was unresolved as whether the bone-forming cells originated from either the host animal or from the neoplasm itself. The present work attempts to answer this question by studying the influences of inoculation sites (subcutaneously, SC; intraperitoneally, IP; in the brain, IB; intracranially, ICR) on both the cartilage- and bone-forming tumor phenotypes. Furthermore the influence of cell culture procedures (two- and three- dimensional cultures) on these phenotypes was investigated. SC administered MXT cancer cells never produce bone-forming tumors, suggesting the existence in the dermis of substance(s) inhibitory to the formation of cartilage or bone. On the contrary, our data clearly demonstrate that bone-forming tumors can be obtained by either IP route, in a way which mimics endochondral ossification, or in the brain (IB), a region usually devoid of connective tissue. This observation substantiates the hypothesis according to which the tumor itself is able to produce osseous tissue. Another main finding is the increasing occurrence of skeletal tissues produced by cells proceeding from three-dimensional culture. Finally, ICR and IB tumors exerted a bone-lytic action against the host skull suggesting that tumor cells either produce osteolytic substances (prostaglandins, enzymes) and/or that they contain various cell types exhibiting different properties toward osteogenesis. This model offers new perspectives for studying the mechanisms of both normal and pathologic osteogenesis.

Animals↗