The skeletal attachment of tendons--tendon "entheses"

Tendon entheses can be classed as fibrous or fibrocartilaginous according to the tissue present at the skeletal attachment site. The former can be "bony" or "periosteal", depending on whether the tendon is directly attached to bone or indirectly to it via the periosteum. At fibrocartilaginous entheses, the uncalcified fibrocartilage dissipates collagen fibre bending and tendon narrowing away from the tidemark; calcified fibrocartilage anchors the tendon to the bone and creates a diffusion barrier between the two. Where there are additional fibrocartilaginous specialisations in the tendon and/or bone next to the enthesis, an "enthesis organ" is created that reduces wear and tear. Little attention has been paid to bone at entheses, despite the obvious bearing this has on the mechanical properties of the interface and the clinical importance of avulsion fractures. Disorders at entheses (enthesopathies) are common and occur in conditions such as diffuse idiopathic skeletal hyperostosis and the seronegative spondyloarthropathies. They are also commonly seen as sporting injuries such as tennis elbow and jumper's knee.     

A TGF-beta-inducible cell adhesion molecule, betaig-h3, is downregulated in melorheostosis and involved in osteogenesis

Melorheostosis is a rare bone disease characterized by linear hyperostosis and associated soft tissue abnormalities. The skin overlying the involved bone lesion is often tense, shiny, erythematous, and scleodermatous. In order to look for genes differentially expressed between the normal and involved skin, we cultured skin fibroblasts from the skin lesions of several afflicted patients, and identified differentially expressed genes by reverse dot-blot hybridization. We found that the genes human TGF-beta-induced gene product (betaig-h3), osteoblast-specific factor 2, osteonectin, fibronectin, and type I collagen were all downregulated in the affected skin fibroblasts, with betaig-h3 the most significantly affected. The expression of betaig-h3 was induced by TGF-beta in both affected and normal fibroblasts. In an effort to determine the mechanism of bone and skin abnormalities in melorheostosis, we made recombinant betaig-h3. Both immobilized and soluble recombinant betaig-h3 proteins with or without an RGD motif inhibited bone nodule formation of osteoblasts in vitro. Taken together, our results suggest that altered expression of several adhesion proteins may contribute to the development of hyperostosis and concomitant soft tissue abnormalities of melorheostosis, with betaig-h3 in particular playing an important role in osteogenesis.     

Porotic hyperostosis: representative of a childhood condition

Porotic hyperostosis is currently considered to be one of several stress markers available for assessing the health and nutritional status of past human populations. The present study questions one of the basic assumptions underlying its use; that is, that the occurrence of porotic hyperostosis in an individual represents an episode of anemia that was current or had occurred within a relatively short period prior to death. A synthesis of data from a Romano-British site Poundbury Camp, anthropological and clinical studies, and information on bone physiology suggests that lesions of porotic hyperostosis seen in adults are most probably representative of a childhood episode of anemia. Lesions seen in adults are the result of bone changes occurring in the growth period that have not undergone complete remodelling. This viewpoint has implications for future interpretation of data on porotic hyperostosis obtained from skeletal collections.     

Recognition of sickle cell anemia in skeletal remains of children

The present study discusses in detail the osteological changes associated with sickle cell anemia in children and their importance in differential diagnosis. Posterior calcaneal and specific articular surface disruptive metacarpal lesions are diagnostic for sickle cell anemia. Calvarial thickening, tibial and femoral cortical bone thickening, and bowing are of more limited utility in differential diagnosis. Granular osteoporosis, pelvic demineralization and rib broadening are nonspecific. Localized calvarial “ballooning,” previously not described, may have diagnostic significance. Bone marrow hyperplastic response (porotic hyperostosis) in sickle cell anemia produces minimal radiologic changes contrasted with that observed in thalassemia and blood loss/hemolytic phenomenon. Two other issues, the osteological criteria for discriminating among the anemias and the purported relationship between porotic hyperostosis and iron deficiency anemia, are also discussed. There is sufficient information to properly diagnose the four major groups of anemias, and further, to establish that iron deficiency is only indirectly associated with porotic hyperostosis. The hyperproliferative bone marrow response (manifest as porotic hyperostosis) to blood loss or hemolysis exhausts iron stores, resulting in secondary iron deficiency. Am J Phys Anthropol 104:213–226, 1997. © 1997 Wiley-Liss, Inc.     

Amino acid analysis of bone from a possible case of prehistoric iron deficiency anemia from the American southwest

It is possible that dietary conditions can result in the production of abnormal bone protein. For example, a heavily maize-dependent diet could be deficient in one or more essential amino acids necessary to normal human biochemistry and consequently necessary for normal bone protein synthesis. Amino acid analysis of bone tissues, thus, could provide a useful diagnostic tool in paleopathology. To test this potential we have compared the amino acid analyses of bone samples from a prehistoric Southwest Indian child exhibiting porotic hyperostosis with samples taken from (1) two children's skeletons lacking bone lesions but from the same area and time, (2) a modern child who died from accidental causes, and (3) adult human compact bone. Analytical results of the nonpathological prehistoric specimens were virtually identical to that of the modern infant, indicating remarkable preservation of bone protein. The pathological bone sample differed from the three control specimens by having as much as 25% less of those amino acids containing hydroxyl group and acidic side chains. We interpret the amino acid profile for the diseased child as indicating the presence of a greater proportion of helical protein (or less noncollagenous protein) as well as a lowered degree of hydroxylation of proline and lysine. One explanation for our data is that protein biosynthesis is altered in the child exhibiting porotic hyperostosis, and either some proteins important in the early phases of mineralization are not produced in sufficient quantity, or some necessary enzyme cofactors (e.g., dietary ferrous ions) are missing. We conclude that our data are compatible with, but do not prove, the hypothesis that the porotic hyperostosis exhibited by the Southwest Indian child is the result of iron deficiency anemia.     

Involvement of bone tissue in chicken infected with the myeloblastic MAV 2-0 virus. Generalized cortical hyperostosis

An affection of osseous tissue appears in chicken have been injected at the embryonic state with retrovirus myeloblastic MAV 2-0 in solution. The structural lesions are different from these examined in human or murine osteopetrosis, considered to be an general cortical hyperostosis.     

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.     

Porotic hyperostosis: a new perspective.

Porotic hyperostosis is a paleopathologic condition that has intrigued researchers for over a century and a half. It is now generally accepted that anemia, most probably an iron deficiency anemia, is the etiologic factor responsible for lesion production. Although there can be a number of factors involved in the development of iron deficiency anemia, a dietary explanation has often been invoked to explain the occurrence of porotic hyperostosis in past human skeletal populations. In fact, porotic hyperostosis has been referred to as a "nutritional" stress indicator. Traditionally those groups with a higher incidence of porotic hyperostosis have been considered to be less successful in adapting to their environment or more nutritionally disadvantaged than other groups. A new perspective is emerging that is challenging previous views of the role of iron in health and disease, thus having profound implications for the understanding of porotic hyperostosis. There is a new appreciation of the adaptability and flexibility of iron metabolism; as a result it has become apparent that diet plays a very minor role in the development of iron deficiency anemia. It is now understood that, rather than being detrimental, hypoferremia (deficiency of iron in the blood) is actually an adaptation to disease and microorganism invasion. When faced with chronic and/or heavy pathogen loads individuals become hypoferremic as part of their defense against these pathogens, thus increasing their susceptibility to iron deficiency anemia. Within the context of this new perspective porotic hyperostosis is seen not as a nutritional stress indicator, but as a indication that a population is attempting to adapt to the pathogen load in its environment.     

Localization of the gene for sclerosteosis to the van Buchem disease-gene region on chromosome 17q12-q21.

Sclerosteosis is an uncommon, autosomal recessive, progressive, sclerosing, bone dysplasia characterized by generalized osteosclerosis and hyperostosis of the skeleton, affecting mainly the skull and mandible. In most patients this causes facial paralysis and hearing loss. Other features are gigantism and hand abnormalities. In the present study, linkage analysis in two consanguineous families with sclerosteosis resulted in the assignment of the sclerosteosis gene to chromosome 17q12-q21. This region was analyzed because of the recent assignment to this chromosomal region of the gene causing van Buchem disease, a rare autosomal recessive condition with a hyperostosis similar to sclerosteosis. Because of the clinical similarities between sclerosteosis and van Buchem disease, it has previously been suggested that both conditions might be caused by mutations in the same gene. Our study now provides genetic evidence for this hypothesis.     

Anemia and childhood mortality: latitudinal patterning along the coast of pre-Columbian Peru

Hrdlicka ([1914] Smithson. Inst. Misc. Collect. 61:1-69) reported that pre-Columbian skeletal material from the coastal lowland Andean region exhibited a high frequency of porotic hyperostosis, a pathological condition of bone that generally is thought to indicate childhood anemia. While subsequent studies tended to reinforce this conclusion, factors implicated in the condition have yet to be fully explored in the region as a whole. This study explores regional and intravalley variation as one step in establishing biocultural variables that increase the apparent risk of childhood anemia. The study sample includes 1,465 individuals: 512 from Peruvian collections housed at the Field Museum of Natural History, and 953 from systematically excavated contexts from Moquegua, Peru. Environmental stressors, such as parasites and disease, rather than specific dietary practices were found to be more likely associated with childhood anemia in these coastal Andean samples. The study supports cribra orbitalia as an earlier expression of porotic hyperostosis and suggests that porotic hyperostosis, as recorded here, cannot be easily dismissed as a result of cranial shape modification. No clear temporal patterns were observed. Finally, the study establishes that comparing data for children and adults can reveal the relative association between childhood anemia and mortality. Childhood mortality associated with anemia was elevated where the presence of tuberculosis or tuberculosis-like conditions was more common and the presence of water-borne pathogens was negligible. In contrast, those buried at lower altitudes, closer to the coast, and consuming mainly marine resources were less likely to die in childhood with anemia than in the other contexts studied.     

Vertebral lesions in a titanosaurian dinosaur from the Lower-Upper Cretaceous of Brazil

In this paper we describe macroscopically two types of bone lesions on a caudal vertebra of an indeterminate titanosaur recovered from the Lower-Upper Cretaceous (Albian-Cenomanian) Açu Formation in the Potiguar Basin, Brazil. The first type of lesion corresponds to cystic lesions on cranial and caudal joint surfaces of the vertebral body, which are identified as subchondral cysts. The second type of lesion corresponds to an irregular bone overgrowth located on longitudinal ligament insertion points. This ossification can be associated with an axial spondyloarthropathy or diffuse idiopathic skeletal hyperostosis (DISH). Bone overgrowth on vertebrae is well documented in the dinosaur fossil record, whereas this is only the second case recorded of subchondral cysts.     

Arginine vasopressin increases the rate of protein synthesis in isolated perfused adult rat heart via the V1 receptor

The effect of daidzein on cortical bone in vitro was investigated. Femoral-diaphyseal tissues obtained from elderly female rats were cultured for 24 h in Dulbecco's modified Eagle's medium (high glucose, 4.5%) supplementation with antibiotics and bovine serum albumin. The experimental cultures contained 10-7 to 10-5 M daidzein. The presence of daidzein (10-6 and 10-5 M) caused a significant increase of alkaline phosphatase activity, deoxyribonucleic acid (DNA) and calcium contents in bone tissues. This effect was equal to that of genistein (10-6 and 10-5 M). Daidzein (10-5 M) or genistein (10-5 M)-induced increase of calcium content and alkaline phosphatase activity in bone tissues was completely prevented by cycloheximide (10-6 M), an inhibitor of protein synthesis. Anabolic effect of daidzein and genistein on bone components was equal to that of 17-estradiol (10-8 M). The effect of isoflavohoids was not enhanced by the addition of 17-estradiol. The combination of daidzein and genistein did not have an additive effect. These findings indicate that daidzein has an anabolic effect on bone metabolism in tissue culture in vitro, and that this effect is equal to genistein effect. Isoflavonoids may stimulate bone formation and mineralization.     

Van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12-q21.

Van Buchem disease (hyperostosis corticalis generalisata; OMIM 239100 [http://www3.ncbi.nlm.nih. gov:80/htbin-post/Omim/dispmim?239100]) is an autosomal recessive disorder characterized by hyperostosis of the skull, mandible, clavicles, ribs, and diaphyseal cortices of the long bones. The most striking clinical features are the enlargement of the jaw and the thickness of the skull, which may lead to facial nerve palsy, hearing loss, and optic atrophy. Increased formation, by osteoblasts, of qualitatively normal bone has been proposed as the underlying pathological mechanism, but the molecular defect is unknown. We studied 11 van Buchem patients and their highly inbred family, who live in The Netherlands in a small ethnic isolate, that had a common ancestor approximately 9 generations ago. A genomewide search with highly polymorphic microsatellite markers showed linkage to marker D17S1299 on chromosome 17q12-21 (maximum LOD score of 8.82 at a recombination fraction [straight theta] of .01). Analysis of additional markers from that region delineated a candidate region of <1 cM, between markers D17S1787 and D17S934. Interestingly, the only marker not showing recombination with the disease locus was an intragenic marker of the thyroid-hormone receptor alpha1 (THRA1) gene, which generated a LOD score of 12.84 at straight theta=.00. Since thyroid hormones are known to stimulate bone resorption, the THRA1 gene might be involved in the etiology and pathogenesis of van Buchem disease. Unraveling the underlying mechanism for this disorder could contribute to the understanding of the regulatory processes conditioning bone density and the underlying pathological processes.     

Hyperostosis frontalis interna: a Nubian case

The aim of this article is to present evidence of hyperostosis frontalis interna in a 40-year-old female recovered from a Meroitic cemetery (ca. 300 A.D.) in Sudanese Nubia. A review of the literature concerning the Morgagni-Stewart-Morel (MSM) syndrome suggests that the changes in the skull fragment are consistent with this diagnosis. This case is the earliest example of the condition so far reported, and therefore, in archaeological time and space, this is a disease not only of modern civilization, but also of antiquity. Current endocrinological reports suggest that the hyperostosis is the hallmark of a generalized disorder of bone metabolism, with increased androgens, prolactin, and somatotropins. Hyperostosis frontalis interna is the central feature of a syndrome first described over 200 years ago by the early pathologist Giovanni Batistta Morgagni, professor of anatomy at Padua (1719). He found thickening of the internal tables of the frontal bones in association with virilism and obesity. Stewart (1928) and Morel (1929) independently added several neuropsychiatric problems to this complex and questioned the possibility of an endocrine basis for the syndrome.     

Familial infantile cortical hyperostosis in a large Canadian family.

Infantile cortical hyperostosis is a rare proliferative bone disease affecting infants under the age of 6 months. In 1961 a large family of French-Canadian origin in which 14 children in three generations were affected was described. Since then 20 new cases have been found in this family. This is the largest familial aggregation of this disease reported in the literature to date. On the basis of the findings in this pedigree, the familial form of the disease appears to be transmitted by a single autosomal dominant gene with incomplete penetrance and variable expressivity.     

A possible case of melorheostosis from antiquity

An unusual case of discontinuous hard tissue hyperostosis is described in a 25-30–year-old female dating between 4000 and 5500 BP from northern Chile. This specimen was one of 104 individuals examined from the Morro-1 site, which is known to represent the Chinchorro culture. The only other reported case from antiquity dates to 500 AD (Lester [1969] J. Bone Joint Surg. [Am.] 49:142–143). A review and comparison of this case to the medical literature supports a diagnosis of melorheostosis. Differential diagnosis is presented with the ruling out of nonspecific manifestations of osteomyelitis/periostitis as the most likely alternative diagnosis. © 1995 Wiley-Liss, Inc.     

Pseudofracture: An Acute Peripheral Tissue Trauma Model

Following trauma there is an early hyper-reactive inflammatory response that can lead to multiple organ dysfunction and high mortality in trauma patients; this response is often accompanied by a delayed immunosuppression that adds the clinical complications of infection and can also increase mortality.^1-9 Many studies have begun to assess these changes in the reactivity of the immune system following trauma.^10-15 Immunologic studies are greatly supported through the wide variety of transgenic and knockout mice available for in vivo modeling; these strains aid in detailed investigations to assess the molecular pathways involved in the immunologic responses.^16-21The challenge in experimental murine trauma modeling is long term investigation, as fracture fixation techniques in mice, can be complex and not easily reproducible.^22-30This pseudofracture model, an easily reproduced trauma model, overcomes these difficulties by immunologically mimicking an extremity fracture environment, while allowing freedom of movement in the animals and long term survival without the continual, prolonged use of anaesthesia. The intent is to recreate the features of long bone fracture; injured muscle and soft tissue are exposed to damaged bone and bone marrow without breaking the native bone.The pseudofracture model consists of two parts: a bilateral muscle crush injury to the hindlimbs, followed by injection of a bone solution into these injured muscles. The bone solution is prepared by harvesting the long bones from both hindlimbs of an age- and weight-matched syngeneic donor. These bones are then crushed and resuspended in phosphate buffered saline to create the bone solution.Bilateral femur fracture is a commonly used and well-established model of extremity trauma, and was the comparative model during the development of the pseudofracture model. Among the variety of available fracture models, we chose to use a closed method of fracture with soft tissue injury as our comparison to the pseudofracture, as we wanted a sterile yet proportionally severe peripheral tissue trauma model. ³¹Hemorrhagic shock is a common finding in the setting of severe trauma, and the global hypoperfusion adds a very relevant element to a trauma model. ^32-36 The pseudofracture model can be easily combined with a hemorrhagic shock model for a multiple trauma model of high severity. ³⁷Download video file.^{(62M, mov)}     

First report of Troglotrema acutum (Digenea, Troglotrematidae) in the Eurasian badger Meles meles in the Iberian Peninsula and presumptive lesions caused in the host

A total of 109 badger Meles meles skulls from Catalonia (north-eastern Iberian Peninsula) were studied for helminths. The tremadode Troglotrema acutum is reported here for the first time in the Eurasian badger in the Iberian Peninsula and southern Europe. Three methodologies were used to detect this trematode: an examination for surface lesions, axial computed tomography and fresh skull dissection. The damage caused in the affected skulls is described, along with details regarding the use of computed tomography to detect hyperostosis, leakage in the sinus structure and bone surface erosion in the affected skulls.     

Effects of fluoride ingestion on white-tailed deer (Odocoileus virginianus)

The effects of the addition of 25 or 50 ppm fluoride (F), as sodium fluoride (NaF), to the rations of 5-mo-old male white-tailed deer were similar to those observed in domestic cattle fed similar amounts of fluoride. The ingestion of 50 ppm F for 2 yr resulted in the accumulation of over 7,000 ppm F in bone ash. Accumulation of fluoride in antlers was extensive and occurred more rapidly than in skeletal tissue. Fluoride ingestion resulted in lesions on the developing incisors that were similar, but not identical to those seen in other species. Increased molar wear in the deer fed 50 ppm F was minimal, and no gross pathology of the mandible was observed. Only mild hyperostosis of the long bones was evident.     

Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density

Bone is a dynamic tissue that is subject to the balanced processes of bone formation and bone resorption. Imbalance can give rise to skeletal pathologies with increased bone density. In recent years, several genes underlying such sclerosing bone disorders have been identified. The LDL receptor-related protein 5 (LRP5) gene has been shown to be involved in both osteoporosis-pseudoglioma syndrome and the high-bone-mass phenotype and turned out to be an important regulator of peak bone mass in vertebrates. We performed mutation analysis of the LRP5 gene in 10 families or isolated patients with different conditions with an increased bone density, including endosteal hyperostosis, Van Buchem disease, autosomal dominant osteosclerosis, and osteopetrosis type I. Direct sequencing of the LRP5 gene revealed 19 sequence variants. Thirteen of these were confirmed as polymorphisms, but six novel missense mutations (D111Y, G171R, A214T, A214V, A242T, and T253I) are most likely disease causing. Like the previously reported mutation (G171V) that causes the high-bone-mass phenotype, all mutations are located in the aminoterminal part of the gene, before the first epidermal growth factor-like domain. These results indicate that, despite the different diagnoses that can be made, conditions with an increased bone density affecting mainly the cortices of the long bones and the skull are often caused by mutations in the LRP5 gene. Functional analysis of the effects of the various mutations will be of interest, to evaluate whether all the mutations give rise to the same pathogenic mechanism.