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PubMed1998

Salter-Harris type III epiphyseal fractures of the proximal phalanx.

Of 823 pediatric hand fractures treated between 1981 through 1996, only 11 (1.3%) were Salter-Harris type III fractures of the proximal phalanx. We review the anatomic basis, etiology, age prevalence, treatment, and results of these epiphyseal injuries. The average age at injury was 14.9 years, with a narrow range from 14 years 2 months to 15 years 11 months. Nine of 11 fractures were displaced and treated with open reduction and internal fixation. At an average follow-up of 21 months, 9 of 11 had full joint motion. The other two had minimal loss of motion, and all had normal function and collateral ligament stability. The displacement and size of the epiphyseal fragment, avulsed and rotated by the collateral ligament, are often underestimated by radiographs. We found that anatomic reduction and fixation yielded good results in all displaced fractures. This restores both the stability of the collateral ligament and a smooth articular surface.

Adolescent↗
PubMed1996

An unknown spondylo-meta-epiphyseal dysplasia in sibs with extreme short stature.

In three sibs of Jordanian descent a unique type of severe spondylo-meta-epiphyseal dysplasia results in extreme disproportionate dwarfism. They have a distinct facial appearance with hypotelorism, prognathia, and hypodontia. The limbs are short and the hands and feet stubby. Radiologically, the irregular end plates of the vertebral bodies, the very small and late appearing epiphyseal ossification centres, and the hypoplastic acetabular roofs are most impressive. Histopathologic studies of the growth plate demonstrate characteristic findings with fingerprint-like inclusion bodies in the hypertrophic chondrocytes. This seems to be a distinct, autosomal recessive skeletal dysplasia.

Adolescent↗
PubMed2000

Expression and release of insulin-like growth factor binding proteins in isolated epiphyseal growth plate chondrocytes from the ovine fetus.

Insulin-like growth factor-II (IGF-II) is an autocrine modulator of epiphyseal chondrogenesis in the fetus. The cellular availability of IGFs are influenced by the IGF-binding proteins (IGFBPs). In this study, we investigated the control of expression and release of IGFBPs from isolated epiphyseal growth plate chondrocytes from the ovine fetus by hormones and growth factors implicated in the chondrogenic process. Chondrocytes were isolated from the proliferative zone of the fetal ovine proximal tibial growth plate and maintained in monolayer culture at early passage number. Culture media conditioned by chondrocytes under basal conditions released IGFBPs of 24, 34, and 29 kDa, and a less abundant species of 39-43 kDa that were identified immunologically as IGFBP-4, IGFBP-2, IGFBP-5, and IGFBP-3, respectively. Messenger RNAs encoding each species were identified by Northern blot analysis within chondrocytes, as was mRNA encoding IGFBP-6. Exposure to IGF-I or IGF-II (13 or 26 nM) caused an increase in expression and release of IGFBP-3. The release of IGFBP-2 and IGFBP-5 were also potentiated without changes to steady state mRNA, and for IGFBP-5 this was due in part to a release from the cell membrane in the presence of IGF-II. Insulin (16.7 or 167 nM) selectively increased mRNA and the release of IGFBP-3, while cortisol (1 or 5 microM) inhibited both mRNA and release of IGFBP-2 and IGFBP-5. Transforming growth factor-beta1 (TGF-beta1) (0.1 or 0.2 nM) increased the expression and release of IGFBP-3, and caused an increase in mRNAs encoding IGFBP-2 and IGFBP-5. Neither growth hormone (GH), fibroblast growth factor-2, nor thyroxine (T(4)) had any effect on IGFBP expression or release. The results suggest that IGFBP expression and release within the developing growth plate can be modulated by IGF-II and other trophic factors, thus controlling IGF availability and action.

Animals↗
PubMed2002

Clinical phenotype and molecular diagnosis of multiple epiphyseal dysplasia with relative hip sparing during childhood (EDM2).

We report on a family of 19 individuals over four generations in which 12 members are affected with a variant of multiple epiphyseal dysplasia. Beginning in childhood, the disease leads to pain and stiffness of knees, ankles, elbows and finger joints. Some adult patients repeatedly suffer from free articular bodies resulting in locking of the joint. Finally, affected individuals are prone to the development of early degenerative joint disease. Mutation screening of candidate regions revealed a novel point mutation at position -1 in the COL9A2 exon 3/intron 3 splicing region. This G --> C substitution most probably induces an alteration of the splicing process. Family screening was carried out by both automated sequencing and by digestion of amplicons with BsaWI. We confirmed the nucleotide substitution in eight clinically affected family members as well as in three presymptomatic young children. Electron microscopy showed that the diameter of collagen fibrils from arthroscopically removed free articular bodies of two patients was not obviously different from that of normal articular cartilage. Together with previous reports our results indicate that mutations leading to skipping of exon 3 within the COL3 domain of the alpha2-chain of collagen type IX may be relatively common in patients with a special subtype of multiple epiphyseal dysplasia (MED) in which the hips are not markedly affected at early age (EDM2). In these patients and their families, mutation screening of the candidate regions may help to confirm the diagnosis, lead to appropriate advice for lifestyle and well based genetic counseling.

Adult↗
PubMed1986

Syndrome of short stature, microcephaly, mental retardation, and multiple epiphyseal dysplasia--Lowry-Wood syndrome.

We describe a brother and a sister with a syndrome of short stature, microcephaly, mental retardation, and multiple epiphyseal dysplasia. The parents were normal. This appears to be the second example of the syndrome first described by Lowry and Wood [1975] in two boys who had epiphyseal dysplasia, short stature, microcephaly, and nystagmus; one of these patients was mildly mentally retarded. The Lowry-Wood syndrome probably is an autosomal recessive trait.

Bone and Bones↗
PubMed1992

Anthropometric studies in five children and their mother with a severe form multiple epiphyseal dysplasia.

We report on a form of multiple epiphyseal dysplasia with striking acromelic shortness in a woman and five of her ten children. The somatometric and metacarpo-phalangeal pattern profile of the affected individual showed short limb dwarfism and shortness of all the tubular bones of the hand. Epiphyseal irregularities and shortness of the 4th metatarsal bones were outstanding. The disorder showed a dominant and probably autosomal pattern of inheritance with variability of expression. The measurement of metacarpo-phalangeal profiles allowed an objective and quantitative assessment of brachydactyly. In the family reported here, there was a clear discrepancy between the severity of shortness of hands and feet and the severity of shortness of stature. This family also illustrates the effects of a single gene in a large kindred, therefore describing the range and variability of a phenotype not otherwise available.

Anthropometry↗
PubMed1993

Spondylo-meta-epiphyseal dysplasia (SMED), short limb-hand type: a congenital familial skeletal dysplasia with distinctive features and histopathology.

We report on a "new" severe short-limb bone dysplasia which can be labeled descriptively a spondylo-meta-epiphyseal dysplasia. The 3 patients were born to 2 unrelated Sepharadic Jewish families and a Puerto Rican family. Clinical abnormalities include small stature with short limbs including short hands, a short nose with wide nasal bridge and wide nostrils, a long philtrum, ocular hypertelorism, retro/micrognathia, and a narrow chest. Radiological abnormalities include platyspondyly, short tubular bones with very abnormal metaphyses and epiphyses beyond early infancy, short ribs, and a typical evolution of bony changes over time. Chondroosseous morphology and ultrastructure document sparse matrix and degenerating chondrocytes surrounded by dense amorphous material in the 1 patient studied. Consanguinity is present in 1 family. In addition to the described patient, 2 other short-limb sibs, who did not survive infancy, were born into this family. Even in the absence of any photographic or radiologic documentation of these other 2 infants, autosomal recessive mode of inheritance seems probable.

Bone Diseases, Developmental↗
PubMed2003

Familial multiple epiphyseal dysplasia due to a matrilin-3 mutation: further delineation of the phenotype including 40 years follow-up.

In this study, we followed-up the family with bilateral hereditary micro-epiphyseal dysplasia (BHMED) originally described by Elsbach [1959: J Bone Joint Surg [Br] 41-B:514-523]. Clinical re-examination of all available family members resulted in further delineation of the clinical and radiological phenotype, which is distinct from common multiple epiphyseal dysplasia (MED). Linkage analysis excluded EDM1, EDM2, and EDM3 as candidate genes. Linkage and mutation analysis of matrilin-3 (MATN-3) revealed a new pathogenic mutation confirming that BHMED is indeed a distinct disease entity among MED and MED-like disorders.

Adolescent↗
PubMed2003

Autosomal recessive multiple epiphyseal dysplasia with homozygosity for C653S in the DTDST gene: double-layer patella as a reliable sign.

Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene result in a family of skeletal dysplasias, which comprise lethal (achondrogenesis type 1B and atelosteogenesis type 2) and non-lethal conditions (diastrophic dysplasia and recessive multiple epiphyseal dysplasia (rMED)). The most frequent mutation is R279W, which in a homozygous state results in rMED with bilateral clubfoot, MED, and "double layered" patella. We describe three patients with rMED caused by a previously unreported homozygous mutation in the DTDST gene. The three patients (from two families) were born to healthy, non-consanguineous parents. All developed signs of hip dysplasia in early childhood and two had episodes of recurrent patella dislocation. Two underwent bilateral total hip replacements at ages 13 and 14 years. The feet, external ears, and palate were normal. Stature was normal in all cases. Radiographs showed dysplastic femoral heads, mild generalized epiphyseal dysplasia, abnormal patella ossification, and normal hands and feet. Direct sequence analysis of genomic DNA demonstrated a homozygous 1984T > A (C653S) change in the DTDST gene in all patients. The clinically normal parents were heterozygous for the change. This is the first description of a homozygous C653S mutation of the DTDST gene. Hip dysplasia and patella hypermobility dominates the otherwise mild phenotype. These patients further expand the range of causative mutations in the DTD skeletal dysplasia family.

Adolescent↗
PubMed2005

Novel COL9A3 mutation in a family with multiple epiphyseal dysplasia.

Multiple epiphyseal dysplasia (MED) is a common skeletal dysplasia characterized by mild to moderate short stature, early-onset of osteoarthritis (OA) mainly in the hip and knee joints, and abnormally small and/or irregular epiphyses. MED is clinically and genetically heterogeneous. Six causative genes of MED have been reported, including type IX collagen genes (COL9A1, COL9A2, COL9A3). All the type IX collagen mutations previously reported cause exon skipping that loses the COL3 domain. Here we have identified a novel COL9A3 mutation co-segregating in a three-generation family with MED. The mutation (IVS3 + 5G > A) was speculated to lose the COL3 domain by skipping of exon 3, which was confirmed by in vitro analysis. The patients were of normal height and had minimal complaints with phenotypes being more severe in male patients. The radiographic phenotypes of the patients were relatively milder than those of previously reported cases, and were indistinguishable to common, idiopathic OA.

Adult↗
PubMed2005

Fate of the hypertrophic chondrocyte: microenvironmental perspectives on apoptosis and survival in the epiphyseal growth plate.

The goal of this review is to examine the fate of the hypertrophic chondrocyte in the epiphyseal growth plate and consider the impact of the cartilage microenvironment on cell survival and apoptosis. Early investigations pointed to a direct role of the hypertrophic chondrocyte in osteogenesis. The terminally differentiated cells were considered to undergo a dramatic change in shape, size, and phenotype, and assume the characteristics of an osteoblast. While some studies have supported the notion of transdifferentiation, much of the evidence in favor of reprogramming epiphyseal chondrocytes is circumstantial and based on microscopic evaluation of cells that are present at the chondro-osseous junction. Although these investigations provided a novel perspective on endochondral bone formation, they were flawed by the failure to consider the importance of stem cells in osseous tissue formation. Subsequent studies indicated that many, if not all, of the cells of the cartilage plate die through the induction of apoptosis. With respect to agents that mediate apoptosis, at the chondro-osseous junction, solubilization of mineral and hydrolysis of organic matrix constituents by septoclasts generates high local concentrations of ions, peptides, and glycans, and secreted matrix metalloproteins. Individually, and in combination, a number of these agents serve as potent chondrocyte apoptogens. We present a new concept: hypertrophic cells die through the induction of autophagy. In the cartilage microenvironment, combinations of local factors cause chondrocytes to express an initial survival phenotype and oxidize their own structural macromolecules to generate ATP. While delaying death, autophagy leads to a state in which cells are further sensitized to changes in the local microenvironment. One such change is similar to ischemia reperfusion injury, a condition that leads to tissue damage and cell death. In the growth cartilage, an immediate effect of this type of injury is sensitization to local apoptogens. These two concepts (type II programmed cell death and ischemia reperfusion injury) emphasize the importance of the local microenvironment, in particular pO(2), in directing chondrocyte survival and apoptosis.

Animals↗
PubMed2002

Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) constitute a bone dysplasia family, which is both genetically and phenotypically heterogeneous. The disease spectrum ranges from mild MED, which manifests with pain and stiffness in the joints and delayed and irregular ossification of the epiphyses, to the more severe PSACH, which is characterized by marked short stature, deformity of the legs, and ligamentous laxity. PSACH is almost exclusively caused by mutations in cartilage oligomeric matrix protein (COMP) whereas various forms of MED are caused by mutations in the genes encoding COMP, type IX collagen (COL9A1, COL9A2, and COL9A3), matrilin-3 (MATN3), and solute carrier member 26, member 2 gene (SLC26A2). In this review we discuss specific disease-causing mutations and the clustering of these mutations in functionally and structurally important regions of the respective gene products, genotype to phenotype correlations, and the diagnostic relevance of mutation screening in these osteochondrodysplasias.

Achondroplasia↗
PubMed2004

Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia.

Multiple epiphyseal dysplasia (MED) is a common skeletal dysplasia characterized by joint pain and stiffness, delayed and irregular ossification of epiphyses, and early-onset osteoarthritis. Six genes responsible for MED have been identified, including COMP, COL9A1, COL9A2, COL9A3, DSTDT and MATN3. MATN3 encodes matrilin-3, a cartilage-specific extracellular matrix protein. To date, seven different MATN3 mutations have been identified; all are located within the beta-sheet regions of the von Willebrand factor type A (vWFA) domain, which is encoded by exon 2. We examined MATN3 mutations in27 Japanese MED patients who were possibly autosomal dominant inheritance and had been excluded for COMP mutations. Ten of them had a positive family history. We examined all eight exons of MATN3 by PCR and direct sequencing from genomic DNA. We have identified four missense mutations in eight unrelated families; two are novel, and two have been characterized previously. Like previously characterized MATN3 mutations, those identified in this study are clustered within exon 2, specifically in and around the 2nd beta-sheet region of the vWFA domain (aa. 120-127). Contrary to the previous assumption that the MATN3 mutation in MED is confined to the beta-sheet regions, one novel mutation (p.F105S) is located outside the beta-sheet region, within an alpha-helix region.

Adolescent↗
PubMed1994

Effects of tiludronate on bone mass, structure, and turnover at the epiphyseal, primary, and secondary spongiosa in the proximal tibia of growing rats after sciatic neurectomy.

To evaluate the effects of tiludronate on the mass, structure, and turnover of cancellous bone regions in immobilized rat tibiae, we performed a 4 week dosing experiment. The right hindlimbs of 84 Sprague-Dawley rats (5 weeks old) wee neurectomized or sham operated. Animals were assigned to seven groups (n = 12 each); group 1 was sham operated, and groups 2-7 were neurectomized. Groups 1 and 2 were given vehicle only (distilled water), and groups 3, 4, and 5 were given tiludronate orally at doses of 25, 50, and 100 mg/kg body weight (BW)/day, respectively, throughout the experimental period. Group 6 was given 100 mg/kg BW/day of the agent for the first 2 weeks only, and group 7 received vehicle only for the first 2 weeks and then 100 mg/kg BW/day of the agent for the last 2 weeks. After tetracycline labeling was performed, the right tibiae were removed from the animals and processed to yield undecalcified sections. Histomorphometry was performed in the epiphyseal, primary, and secondary spongiosa of the proximal tibia. In group 2, trabecular bone volume (BV/TV) and trabecular number (Tb.N) were significantly decreased in the primary and secondary spongiosae, but this did not occur in the epiphyseal spongiosa. Osteoid surface (OS/BS) was decreased and osteoclast surface (Oc.S/BS) was increased in the secondary spongiosa. Tiludronate increased BV/TV and Tb.N in the primary spongiosa by reducing the values for the parameters of osteoclast surface (Oc.S/BS) and osteoclast number (Oc.N/BS). Osteoid surface in this region was not decreased by the agent. In groups 4 and 5, tiludronate prevented bone loss in the secondary spongiosa by reducing both OS/BS and Oc.S/BS. In group 6, BV/TV in the primary spongiosa was maintained at the level of group 1, but Oc.S/BS and Oc.N/BS were elevated. In the secondary spongiosa, bone mass was preserved and the reduction in these parameters was maintained. In group 7, however, BV/TV was increased in the primary spongiosa as a result of a reduction in osteoclastic resorption; in the secondary spongiosa, however, BV/TV was decreased and trabecular turnover was not reduced at the end of the experiment in these growing animals. Mineral apposition rates were not reduced by tiludronate. This study clearly demonstrated that this agent prevented immobilization bone loss by inhibiting resorption.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed2007

Development of the terminally differentiated state sensitizes epiphyseal chondrocytes to apoptosis through caspase-3 activation.

The maturation of epiphyseal chondrocytes is accompanied by dramatic changes in energy metabolism and shifts in proteins concerned with the induction of apoptosis. We evaluated the role of mitochondria in this process by evaluating the membrane potential (Delta psi m) of chondrocytes of embryonic tibia and the epiphyseal growth plate. We observed that there was a maturation-dependent change in fluorescence, indicating a fall in the Delta psi m. The level of mitochondrial Bcl-2 was decreased during maturation, while in the same time period there was an obvious increase in Bax levels in the mitochondrial fraction of the terminally differentiated chondrocytes. Bcl(xL), another anti-apoptotic protein, was also robustly expressed in the mitochondrial fraction, but its expression was not dependent on the maturation status of the chondrocytes. We found that caspase-3 was present throughout the growth plate and in hypertrophic cells in culture. We blocked caspase-3 activity and found that alkaline phosphatase staining and mineral formation was decreased, and the cells had lost their characteristic shape. Moreover, we noted that the undifferentiated cells were insensitive to elevated concentrations of inorganic phosphate (Pi). It is concluded that during hypertrophy, the change in membrane potential, the increased binding of a pro-apoptotic protein to mitochondria, and the activation of caspase-3 serve to prime cells for apoptosis. Only when the terminally differentiated chondrocytes are challenged with low levels of apoptogens there is activation of apoptosis.

Animals↗
PubMedDate not supplied

High-resolution magnetic resonance imaging of normal porcine cartilaginous epiphyseal maturation.

The aim of this study was to determine whether high-resolution magnetic resonance (MR) imaging could differentiate epiphyseal and articular cartilage in the cartilaginous epiphysis and demonstrate its developmental changes. T1- and T2-weighted (T1W and T2W) spin-echo sequences at 50-mm field of view (FOV) of hip joints were obtained from 14 piglets (newborn to 6 months). Subsequently, high-resolution MR images (15-mm FOV) of a biopsy core of the proximal femoral cartilaginous epiphysis were correlated with histology. Newborn cartilaginous epiphysis demonstrated homogeneous signal intensity on T1W and T2W imaging with abundant cartilage canals. From 2 weeks of age, the cartilaginous epiphysis showed a diminution of cartilage canals, with three zones evident on T2W imaging consisting of a low-signal middle zone separating two higher signal zones. Histologic evaluation demonstrated four distinct morphologic laminas with a decrease in overall cartilage thickness with age. The laminas were not as well defined in the newborn compared with the older piglets. No simple correlation was found between the MR zonal pattern and the morphological laminas on histology. No distinct demarcation between the articular cartilage and epiphyseal cartilage was present. MR can visualize cartilage canals and demonstrate changes in the cartilaginous epiphysis that occur with maturation. What component of the cartilaginous epiphysis that accounts for the MR differences seen between newborn and older piglets remains unclear.

Animals↗
PubMed1994

A large family with features of pseudoachondroplasia and multiple epiphyseal dysplasia: exclusion of seven candidate gene loci that encode proteins of the cartilage extracellular matrix.

We have identified a large family with a dominantly inherited chondrodysplasia characterized by a waddling gait, short limbs, and early onset osteoarthritis. The radiographic presentation resembles pseudoachondroplasia in childhood and multiple epiphyseal dysplasia in adults. Electron microscopic examination of cartilage reveals accumulation of material within the rough endoplasmic reticulum similar to that seen in pseudoachondroplasia and the Fairbank type of multiple epiphyseal dysplasia. By linkage analysis, we have excluded the genes for aggrecan, decorin, hexabrachion (tenascin), type II procollagen, the alpha 1 chain of type XI procollagen, the alpha 1 chain of type IX procollagen, and link protein, candidate genes that encode structural components of the cartilage extracellular matrix, as the disease locus for this disorder.

Abnormalities, Multiple↗
PubMed1979

Bone formation in cartilage produced by transplanted epiphyseal chondrocytes.

Chondrocytes were isolated from rat epiphyseal cartilage, cultured in vitro, and exposed to exogenous tracers which accumulated in their lysosomes. The cells were then injected into the posterior tibial muscle of animals from the same outbred strain, where they reconstructed calcifying hyaline cartilage. The mineralization of the tissue was followed by ingrowth of blood capillaries from the host bed. Macrophage-like cells surrounding the vessels phagocytized degenerated chondrocytes and unmineralized matrix, whereas multinucleated chondroclasts removed some of the mineralized cartilage matrix. Mesenchyme-like cells accompanying the invading vessels attached to the remaining septa of calcified cartilage matrix and developed into osteoblasts depositing bone matrix on the surface of these septa. The apparent lack of inherent tracer labeling of the lysosomes in the different bone cells indicate that they were derived from the host. No signs of transformation of chondrocytes into bone cells were observed. When isolated rat epiphyseal chondrocytes were injected into the wall of the hamster cheek pouch, calcifying cartilage was reconstructed without signs of subsequent ossification. Transplantation of cartilage reconstructed in the hamster into the dorsal muscles of rats was, however, followed by formation of bone by a sequence analogous to that described above. Such an osteogenetic response was also obtained when the cartilage had been devitalized before transplantation. These experiments show that calcified cartilage, developing in or grafted into an intramuscular site, is able to induce and serve as a substrate for endochondral bone formation, similar to that occurring during normal development. They further indicate that bone induction by calcified cartilage does not require the presence of living chondrocytes.

Animals↗