Blomstrand osteochondrodysplasia: three novel cases and histological evidence for heterogeneity

Oostra, Roelof‐Jan; Harten, J.J. van der; Rijnders, W. P. H. A.; Scott, R. K.; Young, Martin; Trump, Dorothy

doi:10.1007/pl00008195

Cited by 45 publications

(32 citation statements)

References 21 publications

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“…35 Histological analysis of the bone-perichondrial ring in Blomstrand fetuses revealed that in contrast to control or FGFR3-mutated fetuses, only cortical/periosteal bone was present and associated with defective bone-perichondrial ring development (personal data). 36 This observation is supported by data obtained in PTHrP and PTHR1 knockout mice 46 -48 and indicates that formation of the bone-perichondrial ring is not similarly affected by FGFR3 and PTHR1 mutations. Further analysis of genetically manipulated mice overexpressing both FGFR3 and PTHR1 genes should help define the specific defects.…”

Section: Discussionsupporting

confidence: 79%

“…In addition, analysis of endochondral growth plate from fetuses with Blomstrand's lethal chondrodysplasia has shown increased bone collar (cortical bone) thickness and/or thickening of subperiosteal ossification overgrowing the growth plate, but no inward growth of bone-perichondrial ring (personal data). 36 Conversely, although not histologically documented, defective boneperichondrial ring formation in patients with Jansen's metaphyseal chondrodysplasia is strongly suggested by the striking widening of the metaphysis associated with an irregular metaphyseal border on X-ray analysis. 35 Thus, PTHR1 mutations in humans, as FGFR3 mutations, are associated with defective perichondrial bone formation in addition to abnormal endochondral ossification.…”

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confidence: 99%

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Parathyroid Hormone Receptor Type 1/Indian Hedgehog Expression Is Preserved in the Growth Plate of Human Fetuses Affected with Fibroblast Growth Factor Receptor Type 3 Activating Mutations

Cormier

Delezoide

Benoist-Lasselin

et al. 2002

The American Journal of Pathology

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The fibroblast growth factor receptor type 3 (FGFR3) and Indian hedgehog (IHH)/parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1) systems are both essential regulators of endochondral ossification. Based on mouse models, activation of the FGFR3 system is suggested to regulate the IHH/PTHR1 pathway. To challenge this possible interaction in humans, we analyzed the femoral growth plates from fetuses carrying activating FGFR3 mutations (9 achondroplasia, 21 and 8 thanatophoric dysplasia types 1 and 2, respectively) and 14 age-matched controls by histological techniques and in situ hybridization using riboprobes for human IHH, PTHR1, type 10 and type 1 collagen transcripts. We show that bone-perichondrial ring enlargement and growth plate increased vascularization in FGFR3-mutated fetuses correlate with the phenotypic severity of the disease. PTHR1 and IHH expression in growth plates, bone-perichondrial rings and vascular canals is not affected by FGFR3 mutations, irrespective of the mutant genotype and age, and is in keeping with cell phenotypes. These results indicate that in humans , FGFR3 signaling does not downregulate the main players of the IHH/PTHR1 pathway. Endochondral bone ossification is a highly regulated process involved in the formation and growth of cartilaginous templates of long bones, vertebrae, and some craniofacial bones. It requires the linear phenotypic progression of undifferentiated mesenchymal cells into hypertrophic chondrocytes and the subsequent replacement of mineralized cartilage matrix by bone.1-4 As part of this process, resting chondrocytes at the growth plate proliferate, then mature and differentiate into hypertrophic chondrocytes and finally undergo apoptosis after mineralization of the surrounding extracellular matrix. Lacunae formed in this way in the mineralized matrix are invaded by blood vessels and bone cells. At each stage, chondrocytes express specific markers including type 2 collagen in the resting, proliferative, and prehypertrophic zones, and type 10 collagen when hypertrophic.In addition to endochondral ossification, development and growth of bones formed via a cartilage model involve a distinct pattern of bone formation, namely perichondrial bone formation, 2,3,5 a process whereby bone is formed outside and around the cartilage anlage. When ossification starts, perichondrial ossification generates the primitive cortical bone (or bone collar) and its associated periosteum, and the bone-perichondrial ring that develops around the growth plate at the cartilage/bone junction. Bone-perichondrial ring (also called ossification groove of Ranvier) 5,6 comprises the bony ring (also called ring of Lacroix) 5,6 covered on the periosteal side by a loose connective tissue that acts as a germinative (cambium) layer, assuring growth in width. Its growth in length is insured by a germinative zone localized at the epiphyseal tip of the ring.Two main systems, namely the fibroblast growth factor receptor type 3 (FGFR3) and the Indian hedgehog (IHH)/

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Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

Parathyroid Hormone Receptor Type 1/Indian Hedgehog Expression Is Preserved in the Growth Plate of Human Fetuses Affected with Fibroblast Growth Factor Receptor Type 3 Activating Mutations

Cormier

Delezoide

Benoist-Lasselin

et al. 2002

The American Journal of Pathology

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“…Loss of PTH1R causes Blomstrand chondrodysplasia, which is characterized by a chondrodysplasia quite similar to what has been FETAL AND NEONATAL MINERAL METABOLISM found in Pth1r null fetal mice (296,489). It is embryonically lethal; therefore, there are no cord blood measurements of calcium, phosphorus, etc.…”

Section: E Human Datamentioning

confidence: 85%

Bone Development and Mineral Homeostasis in the Fetus and Neonate: Roles of the Calciotropic and Phosphotropic Hormones

Kovacs

2014

Physiological Reviews

211

188

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Mineral and bone metabolism are regulated differently in utero compared with the adult. The fetal kidneys, intestines, and skeleton are not dominant sources of mineral supply for the fetus. Instead, the placenta meets the fetal need for mineral by actively transporting calcium, phosphorus, and magnesium from the maternal circulation. These minerals are maintained in the fetal circulation at higher concentrations than in the mother and normal adult, and such high levels appear necessary for the developing skeleton to accrete a normal amount of mineral by term. Parathyroid hormone (PTH) and calcitriol circulate at low concentrations in the fetal circulation. Fetal bone development and the regulation of serum minerals are critically dependent on PTH and PTH-related protein, but not vitamin D/calcitriol, fibroblast growth factor-23, calcitonin, or the sex steroids. After birth, the serum calcium falls and phosphorus rises before gradually reaching adult values over the subsequent 24 -48 h. The intestines are the main source of mineral for the neonate, while the kidneys reabsorb mineral, and bone turnover contributes mineral to the circulation. This switch in the regulation of mineral homeostasis is triggered by loss of the placenta and a postnatal fall in serum calcium, and is followed in sequence by a rise in PTH and then an increase in calcitriol. Intestinal calcium absorption is initially a passive process facilitated by lactose, but later becomes active and calcitriol-dependent. However, calcitriol's role can be bypassed by increasing the calcium content of the diet, or by parenteral administration of calcium.

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“…These Pthr1-null fetuses are globally smaller than wt and display the Pthrp-null phenotype of accelerated endochondral ossification and dysplasia combined with the Hoxa3-or Pth-null phenotype of significant undermineralization of the skeleton [39]. The human equivalent of absence of the PTH1R, Blomstrand chondrodysplasia, shows similar features [46,47].…”

Section: Role Of Pthrp and Pth In Combinationmentioning

confidence: 80%

Bone Development in the Fetus and Neonate: Role of the Calciotropic Hormones

Kovacs

2011

Curr Osteoporos Rep

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During embryonic and fetal development much of the skeleton initiates as a cartilaginous scaffold, which is progressively resorbed and replaced by bone. Endochondral bone formation continues until the growth plates fuse during puberty. At all life stages adequate delivery of mineral is required for the skeleton to achieve and maintain appropriate mineral content and strength. During fetal development the placenta actively transports calcium, phosphorus, and magnesium. Postnatally passive and then active absorption from the intestines becomes the main supply of minerals to the skeleton. Animal and human data indicate that fetal bone development requires parathyroid hormone (PTH) and PTH-related protein but not vitamin D/calcitriol, calcitonin, or (possibly) sex steroids. During the postnatal period, when intestinal calcium absorption becomes an active process, skeletal development begins to depend upon vitamin D/calcitriol but this requirement can be bypassed by increasing the calcium content of the diet or by administering intermittent calcium infusions.

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Blomstrand osteochondrodysplasia: three novel cases and histological evidence for heterogeneity

Cited by 45 publications

References 21 publications

Parathyroid Hormone Receptor Type 1/Indian Hedgehog Expression Is Preserved in the Growth Plate of Human Fetuses Affected with Fibroblast Growth Factor Receptor Type 3 Activating Mutations

Parathyroid Hormone Receptor Type 1/Indian Hedgehog Expression Is Preserved in the Growth Plate of Human Fetuses Affected with Fibroblast Growth Factor Receptor Type 3 Activating Mutations

Bone Development and Mineral Homeostasis in the Fetus and Neonate: Roles of the Calciotropic and Phosphotropic Hormones

Bone Development in the Fetus and Neonate: Role of the Calciotropic Hormones

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