acid-phosphatase and Bone-Diseases--Developmental

Craniometaphyseal dysplasia (CMD) is a rare genetic disorder encompassing hyperostosis of craniofacial bones and metaphyseal widening of tubular bones. Dental abnormalities are features of CMD that have been little discussed in the literature. We performed dentofacial examination of patients with CMD and evaluated consequences of orthodontic movement in a mouse model carrying a CMD knock-in (KI) mutation (Phe377del) in the Ank gene. All patients have a history of delayed eruption of permanent teeth. Analysis of data obtained by cone-beam computed tomography showed significant bucco-lingual expansion of jawbones, more pronounced in mandibles than in maxillae. There was no measurable increase in bone density compared with that in unaffected individuals. Orthodontic cephalometric analysis showed that patients with CMD tend to have a short anterior cranial base, short upper facial height, and short maxillary length. Microcomputed tomography (micro-CT) analysis in homozygous Ank (KI/KI) mice, a model for CMD, showed that molars can be moved by orthodontic force without ankylosis, however, at a slower rate compared with those in wild-type Ank (+/+) mice (p < .05). Histological analysis of molars in Ank (KI/KI) mice revealed decreased numbers of TRAP(+) osteoclasts on the bone surface of pressure sides. Based on these findings, recommendations for the dental treatment of patients with CMD are provided.

Topics: Acid Phosphatase; Animals; Bone Density; Bone Diseases, Developmental; Cephalometry; Cone-Beam Computed Tomography; Craniofacial Abnormalities; Disease Models, Animal; Gene Knock-In Techniques; Humans; Hyperostosis; Hypertelorism; Isoenzymes; Mandible; Maxilla; Mice; Mutation; Osteoclasts; Phenylalanine; Phosphate Transport Proteins; Sequence Deletion; Skull Base; Tartrate-Resistant Acid Phosphatase; Tooth Abnormalities; Tooth Movement Techniques; Vertical Dimension; X-Ray Microtomography

Vertebral and metaphyseal dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases are the hallmarks of the genetic disorder spondyloenchondrodysplasia. We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals and showed that these mutations abolish enzyme function in the serum and cells of affected individuals. Phosphorylated osteopontin, a protein involved in bone reabsorption and in immune regulation, accumulates in serum, urine and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibit an altered cytokine profile and are more potent than matched control cells in stimulating allogeneic T cell proliferation in mixed lymphocyte reactions. These findings shed new light on the role of osteopontin and its regulation by TRAP in the pathogenesis of common autoimmune disorders.

Topics: Acid Phosphatase; Autoimmune Diseases; Autoimmunity; Bone and Bones; Bone Diseases, Developmental; Brain; Calcium; Child; Genetic Predisposition to Disease; Homozygote; Humans; Isoenzymes; Male; Mutation; Osteochondrodysplasias; Osteopontin; Phosphorylation; Radiography; Tartrate-Resistant Acid Phosphatase

We studied ten individuals from eight families showing features consistent with the immuno-osseous dysplasia spondyloenchondrodysplasia. Of particular note was the diverse spectrum of autoimmune phenotypes observed in these individuals (cases), including systemic lupus erythematosus, Sjögren's syndrome, hemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynaud's disease and vitiligo. Haplotype data indicated the disease gene to be on chromosome 19p13, and linkage analysis yielded a combined multipoint log(10) odds (LOD) score of 3.6. Sequencing of ACP5, encoding tartrate-resistant acid phosphatase, identified biallelic mutations in each of the cases studied, and in vivo testing confirmed a loss of expressed protein. All eight cases assayed showed elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature. Our findings reveal a previously unrecognized link between tartrate-resistant acid phosphatase activity and interferon metabolism and highlight the importance of type I interferon in the genesis of autoimmunity.

Topics: Acid Phosphatase; Animals; Autoimmunity; Bone Diseases, Developmental; Cattle; Chromosomes, Human, Pair 19; Female; Gene Expression Regulation; Humans; Inflammation; Interferon Type I; Isoenzymes; Lupus Erythematosus, Systemic; Male; Models, Molecular; Mutation; Mutation, Missense; Phenotype; Sclerosis; Tartrate-Resistant Acid Phosphatase

Craniometaphyseal dysplasia (CMD) is a monogenic human disorder characterized by thickening of craniofacial bones and flaring metaphyses of long bones. Mutations for autosomal dominant CMD have been identified in the progressive ankylosis gene ANKH. Previous studies of Ank loss-of-function models, Ank(null/null) and Ank(ank/ank) mice, suggest that Ank plays a role in the regulation of bone mineralization. However, the mechanism for Ank mutations leading to CMD remains unknown. We generated the first knockin (KI) mouse model for CMD expressing a human mutation (Phe377 deletion) in ANK. Homozygous Ank knockin mice (Ank(KI/KI)) replicate many typical features of human CMD including hyperostosis of craniofacial bones, massive jawbones, decreased diameters of cranial foramina, obliteration of nasal sinuses, fusion of middle ear bones, and club-shaped femurs. In addition, Ank(KI/KI) mice have increased serum alkaline phosphatase and TRACP5b, as reported in CMD patients. Biochemical markers of bone formation and bone resorption, N-terminal propeptide of type I procollagen and type I collagen cross-linked C-terminal telopeptide, are significantly increased in Ank(KI/KI) mice, suggesting increased bone turnover. Interestingly, Ank(KI/KI) bone marrow-derived macrophage cultures show decreased osteoclastogenesis. Despite the hyperostotic phenotype, bone matrix in Ank(KI/KI) mice is hypomineralized and less mature, indicating that biomechanical properties of bones may be compromised by the Ank mutation. We believe this new mouse model will facilitate studies of skeletal abnormalities in CMD at cellular and molecular levels.

Topics: Acid Phosphatase; Alkaline Phosphatase; Animals; Bone Diseases, Developmental; Collagen Type I; Disease Models, Animal; Humans; Isoenzymes; Macrophages; Membrane Proteins; Mice; Mice, Transgenic; Phosphate Transport Proteins; Sequence Deletion; Skull; Tartrate-Resistant Acid Phosphatase

Topics: Acid Phosphatase; Alkaline Phosphatase; Bone Diseases, Developmental; Child, Preschool; Female; Humans; Moyamoya Disease

Topics: Acid Phosphatase; Animal Feed; Animals; Bone Diseases, Developmental; Cartilage; Epiphyses; Histocytochemistry; Hypertrophy; Microscopy, Electron; Orotic Acid; Ossification, Heterotopic; Rats; Tibia

Topics: Acid Phosphatase; Adolescent; Alkaline Phosphatase; Arm; Bone and Bones; Bone Diseases, Developmental; Child; Child, Preschool; Collagen; Diagnosis, Differential; Female; Haversian System; Humans; Infant; Infant, Newborn; Leg; Male; Metabolism, Inborn Errors; Osteitis Deformans; Pelvic Bones; Radiography; Skull; Syndrome