-
Advances in Clinical and Experimental... Jun 2021Skeletal dysplasias are a heterogeneous group of congenital bone and cartilage disorders with a genetic etiology. The current classification of skeletal dysplasias... (Review)
Review
Skeletal dysplasias are a heterogeneous group of congenital bone and cartilage disorders with a genetic etiology. The current classification of skeletal dysplasias distinguishes 461 diseases in 42 groups. The incidence of all skeletal dysplasias is more than 1 in every 5000 newborns. The type of dysplasia and associated abnormalities affect the lethality, survival and long-term prognosis of skeletal dysplasias. It is crucial to distinguish skeletal dysplasias and correctly diagnose the disease to establish the prognosis and achieve better management. It is possible to use prenatal ultrasonography to observe predictors of lethality, such as a bell-shaped thorax, short ribs, severe femoral shortening, and decreased lung volume. Individual lethal or life-limiting dysplasias may have more or less specific features on prenatal ultrasound. The prenatal features of the most common skeletal dysplasias, such as thanatophoric dysplasia, osteogenesis imperfecta type II, achondrogenesis, and campomelic dysplasia, are discussed in this article. Less frequent dysplasias, such as asphyxiating thoracic dystrophy, fibrochondrogenesis, atelosteogenesis, and homozygous achondroplasia, are also discussed.
Topics: Female; Humans; Infant, Newborn; Osteochondrodysplasias; Osteogenesis Imperfecta; Pregnancy; Receptor, Fibroblast Growth Factor, Type 3; Thanatophoric Dysplasia; Ultrasonography, Prenatal
PubMed: 34019743
DOI: 10.17219/acem/134166 -
Proceedings of the National Academy of... Feb 2021Cartilage is essential throughout vertebrate life. It starts developing in embryos when osteochondroprogenitor cells commit to chondrogenesis, activate a...
Cartilage is essential throughout vertebrate life. It starts developing in embryos when osteochondroprogenitor cells commit to chondrogenesis, activate a pancartilaginous program to form cartilaginous skeletal primordia, and also embrace a growth-plate program to drive skeletal growth or an articular program to build permanent joint cartilage. Various forms of cartilage malformation and degeneration diseases afflict humans, but underlying mechanisms are still incompletely understood and treatment options suboptimal. The transcription factor SOX9 is required for embryonic chondrogenesis, but its postnatal roles remain unclear, despite evidence that it is down-regulated in osteoarthritis and heterozygously inactivated in campomelic dysplasia, a severe skeletal dysplasia characterized postnatally by small stature and kyphoscoliosis. Using conditional knockout mice and high-throughput sequencing assays, we show here that SOX9 is required postnatally to prevent growth-plate closure and preosteoarthritic deterioration of articular cartilage. Its deficiency prompts growth-plate chondrocytes at all stages to swiftly reach a terminal/dedifferentiated stage marked by expression of chondrocyte-specific () and progenitor-specific ( and ) genes. Up-regulation of osteogenic genes (, , and ) and overt osteoblastogenesis quickly ensue. SOX9 deficiency does not perturb the articular program, except in load-bearing regions, where it also provokes chondrocyte-to-osteoblast conversion via a progenitor stage. Pathway analyses support roles for SOX9 in controlling TGFβ and BMP signaling activities during this cell lineage transition. Altogether, these findings deepen our current understanding of the cellular and molecular mechanisms that specifically ensure lifelong growth-plate and articular cartilage vigor by identifying osteogenic plasticity of growth-plate and articular chondrocytes and a SOX9-countered chondrocyte dedifferentiation/osteoblast redifferentiation process.
Topics: Animals; Cartilage, Articular; Cell Differentiation; Cell Lineage; Chondrocytes; Chondrogenesis; Growth Plate; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoblasts; Osteogenesis; SOX9 Transcription Factor
PubMed: 33597301
DOI: 10.1073/pnas.2019152118 -
Cellular and Molecular Life Sciences :... Sep 2022The transcription factor SOX9 is essential for the development of multiple organs including bone, testis, heart, lung, pancreas, intestine and nervous system. Mutations... (Review)
Review
The transcription factor SOX9 is essential for the development of multiple organs including bone, testis, heart, lung, pancreas, intestine and nervous system. Mutations in the human SOX9 gene led to campomelic dysplasia, a haploinsufficiency disorder with several skeletal malformations frequently accompanied by 46, XY sex reversal. The mechanisms underlying the diverse SOX9 functions during organ development including its post-translational modifications, the availability of binding partners, and tissue-specific accessibility to target gene chromatin. Here we summarize the expression, activities, and downstream target genes of SOX9 in molecular genetic pathways essential for organ development, maintenance, and function. We also provide an insight into understanding the mechanisms that regulate the versatile roles of SOX9 in different organs.
Topics: Campomelic Dysplasia; Chromatin; Disorders of Sex Development; Humans; Male; Mutation; Organogenesis; SOX9 Transcription Factor
PubMed: 36114905
DOI: 10.1007/s00018-022-04543-4 -
Indian Journal of Human Genetics Sep 2011
PubMed: 22346005
DOI: 10.4103/0971-6866.92085 -
Connective Tissue Research Jan 2017SOX9 is a pivotal transcription factor in developing and adult cartilage. Its gene is expressed from the multipotent skeletal progenitor stage and is active throughout... (Review)
Review
SOX9 is a pivotal transcription factor in developing and adult cartilage. Its gene is expressed from the multipotent skeletal progenitor stage and is active throughout chondrocyte differentiation. While it is repressed in hypertrophic chondrocytes in cartilage growth plates, it remains expressed throughout life in permanent chondrocytes of healthy articular cartilage. SOX9 is required for chondrogenesis: it secures chondrocyte lineage commitment, promotes cell survival, and transcriptionally activates the genes for many cartilage-specific structural components and regulatory factors. Since heterozygous mutations within and around SOX9 were shown to cause the severe skeletal malformation syndrome called campomelic dysplasia, researchers around the world have worked assiduously to decipher the many facets of SOX9 actions and regulation in chondrogenesis. The more we learn, the more we realize the complexity of the molecular networks in which SOX9 fulfills its functions and is regulated at the levels of its gene, RNA, and protein, and the more we measure the many gaps remaining in knowledge. At the same time, new technologies keep giving us more means to push further the frontiers of knowledge. Research efforts must be pursued to fill these gaps and to better understand and treat many types of cartilage diseases in which SOX9 has or could have a critical role. These diseases include chondrodysplasias and cartilage degeneration diseases, namely osteoarthritis, a prevalent and still incurable joint disease. We here review the current state of knowledge of SOX9 actions and regulation in the chondrocyte lineage, and propose new directions for future fundamental and translational research projects.
Topics: Animals; Campomelic Dysplasia; Cell Differentiation; Chondrocytes; Chondrogenesis; Gene Expression Regulation; Humans; SOX9 Transcription Factor; Transcription, Genetic
PubMed: 27128146
DOI: 10.1080/03008207.2016.1183667 -
Pediatric Radiology Jan 2019Perinatal hypophosphatasia (HPP) is a rare, potentially life-threatening, inherited, systemic metabolic bone disease that can be difficult to recognize in utero and... (Review)
Review
Perinatal hypophosphatasia (HPP) is a rare, potentially life-threatening, inherited, systemic metabolic bone disease that can be difficult to recognize in utero and postnatally. Diagnosis is challenging because of the large number of skeletal dysplasias with overlapping clinical features. This review focuses on the role of fetal and neonatal imaging modalities in the differential diagnosis of perinatal HPP from other skeletal dysplasias (e.g., osteogenesis imperfecta, campomelic dysplasia, achondrogenesis subtypes, hypochondrogenesis, cleidocranial dysplasia). Perinatal HPP is associated with a broad spectrum of imaging findings that are characteristic of but do not occur in all cases of HPP and are not unique to HPP, such as shortening, bowing and angulation of the long bones, and slender, poorly ossified ribs and metaphyseal lucencies. Conversely, absent ossification of whole bones is characteristic of severe lethal HPP and is associated with very few other conditions. Certain features may help distinguish HPP from other skeletal dysplasias, such as sites of angulation of long bones, patterns of hypomineralization, and metaphyseal characteristics. In utero recognition of HPP allows for the assembly and preparation of a multidisciplinary care team before delivery and provides additional time to devise treatment strategies.
Topics: Diagnosis, Differential; Female; Humans; Hypophosphatasia; Infant, Newborn; Pregnancy; Prenatal Diagnosis
PubMed: 30284005
DOI: 10.1007/s00247-018-4239-0 -
Human Mutation Dec 2019Campomelic dysplasia (CD) is an autosomal dominant, perinatal lethal skeletal dysplasia characterized by a small chest and short long bones with bowing of the lower...
Campomelic dysplasia (CD) is an autosomal dominant, perinatal lethal skeletal dysplasia characterized by a small chest and short long bones with bowing of the lower extremities. CD is the result of heterozygosity for mutations in the gene encoding the chondrogenesis master regulator, SOX9. Loss-of-function mutations have been identified in most CD cases so it has been assumed that the disease results from haploinsufficiency for SOX9. Here, we identified distal truncating SOX9 mutations in four unrelated CD cases. The mutations all leave the dimerization and DNA-binding domains intact and cultured chondrocytes from three of the four cases synthesized truncated SOX9. Relative to CD resulting from haploinsufficiency, there was decreased transactivation activity toward a major transcriptional target, COL2A1, consistent with the mutations exerting a dominant-negative effect. For one of the cases, the phenotypic consequence was a very severe form of CD, with a pronounced effect on vertebral and limb development. The data identify a novel molecular mechanism of disease in CD in which the truncated protein leads to a distinct and more significant effect on SOX9 function.
Topics: Campomelic Dysplasia; Cells, Cultured; Chondrocytes; Collagen Type II; Female; Haploinsufficiency; Humans; Pregnancy; Prenatal Diagnosis; SOX9 Transcription Factor; Sequence Deletion; Exome Sequencing
PubMed: 31389106
DOI: 10.1002/humu.23888 -
Current Topics in Developmental Biology 2019SOX transcription factors participate in the specification, differentiation and activities of many cell types in development and beyond. The 20 mammalian family members... (Review)
Review
SOX transcription factors participate in the specification, differentiation and activities of many cell types in development and beyond. The 20 mammalian family members are distributed into eight groups based on sequence identity, and while co-expressed same-group proteins often have redundant functions, different-group proteins typically have distinct functions. More than a handful of SOX proteins have pivotal roles in skeletogenesis. Heterozygous mutations in their genes cause human diseases, in which skeletal dysmorphism is a major feature, such as campomelic dysplasia (SOX9), or a minor feature, such as LAMSHF syndrome (SOX5) and Coffin-Siris-like syndromes (SOX4 and SOX11). Loss- and gain-of-function experiments in animal models have revealed that SOX4 and SOX11 (SOXC group) promote skeletal progenitor survival and control skeleton patterning and growth; SOX8 (SOXE group) delays the differentiation of osteoblast progenitors; SOX9 (SOXE group) is essential for chondrocyte fate maintenance and differentiation, and works in cooperation with SOX5 and SOX6 (SOXD group) and other types of transcription factors. These and other SOX proteins have also been proposed, mainly through in vitro experiments, to have key roles in other aspects of skeletogenesis, such as SOX2 in osteoblast stem cell self-renewal. We here review current knowledge of well-established and proposed skeletogenic roles of SOX proteins, their transcriptional and non-transcriptional actions, and their modes of regulation at the gene, RNA and protein levels. We also discuss gaps in knowledge and directions for future research to further decipher mechanisms underlying skeletogenesis in health and diseases and identify treatment options for skeletal malformation and degeneration diseases.
Topics: Animals; Bone and Bones; Chondrogenesis; Gene Expression Regulation, Developmental; Humans; Mutation; Osteogenesis; SOX Transcription Factors
PubMed: 30902252
DOI: 10.1016/bs.ctdb.2019.01.007