A case of long-term survival of SADDAN treated with growth hormone for marked short stature.

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is a bone dysplasia caused by a pathogenic variant of fibroblast growth factor receptor 3 (FGFR3). Pathogenic variants in FGFR3 also cause thanatophoric dysplasia (TD) and achondroplasia. Although the findings of SADDAN and TD during the fetal and neonatal periods are similar, they differ in their long-term prognoses. We conducted FGFR3 analysis in one male patient because of the difficulty in differentiating SADDAN from TD during the neonatal period. We found that the patient had a pathogenic variant, p. Lys650Met, which was similar to that previously reported in patients with SADDAN. Reports on long-term survival in patient with SADDAN are scarce, and there have been no reports of treatment with GH. We administered GH therapy for a markedly short stature. After treatment, his height increased by 4 cm each year for 4 years, the frequency of hospitalizations due to respiratory failure decreased, and the health improved. FGFR3 analysis is useful for diagnosing SADDAN during the early neonatal period. GH therapy may have contributed to the patient's long-term survival.

Severe growth retardation during carbohydrate restriction in type 1 diabetes mellitus: A case report.

Carbohydrate restriction is not typically recommended for children with type 1 diabetes mellitus (T1DM) because of concerns regarding growth retardation, ketoacidosis, severe hypoglycemia, and dyslipidemia. There is no consensus regarding the effects of carbohydrate restriction on the growth of children with T1DM. However, some previously reported cases of T1DM exhibited growth retardation during carbohydrate restriction, whereas others showed no obvious impairment. A female child with T1DM exhibited severe height growth velocity impairment during carbohydrate restriction in early childhood. Her height standard deviation score (SDS) was 1.12 at the initial T1DM diagnosis (2 yr and 11 mo of age) and -1.33 at 4 yr and 8 mo of age. Her height velocity was only 1.7 cm/yr (SDS -7.02). Discontinuing carbohydrate restriction substantially improved her height growth velocity. Implementing a carbohydrate-restricted diet in children with T1DM can negatively affect height growth velocity.

Connective tissue growth factor promotes chemotaxis of preosteoblasts through integrin α5 and Ras during tensile force-induced intramembranous osteogenesis.

In vertebrates, new bone formation via intramembranous osteogenesis is a critical biological event for development, remodeling, and fracture healing of bones. Chemotaxis of osteoblast lineage cells is an essential cellular process in new bone formation. Connective tissue growth factor (CTGF) is known to exert chemotactic properties on various cells; however, details of CTGF function in the chemotaxis of osteoblast lineage cells and underlying molecular biological mechanisms have not been clarified. The aim of the present study was to evaluate the chemotactic properties of CTGF and its underlying mechanisms during active bone formation through intramembranous osteogenesis. In our mouse tensile force-induced bone formation model, preosteoblasts were aggregated at the osteogenic front of calvarial bones. CTGF was expressed at the osteogenic front, and functional inhibition of CTGF using a neutralizing antibody suppressed the aggregation of preosteoblasts. In vitro experiments using µ-slide chemotaxis chambers showed that a gradient of CTGF induced chemotaxis of preosteoblastic MC3T3-E1 cells, while a neutralizing integrin α5 antibody and a Ras inhibitor inhibited the CTGF-induced chemotaxis of MC3T3-E1 cells. These findings suggest that the CTGF-integrin α5-Ras axis is an essential molecular mechanism to promote chemotaxis of preosteoblasts during new bone formation through intramembranous osteogenesis.

Ten-m/Odz3 regulates migration and differentiation of chondrogenic ATDC5 cells via RhoA-mediated actin reorganization.

Tenascin-like molecule major (Ten-m)/odd Oz (Odz), a type II transmembrane molecule, is well known to modulate neural development. We have reported that Ten-m/Odz3 is expressed in cartilaginous tissues and cells. Actin cytoskeleton and its regulator ras homolog gene family member A (RhoA) are closely associated with chondrogenesis. The present study aimed to evaluate the function and molecular mechanism of Ten-m/Odz3 during chondrogenesis, focusing on RhoA and the actin cytoskeleton. Ten-m/Odz3 was expressed in precartilaginous condensing mesenchyme in mouse limb buds. Ten-m/Odz3 knockdown in ATDC5 induced actin cytoskeleton reorganization and change of cell shape through modulation of RhoA activity and FGF2 expression. Ten-m/Odz3 knockdown suppressed ATDC5 migration and expression of genes associated with chondrogenesis, such as Sox9 and type II collagen, via RhoA. On the other hand, Ten-m/Odz3 knockdown inhibited proliferation of ATDC5 in a RhoA-independent manner. These findings suggest that Ten-m/Odz3 plays an important role in early chondrogenesis regulating RhoA-mediated actin reorganization.

Methionine Enkephalin Suppresses Osteocyte Apoptosis Induced by Compressive Force through Regulation of Nuclear Translocation of NFATc1.

Mechanical stress stimulates bone remodeling, which occurs through bone formation and resorption, resulting in bone adaptation in response to the mechanical stress. Osteocytes perceive mechanical stress loaded to bones and promote bone remodeling through various cellular processes. Osteocyte apoptosis is considered a cellular process to induce bone resorption during mechanical stress-induced bone remodeling, but the underlying molecular mechanisms are not fully understood. Recent studies have demonstrated that neuropeptides play crucial roles in bone metabolism. The neuropeptide, methionine enkephalin (MENK) regulates apoptosis positively and negatively depending on cell type, but the role of MENK in osteocyte apoptosis, followed by bone resorption, in response to mechanical stress is still unknown. Here, we examined the roles and mechanisms of MENK in osteocyte apoptosis induced by compressive force. We loaded compressive force to mouse parietal bones, resulting in a reduction of MENK expression in osteocytes. A neutralizing connective tissue growth factor (CTGF) antibody inhibited the compressive force-induced reduction of MENK. An increase in osteocyte apoptosis in the compressive force-loaded parietal bones was inhibited by MENK administration. Nuclear translocation of NFATc1 in osteocytes in the parietal bones was enhanced by compressive force. INCA-6, which inhibits NFAT translocation into nuclei, suppressed the increase in osteocyte apoptosis in the compressive force-loaded parietal bones. NFATc1-overexpressing MLO-Y4 cells showed increased expression of apoptosis-related genes. MENK administration reduced the nuclear translocation of NFATc1 in osteocytes in the compressive force-loaded parietal bones. Moreover, MENK suppressed Ca2+ influx and calcineurin and calmodulin expression, which are known to induce the nuclear translocation of NFAT in MLO-Y4 cells. In summary, this study shows that osteocytes expressed MENK, whereas the MENK expression was suppressed by compressive force via CTGF signaling. MENK downregulated nuclear translocation of NFATc1 probably by suppressing Ca2+ signaling in osteocytes and consequently inhibiting compressive force-induced osteocyte apoptosis, followed by bone resorption. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.