Our studies have established that loss-of-function mutations in the Wnt signaling antagonist SFRP4 (Secreted Frizzled Related Protein 4) cause Pyle disease, a rare skeletal disease characterized by limb deformity. Pyle disease can also present with a number of dental conditions, including tooth decay and taurodontism. Aside from the sparse clinical descriptions of the tooth anomalies seen in Pyle disease, the role of Sfrp4 in teeth has not been investigated. Here we show that in adult mouse incisors, Sfrp4 is expressed in the mesenchymal and epithelial compartments and their derivatives as well in the developing apex of the molar roots, pulp, odontoblasts, and periodontal ligament. We report that Sfrp4 deletion in mice leads to markedly shorter incisors, with reduced dentin mineral apposition and enamel volume. In addition, we find that Sfrp4 deletion leads to a reduction in the root length and bifurcation height of the developing molars, both features of taurodontism. Rodent incisors grow continuously during the animal's lifetime, thanks to the maintenance and interactions of epithelial (EpSCs) and mesenchymal stem cells (MSCs) at their apex. As such, the mouse incisor is a powerful tool for studying adult stem cells, their interactions, and their regulation. Using this model, we found that Sfrp4 deletion leads to a significant decrease in Gli1+ MSCs and in Ki67 levels in mesenchymal transient amplifying cells and preameloblasts. Sfrp4-null incisors have reduced type I collagen levels and altered amelogenin and Mmp20 secretion accompanied by changes in the enamel maturation stages. When incisor growth is accelerated by preventing occlusion through tooth clipping, Sfrp4-null incisors grow significantly slower than wt incisors do. Our study suggests a key role for Sfrp4 in the fast-growing teeth (incisors) and developing molars, where there is a need to balance the maintenance and differentiation of the stem cell niche.

Osteoclasts are essential for bone resorption, playing a crucial role in skeletal development, homeostasis, and remodeling. Their differentiation depends on the RANK receptor encoded by the TNFRSF11A gene, with defects in this gene linked to osteoclast-poor sclerosing skeletal dysplasias. This report presents a 37-yr-old woman with normal height, valgus deformities that were treated surgically, frequent fractures, scoliosis, mildly elevated BMD, sclerotic diaphyseal bone, and metaphyseal widening. Initially suspected of having dysosteosclerosis, her diagnosis shifted toward Pyle disease due to the valgus deformity and prominent metaphyseal widening and translucency. Genetic analysis identified 2 pathogenic TNFRSF11A variants: a nonsense mutation c.1093G>T, p.(Glu365*) and a frameshift mutation c.1266_1268delinsCC, p.(Leu422Phefs*104). Thus, genetic and clinical assessment converged on the diagnosis of a mild form of dysosteosclerosis. Both mutations introduced premature stop codons but escaped complete nonsense-mediated decay, potentially permitting residual protein function. Analysis of patient-derived osteoclasts cultured on glass surfaces showed partial differentiation. However, in vitro resorptive function was strongly impaired, which was clinically reflected by reduced serum concentration of the bone resorption marker CTx. Despite this impairment, the retained residual resorptive function likely explains the patient's relatively mild clinical presentation. These findings underscore the complex genetic interactions that affect osteoclast function, leading to a spectrum of phenotypes in osteoclast-related bone disorders.

Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly (MDMHB) is an ultra-rare skeletal dysplasia caused by heterozygous intragenic RUNX2 duplications, comprising either exons 3 to 5 or exons 3 to 6 of RUNX2. In this study, we describe a 14-year-old Belgian boy with metaphyseal dysplasia with maxillary hypoplasia but without brachydactyly. Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance. Exome sequencing led to the identification of a de novo heterozygous tandem duplication within RUNX2, encompassing exons 3 to 7. This duplication is larger than the ones previously reported in MDMHB cases since it extends into the C-terminal activation domain of RUNX2. We review previously reported cases with MDMHB and highlight the resemblance of this disorder with Pyle disease, which may be explained by intersecting molecular pathways between RUNX2 and sFRP4. This study expands our knowledge on the genotypic and phenotypic characteristics of MDMHB and the role of RUNX2 in rare bone disorders.

Pyle's disease (PD) is a rare autosomal recessive metaphyseal dysplasia with approximately 30 reported cases and has recently gained interest due to its association with specific genes. While most cases are diagnosed in childhood and are asymptomatic, we present the case of a 39-year-old woman who presented to the Emergency Department with left knee pain, patellar fracture, and "Erlenmeyer flask" deformity. Retrospective review of imaging studies and medical history revealed the symmetric and systemic nature of the skeletal disorder, confirming the diagnosis of PD. Familiarity with this disease is crucial for optimal patient management, and the radiologist plays a crucial role in its diagnosis.

The biosynthetic gene cluster responsible for the production of C2-asymmetric 16-membered dilactones, including pyrenophorol and its derivatives, was discovered through genome mining of polyketides from a sponge-derived fungus. The biosynthetic pathway of the pyrenophorol dilactones was subsequently elucidated. A distinctive flavoenzyme PylE was identified to catalyze the isomerization of the 4-alcohol-2,3-unsaturated moiety within the dilactone scaffold, resulting in the formation of a 1,4-diketone. Further insights into the catalytic mechanism of PylE were obtained through mutagenesis experiments combined with molecular docking.