Dentoalveolar Defects of Hypophosphatasia are Recapitulated in a Sheep Knock-In Model.

Hypophosphatasia (HPP) is the inherited error-of-metabolism caused by mutations in ALPL, reducing the function of tissue-nonspecific alkaline phosphatase (TNAP/TNALP/TNSALP). HPP is characterized by defective skeletal and dental mineralization and is categorized into several clinical subtypes based on age of onset and severity of manifestations, though premature tooth loss from acellular cementum defects is common across most HPP subtypes. Genotype-phenotype associations and mechanisms underlying musculoskeletal, dental, and other defects remain poorly characterized.

Low bone mass and impaired fracture healing in mouse models of Trisomy21 (Down syndrome).

Individuals with Down syndrome (DS), the result of trisomy of human chromosome Hsa21 (Ts21), present with an array of skeletal abnormalities typified by altered craniofacial features, short stature and low bone mineral density (BMD). While bone deficits progress with age in both sexes, low bone mass is more pronounced in DS men than women and osteopenia appears earlier. In the current study, the reproductive hormone status (FSH, LH, testosterone) of 17 DS patients (males, ages range 19-52 years) was measured.

Hyaline cartilage differentiation of fibroblasts in regeneration and regenerative medicine.

Amputation injuries in mammals are typically non-regenerative; however, joint regeneration is stimulated by BMP9 treatment, indicating the presence of latent articular chondrocyte progenitor cells. BMP9 induces a battery of chondrogenic genes in vivo, and a similar response is observed in cultures of amputation wound cells. Extended cultures of BMP9-treated cells results in differentiation of hyaline cartilage, and single cell RNAseq analysis identified wound fibroblasts as BMP9 responsive.

Skeletal response to whole body vibration and dietary calcium and phosphorus in growing pigs.

The quality and strength of the skeleton is regulated by mechanical loading and adequate mineral intake of calcium (Ca) and phosphorus (P). Whole body vibration (WBV) has been shown to elicit adaptive responses in the skeleton, such as increased bone mass and strength. This experiment was designed to determine the effects of WBV and dietary Ca and P on bone microarchitecture and turnover.

Genetic engineering a large animal model of human hypophosphatasia in sheep.

The availability of tools to accurately replicate the clinical phenotype of rare human diseases is a key step toward improved understanding of disease progression and the development of more effective therapeutics. We successfully generated the first large animal model of a rare human bone disease, hypophosphatasia (HPP) using CRISPR/Cas9 to introduce a single point mutation in the tissue nonspecific alkaline phosphatase (TNSALP) gene (ALPL) (1077 C > G) in sheep. HPP is a rare inherited disorder of mineral metabolism that affects bone and tooth development, and is associated with muscle weakness.

A canine in vitro model for evaluation of marrow-derived mesenchymal stromal cell-based bone scaffolds.

Tissue engineered bone grafts based on bone marrow mesenchymal stromal cells (MSCs) are being actively developed for craniomaxillofacial (CMF) applications. As for all tissue engineered implants, the bone-regenerating capacity of these MSC-based grafts must first be evaluated in animal models prior to human trials. Canine models have traditionally resulted in improved clinical translation of CMF grafts relative to other animal models.

In-vitro characterization of canine multipotent stromal cells isolated from synovium, bone marrow, and adipose tissue: a donor-matched comparative study.

Background: The dog represents an excellent large animal model for translational cell-based studies. Importantly, the properties of canine multipotent stromal cells (cMSCs) and the ideal tissue source for specific translational studies have yet to be established. The aim of this study was to characterize cMSCs derived from synovium, bone marrow, and adipose tissue using a donor-matched study design and a comprehensive series of in-vitro characterization, differentiation, and immunomodulation assays.