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Biomedical subjects

David L Glaser

Publications and source records attributed to David L Glaser.

7 recordsLinked to original sources
PubMed2006

A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G --> A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.

Activin Receptors, Type I↗
PubMed2006

Arthroscopy effectively treats ganglion cysts of the shoulder.

UNLABELLED: In the hands of an experienced arthroscopist, arthroscopic decompression of a spinoglenoid notch cyst can lead to resolution of a patient's symptoms and complete functional recovery. In our study, we hypothesized that patients with a spinoglenoid notch cyst who were treated arthroscopically would have return to near normal function of their shoulders and that the outcomes for patients with a spinoglenoid notch cyst and associated labral tears would be no different than the outcomes for patients with a spinoglenoid notch cyst without associated labral tears. We retrospectively evaluated 18 consecutive patients who were treated arthroscopically for a spinoglenoid notch cyst. Nine had isolated arthroscopic decompression, and nine arthroscopic decompression with a labral repair. We used the validated American Shoulder and Elbow Society (ASES) and University of Pennsylvania (Penn) shoulder scores to evaluate patients' outcomes. We found improvements in the postoperative ASES and Penn shoulder scores for all outcomes measured including pain, satisfaction, and function. However, there were no differences in outcome when comparing the group that had decompression with the group that had decompression and labral repair for an associated superior labral anterior posterior tear. LEVEL OF EVIDENCE: Therapeutic study, Level III (retrospective cohort study). See the Guidelines for Authors for a complete description of levels of evidence.

Adolescent↗
PubMed2005

Tendon healing in interleukin-4 and interleukin-6 knockout mice.

Cytokines have been shown to play an important role in tendon and ligament healing by regulating cellular differentiation and activity. The majority of studies that have investigated the role of cytokines in tendon and ligament healing have added them to injured tissue and assessed their effect. Because the efficacy of exogenously applying cytokines is dependent upon many factors such as the correct dosage, timing, and frequency, conflicting results are often reported. To avoid these factors, this study used transgenic mice with knockouts of interleukin-4 (IL4 -/-) and interleukin-6 (IL6 -/-) to investigate their role in tendon healing. Because of the reported roles of both of these cytokines in inflammation and fibroplasia, it was hypothesized that the order of organizational, geometric, and mechanical properties would be (greatest to least) injured IL6 -/-, injured control, and injured IL4 -/- mice. In addition, it was hypothesized that specific cytokines would be upregulated in each knockout group, but not compensate for the lack of IL-4 or IL-6. Mechanical and organizational properties of injured tendons from IL6 -/- mice were inferior to that of control and IL4 -/- mice despite the upregulation of the pro-inflammatory cytokine TNF-alpha. Temporal levels of IL-10 and IL-13 in the IL4 -/- mice resulted in comparable and even superior properties when compared to CTL mice. This study shows that IL-6 could not be compensated for and plays an important role in tendon healing. This study also supports the use of this animal model to further investigate tendon healing.

Animals↗
PubMed2003

Stromal cells of fibrodysplasia ossificans progressiva lesions express smooth muscle lineage markers and the osteogenic transcription factor Runx2/Cbfa-1: clues to a vascular origin of heterotopic ossification?

Fibrodysplasia ossificans progressiva (FOP) is a rare heritable genetic disorder, which is characterized pathologically by sporadic episodes of explosive growth of mesenchymal cells in skeletal muscle followed by cellular differentiation to heterotopic bone through an endochondral process. This study examined the histological origin and differentiation state of stromal cells in early FOP lesions and investigated the association between the phenotype of these FOP cells and bone formation. Interestingly, FOP lesional stromal cells were found to display characteristics of the smooth muscle (SM) cell lineage and are therefore potentially of vascular origin. These cells co-express multiple SM lineage markers along with multiple proteins associated with bone formation including the obligate osteogenic transcription factor Runx2/Cbfa-1. It is hypothesized that the stromal cells of early FOP lesions may be locally recruited vascular cells or cells of the bone marrow stroma and that these cells maintain the potential (given the correct environmental stimuli) to differentiate along an endochondral ossification pathway.

Biopsy↗
PubMed2003

In vivo somatic cell gene transfer of an engineered Noggin mutein prevents BMP4-induced heterotopic ossification.

BACKGROUND: The formation of the skeleton requires inductive signals that are balanced with their antagonists in a highly regulated negative feedback system. Inappropriate or excessive expression of BMPs (bone morphogenetic proteins) or their antagonists results in genetic disorders affecting the skeleton, such as fibrodysplasia ossificans progressiva. BMP signaling mediated through binding to its receptors is a critical step in the induction of abnormal ossification. Therefore, we hypothesized that engineering more effective inhibitors of this BMP-signaling process may lead to the development of therapies for such conditions. METHODS: BMP4-induced heterotopic ossification was used as a model for testing the ability of the BMP antagonist Noggin to block de novo bone formation, either by local or systemic delivery. Since Noggin naturally acts locally, a Noggin mutein, hNOGDeltaB2, was engineered and was shown to circulate systemically, and its ability to block heterotopic ossification was tested in a mouse model with use of adenovirus-mediated somatic cell gene transfer. RESULTS: A mouse model of BMP4-induced heterotopic ossification was developed. Local delivery of wild-type NOG inhibited heterotopic ossification, but systemic administration was ineffective. In contrast, systemic delivery of the adenovirus encoding hNOGDeltaB2 resulted in systemic levels that persisted for more than two weeks and were sufficient to block BMP4-induced heterotopic ossification. CONCLUSIONS: BMP4-induced heterotopic ossification can be prevented in vivo either by local delivery of wild-type Noggin or after somatic cell gene transfer of a Noggin mutein, hNOGDeltaB2. Furthermore, the data in the present study provide proof of concept that a naturally occurring factor can be engineered for systemic delivery toward a desirable pharmacological outcome. CLINICAL RELEVANCE: Blocking bone formation is clinically relevant to disorders of heterotopic ossification in humans, such as fibrodysplasia ossificans progressiva. Furthermore, development of BMP antagonists as therapeutic agents may provide modalities for the treatment of other pathologic conditions that arise from aberrant expression of BMPs and/or from a lack of their antagonists.

Adenoviridae↗
PubMedDate not supplied

Heterotopic ossification.

Heterotopic ossification, the formation of bone in soft tissue, requires inductive signaling pathways, inducible osteoprogenitor cells, and a heterotopic environment conducive to osteogenesis. Little is known about the molecular pathogenesis of this condition. Research into two rare heritable and developmental forms, fibrodysplasia ossificans progressiva and progressive osseous heteroplasia, has provided clinical, pathologic, and genetic insights. In fibrodysplasia ossificans progressiva, overexpression of bone morphogenetic protein 4 and underexpression of multiple antagonists of this protein highlight the potential role of a potent morphogenetic gradient. Research on fibrodysplasia ossificans progressiva also has led to the identification of the genetic cause of progressive osseous heteroplasia: inactivating mutations in the alpha subunit of the gene coding for the stimulatory G protein of adenylyl cyclase. Better understanding of the complex developmental and molecular pathology of these disorders may lead to more effective strategies to prevent and treat other, more common forms of heterotopic ossification.

Adolescent↗