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Biomedical subjects

K M Lyons

Publications and source records attributed to K M Lyons.

At least 19 recordsLinked to original sources
PubMed2001

The type I BMP receptor BmprIB is essential for female reproductive function.

Maintenance of female reproductive competence depends on the actions of several hormones and signaling factors. Recent reports suggest roles for bone morphogenetic proteins (BMPs) in early stages of folliculogenesis. A role for the type I BMP receptor BmprIB as a regulator of ovulation rates in sheep has been described recently, but little is known about the roles of BMP signaling pathways in other aspects of reproductive function. We report here that BMPRIB is essential for multiple aspects of female fertility. Mice deficient in BmprIB exhibit irregular estrous cycles and an impaired pseudopregnancy response. BmprIB mutants produce oocytes that can be fertilized in vitro, but defects in cumulus expansion prevent fertilization in vivo. This defect is associated with decreased levels of aromatase production in granulosa cells. Unexpectedly, levels of mRNA for cyclooxygenase 2, an enzyme required for cumulus expansion, are increased. BmprIB mutants also exhibit a failure in endometrial gland formation. The expression of BmprIB in uterine linings suggests that these defects are a direct consequence of loss of BMP signaling in this tissue. In summary, these studies demonstrate the importance of BMP signaling pathways for estrus cyclicity, estradiol biosynthesis, and cumulus cell expansion in vivo and reveal sites of action for BMP signaling pathways in reproductive tissues.

Animals↗
PubMed2001

Vocal fold mucosal tears: maintaining a high clinical index of suspicion.

Vocal fold mucosal tears have been discussed in the literature rarely, although they are not uncommon clinically. Disruptions in the epithelium usually follow trauma that may result from voice abuse and/or misuse, coughing, and other causes. A high index of suspicion is necessary to avoid missing vocal fold mucosal tears, and strobovideolaryngoscopy is indispensable in making the diagnosis. A brief period of complete voice rest is the standard of care and appears to be helpful in avoiding adverse sequelae and advancing the healing process, but there are no scientific studies to confirm its efficacy. Mucosal tears may heal completely or may be followed by the development of vocal fold masses, scar, and permanent dysphonia.

Adult↗
PubMed2001

Bone morphogenetic protein-3 is a negative regulator of bone density.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-beta) superfamily. Many BMPs are produced in bone and show osteogenic activity, suggesting that they may be determinants of bone mass. BMP3 was originally purified from bone as osteogenin, which induces osteogenic differentiation. Recombinant BMP3 (rhBMP3) has no biological activity, however, leaving its role in skeletal growth unclear. Here we show that BMP3 is an antagonist of osteogenic BMPs: BMP3 dorsalizes Xenopus laevis embryos, inhibits BMP2-mediated induction of Msx2 and blocks BMP2-mediated differentiation of osteoprogenitor cells into osteoblasts. These effects appear to be mediated through activin receptors. Finally, Bmp3(-/-) mice have twice as much trabecular bone as wild-type littermates, indicating that BMP3, the most abundant BMP in adult bone, is a negative determinant of bone density.

Activin Receptors↗
PubMed2001

The molecular control of upper extremity development: implications for congenital hand anomalies.

As the molecular aspects of limb development are being unraveled, more of the congenital anomalies seen by hand surgeons in the clinical setting will have an identifiable molecular basis. The majority of the data available regarding the molecular development of the upper extremity have come from experimental animal studies, specifically the mouse and chicken. These findings are being discovered by either direct surgical and molecular manipulation of the developing limb or by production of mice deficient in specific genes. Relatively few specific human mutations that cause limb abnormalities have been identified. Hand surgeons should be aware of the basic molecular pathways controlling limb development because they are in a unique position to be able to identify patients with such deformities. In turn, detailed clinical descriptions of congenital anomalies affecting the upper extremity will advance the understanding of the cellular events controlled by the molecular pathways of limb development. This review describes the general molecular basis of limb development and correlates it with disease processes affecting the upper extremity.

Animals↗
PubMed2001

Müllerian inhibiting substance signaling uses a bone morphogenetic protein (BMP)-like pathway mediated by ALK2 and induces SMAD6 expression.

Signal reception of Müllerian inhibiting substance (MIS) in the mesenchyme around the embryonic Müllerian duct in the male is essential for regression of the duct. Deficiency of MIS or of the MIS type II receptor, MISRII, results in abnormal reproductive development in the male due to the maintenance of the duct. MIS is a member of the transforming growth factor-beta (TGFbeta) superfamily of secreted protein hormones that signal through receptor complexes of type I and type II serine/threonine kinase receptors. To investigate candidate MIS type I receptors, we examined reporter construct activation by MIS. The bone morphogenetic protein (BMP)-responsive Tlx2 and Xvent2 promoter-driven reporter constructs were stimulated by MIS but the TGFbeta/activin-induced p3TP-lux or CAGA-luc reporter constructs were not. The induction of Tlx2-luc was dependent upon the kinase activity of MISRII and was blocked by a dominant negative truncated ALK2 (tALK2) receptor but not by truncated forms of the other BMP type I receptors ALK1, ALK3, or ALK6. MIS induced activation of a Gal4DBD-Smad1 but not a Gal4DBD-Smad2 fusion protein. This activation could also be blocked by tALK2. The BMP-induced inhibitory Smad, Smad6, was up-regulated by MIS endogenously in Leydig cell-derived lines and is expressed in male but not female Müllerian duct mesenchyme. ALK6 has been shown to function as an MIS type I receptor. Investigation of the pattern of ALK2, MISRII, and ALK6 in the developing urogenital system demonstrated overlapping expression of ALK2 and MISRII in the mesenchyme surrounding the duct while ALK6 was observed only in the epithelium. Examination of ALK6 -/- male animals revealed no defect in duct regression. The reporter construct analysis, pattern of expression of the receptors, and analysis of ALK6-deficient animals suggest that ALK2 is the MIS type I receptor involved in Müllerian duct regression.

Activin Receptors, Type I↗
PubMed2001

BMP3: to be or not to be a BMP.

BACKGROUND: Bone morphogenetic proteins (BMPs) are osteogenic but also have diverse functions during development. BMP3 is a major component of osteogenin, which has osteogenic activity. However, recombinant BMP3 (rhBMP3) has no apparent osteogenic function, raising the possibility that BMP3 has no bone-inducing activity or that the recombinant material is not properly processed. To resolve this apparent discrepancy, we utilized a retroviral system to study the effects of BMP3 in vitro. In addition, we generated Bmp3-deficient mice to elucidate the function of BMP3 in vivo. METHODS: Retroviral as well as mammalian expression constructs were utilized to express BMP3 and to create BMP3 conditioned medium. Alkaline phosphatase (ALP) activity and transcriptional response assays were used to monitor the ability of BMP3 to elicit either a BMP-like or a transforming growth factor beta (TGF-beta)/activin-like response in osteoblastic cell lines. Finally, mice deficient in BMP3 were generated to investigate BMP3 function in vivo. RESULTS: BMP3 was unable to induce an osteogenic response in W-20-17, MC3T3-E1, or C3H10T1/2 cells, although all three cell lines were responsive to BMP2. However, BMP3 inhibited responsiveness to BMP2 in these assays, suggesting that BMP3 antagonizes BMP2 signaling. This inhibition did not occur through inhibition of binding of BMP2 to its receptors. BMP3 activated the TGF-beta/activin-pathway in these cells, suggesting that BMP3 exerts its inhibiting effects by activating a signaling pathway that antagonizes the BMP pathway. To examine the potential functional consequences of BMP3 action, Bmp3-/- mice, which lack BMP3, were generated. On an outbred genetic background, Bmp3-/- mice are viable and show no obvious skeletal phenotype as embryos or neonates. However, adult mice exhibit twice as much trabecular bone as do their wild-type littermates. This observation is consistent with our in vitro observations suggesting that BMP3 is an inhibitor of osteogenesis in vitro and of bone formation in vivo. CONCLUSIONS: BMP3 is an inhibitor of osteogenic BMPs and can signal through a TGF-beta/activin pathway. The ability of BMP3 to antagonize BMP2 activity may thus be a consequence of competition for signaling components common to TGF-beta/activin and BMP pathways. BMP3, the most abundant BMP in demineralized bone, may therefore play an essential role as a modulator of the activity of osteogenic BMPs in vivo. CLINICAL RELEVANCE: Therapies to accelerate bone healing usually utilize administration of exogenous BMP either in recombinant form or by gene therapy approaches. It is conceivable that the potency of osteogenic BMPs would be increased by inhibiting the activation of antagonistic signaling pathways or by increasing levels of rate-limiting signaling components shared by both BMP and TGF-beta/activin pathways.

Animals↗
PubMed2001

Autoimmune inner ear disease: steroid and cytotoxic drug therapy.

The goal of this study was to assess the effects of immunosuppressive therapy on hearing in patients with presumed autoimmune sensorineural hearing loss (AISNHL) and a Western blot assay positive for a 68 kD inner ear antigen. To achieve this objective, we conducted a retrospective review of 39 such patients who were treated with either a steroid alone or with a steroid followed by a cytotoxic agent. Pure-tone average (PTA) at 500 Hz, 1 kHz, 2 kHz, and 3 kHz, and speech discrimination scores (SDS) were used as objective measures of outcome. At the completion of treatment, 23 of the 39 patients (59.0%) exhibited a positive response to therapy. The steroid-only responders (n = 6) tended to demonstrate a greater improvement in PTA (14.8 vs 4.5 dB), while the cytotoxic-agent responders (n = 17) had a significantly greater improvement in SDS (26.2 vs 6.9%; p < 0.01). We conclude that most patients with AISNHL benefit from immunosuppressive therapy and that cytotoxic medications appear to improve SDS, even in some patients who have not responded to corticosteroid therapy.

Adolescent↗
PubMed2000

Transient production of bone morphogenetic protein 2 by allogeneic transplanted transduced cells induces bone formation.

The aim of this study was to evaluate the use of transplantation of genetically modified allogeneic cells as a method to induce bone formation. In this study, we infected a murine osteoprogenitor cell line with a retroviral vector containing the human bone morphogenic protein 2 (BMP2) gene. Transduced cells exhibited more alkaline phosphatase activity than cells treated with any of the tested doses of recombinant human BMP2 protein (rhBMP2). The transduced cells were suspended in a collagen solution and injected into the quadriceps muscle in immunocompetent outbred mice. Radiographic and histological examinations demonstrate abundant ectopic bone formation in 85% of the transplanted animals (n = 13). PCR and Southern blot analysis for the puromycin resistance gene revealed that the transplanted cells were detectable for up to 1 week, but not at later time points. None of the animals developed tumors. Our results suggest that allogeneic BMP2-expressing transduced cells may have therapeutic potential for enhancing new bone formation. This model also provides a simple, inexpensive, and sensitive assay for evaluating in vivo the osteoinductive potentials of secreted proteins without the requirement of protein purification or the use of immunodeficient animals.

Animals↗
PubMed2000

The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb.

Mice carrying a targeted disruption of BmprIB were generated by homologous recombination in embryonic stem cells. BmprIB(-/-) mice are viable and, in spite of the widespread expression of BMPRIB throughout the developing skeleton, exhibit defects that are largely restricted to the appendicular skeleton. Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced. Our results suggest that BMPRIB-mediated signaling is required for cell proliferation after commitment to the chondrogenic lineage. Analyses of BmprIB and Gdf5 single mutants, as well as BmprIB; Gdf5 double mutants suggests that GDF5 is a ligand for BMPRIB in vivo. BmprIB; Bmp7 double mutants were constructed in order to examine whether BMPRIB has overlapping functions with other type I BMP receptors. BmprIB; Bmp7 double mutants exhibit severe appendicular skeletal defects, suggesting that BMPRIB and BMP7 act in distinct, but overlapping pathways. These results also demonstrate that in the absence of BMPRIB, BMP7 plays an essential role in appendicular skeletal development. Therefore, rather than having a unique role, BMPRIB has broadly overlapping functions with other BMP receptors during skeletal development.

Animals↗
PubMed1999

Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the gene encoding alpha-N-acetylglucosaminidase.

The Sanfilippo syndrome type B is an autosomal recessive disorder caused by mutation in the gene (NAGLU) encoding alpha-N-acetylglucosaminidase, a lysosomal enzyme required for the stepwise degradation of heparan sulfate. The most serious manifestations are profound mental retardation, intractable behavior problems, and death in the second decade. To generate a model for studies of pathophysiology and of potential therapy, we disrupted exon 6 of Naglu, the homologous mouse gene. Naglu-/- mice were healthy and fertile while young and could survive for 8-12 mo. They were totally deficient in alpha-N-acetylglucosaminidase and had massive accumulation of heparan sulfate in liver and kidney as well as secondary changes in activity of several other lysosomal enzymes in liver and brain and elevation of gangliosides G(M2) and G(M3) in brain. Vacuolation was seen in many cells, including macrophages, epithelial cells, and neurons, and became more prominent with age. Although most vacuoles contained finely granular material characteristic of glycosaminoglycan accumulation, large pleiomorphic inclusions were seen in some neurons and pericytes in the brain. Abnormal hypoactive behavior was manifested by 4.5-mo-old Naglu-/- mice in an open field test; the hyperactivity that is characteristic of affected children was not observed even in younger mice. In a Pavlovian fear conditioning test, the 4.5-mo-old mutant mice showed normal response to context, indicating intact hippocampal-dependent learning, but reduced response to a conditioning tone, perhaps attributable to hearing impairment. The phenotype of the alpha-N-acetylglucosaminidase-deficient mice is sufficiently similar to that of patients with the Sanfilippo syndrome type B to make these mice a good model for study of pathophysiology and for development of therapy.

Acetylglucosaminidase↗
PubMed1999

Notch signaling imposes two distinct blocks in the differentiation of C2C12 myoblasts.

Notch signal transduction regulates expression of downstream genes through the activation of the DNA-binding protein Su(H)/CBF1. In Drosophila most of Notch signaling requires Su(H); however, some Notch-dependent processes occur in the absence of Su(H) suggesting that Notch signaling does not always involve activation of this factor. Using constitutively active forms of Notch lacking CBF1-interacting sequences we identified a Notch signaling pathway that inhibits myogenic differentiation of C2C12 myoblasts in the absence of CBF1 activation. Here we show that ligand-induced Notch signaling suppresses myogenesis in C2C12 myoblasts that express a dominant negative form of CBF1, providing additional evidence for CBF1-independent Notch signal transduction. Surprisingly mutant forms of Notch deficient in CBF1 activation are unable to antagonize MyoD activity, despite the fact that they inhibit myogenesis. Moreover, Notch-induced antagonism of MyoD requires CBF1 suggesting that the CBF1-dependent pathway mediates a cell-type-specific block in the myogenic program. However, Notch signaling in the absence of CBF1 activation blocks both myogenesis and osteogenesis, indicative of a general block in cellular differentiation. Taken together our data provide evidence for two distinct Notch signaling pathways that function to block differentiation at separate steps during the process of myogenesis in C2C12 myoblasts.

3T3 Cells↗
PubMed1999

Barodontalgia: a review, and the influence of simulated diving on microleakage and on the retention of full cast crowns.

This paper reviews the causes of barodontalgia and reports on a study that indicates a possible cause of barodontalgia in the diver. In the study, extracted teeth had full cast crowns cemented with either a zinc phosphate, a glass ionomer, or a resin cement, and simulated diving to 30 m (3.0 atmospheres) was performed. During simulated diving, the teeth were pressure cycled 15 times to 3 atmospheres and microleakage was monitored. The force required to dislodge the crown was then tested; a significant difference was found between the zinc phosphate and the glass ionomer cement groups (p < 0.01). No difference was found between the resin cement groups. Microleakage was also detected in the zinc phosphate and glass ionomer cement groups and was found to occur sooner, and to a greater extent with zinc phosphate. No microleakage was detected in the resin cement experimental group. This study showed that the retention of full cast crowns to extracted teeth is reduced after pressure cycling and that microleakage does occur if the crowns are cemented with either zinc phosphate cement or glass ionomer cement.

Barotrauma↗
PubMed1998

Mice lacking Bmp6 function.

Bmp6, a member of the 60A subgroup of bone morphogenetic proteins (BMPs), is expressed in diverse sites in the developing mouse embryo from preimplantation stages onwards. To evaluate roles for Bmp6 signaling in vivo, gene targeting was used to generate a null mutation at the Bmp6 locus. The resulting Bmp6 mutant mice are viable and fertile, and show no overt defects in tissues known to express Bmp6 mRNA. The skeletal elements of newborn and adult mutants are indistinguishable from wild-type. However, careful examination of skeletogenesis in late gestation embryos reveals a consistent delay in ossification strictly confined to the developing sternum. In situ hybridization studies in the developing long bones and sternum show that other BMP family members are expressed in overlapping domains. In particular we find that Bmp2 and Bmp6 are coexpressed in hypertrophic cartilage, suggesting that Bmp2 may functionally compensate in Bmp6 null mice. The defects in sternum development in Bmp6 null mice are likely to be associated with a transient early expression of Bmp6 in the sternal bands, prior to ossification. These sternal defects are slightly exacerbated in Bmp5/6 double mutant animals.

Animals↗
PubMed1998

The bone morphogenetic protein 15 gene is X-linked and expressed in oocytes.

We have taken advantage of the sequence relationships among the bone morphogenetic proteins (BMPs) to identify the mouse Bmp15 and human BMP15 genes. The 392-amino acid prepropeptides encoded by these BMP genes exhibit significant homology to each other, although the 70% identity observed between the 125-amino acid mature peptides is considerably lower than that seen in comparisons of other mouse and human orthologs. Both genes share a common structural organization and encode mature peptides that lack the cysteine residue normally involved in the formation of a covalent dimer. In addition, mouse Bmp15 and human BMP15 map to conserved syntenic regions on the X chromosome. We demonstrate, through a combination of Northern blot and in situ hybridization analyses, that mouse Bmp15 is expressed specifically in the oocyte beginning at the one-layer primary follicle stage and continuing through ovulation. Interestingly, BMP-15 is most closely related to and shares a coincident expression pattern with the mouse growth/differentiation factor 9 (GDF-9) gene that is essential for female fertility. Our findings will be important for defining the role of BMP-15 in follicular development.

Amino Acid Sequence↗