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Biomedical subjects

A H Reddi

Publications and source records attributed to A H Reddi.

At least 37 records · Page 2Linked to original sources
PubMed1998

Initiation of fracture repair by bone morphogenetic proteins.

The potential for regeneration and repair of bone is well known. This article conveys the current progress in the realm of bone morphogenetic proteins and their potential for initiating fracture repair cascade. Demineralized bone matrix induces bone formation and has served as a model for the bone repair cascade. A family of bone morphogenetic proteins has been identified, isolated, and cloned from the demineralized bone matrix. Bone morphogenetic proteins are pleiotropic regulators of chemotaxis, mitosis, and differentiation. The bone morphogenetic protein receptors, Types I and II, bind bone morphogenetic proteins and act in collaboration to transduce the phosphorylation of Smad 1 and Smad 5, which enter the nucleus in partnership with Smad 4 to initiate bone morphogenetic protein responses including fracture healing. The accumulated information on bone morphogenetic proteins may aid in accelerating fracture repair and the potential use of bone morphogenetic protein antibodies to inhibit heterotopic bone formation and fibrodysplasia ossificans progressiva.

Antibodies↗
PubMed1998

Osteonecrosis of the femoral head. Potential treatment with growth and differentiation factors.

Basic and clinical research have shown the efficacy of various cellular mediators (bone morphogenetic proteins, interleukins, angiogenic growth factors) in healing bone defects. The potential application of these growth and differentiation factors to other musculoskeletal conditions, including osteonecrosis of the femoral head, only recently has been explored. Osteonecrosis is a disease of unknown pathogenesis that usually progresses to hip joint destruction necessitating total hip arthroplasty. The pathology involves ischemic events followed by death of bone and marrow elements. A process of repair then is initiated, but unless the lesion is small (less than 15% of the femoral head involved), this repair process is usually ineffective. The net result is weakening of subchondral bone with subsequent collapse of the articular surface. Because the results of hip arthroplasty in patients with osteonecrosis are relatively poor, much focus has been on modalities aimed at femoral head preservation. The surgical alternatives may include core decompression, osteotomy, nonvascularized, and vascularized bone grafting, which might be enhanced with the use of growth and differentiation factors. At least three of these factors are potential candidates as therapeutic modalities: cytokines (such as interleukins, tumor necrosis factors, and signaling molecules such as fibroblast growth factors, platelet derived growth factors, insulinlike growth factors, and transforming growth factor betas), bone morphogenetic proteins, and angiogenic factors. Despite considerable effort, evaluation of these growth and differentiation factors has been hampered by the lack of an animal model that adequately simulates the pathology of osteonecrosis in humans. Therefore, investigators have attempted to model certain aspects of the disease process. Recently, several investigators have attempted to mimic osteonecrosis in the femoral head of large mammals by combinations of devascularization, freezing, osteotomy of the femoral neck, or creation of a head defect. Results from some of these studies have confirmed the potential for growth and differentiation factors to effect more rapid healing and filling of defects with biomechanically competent and viable bone. The application of this therapy shows promise, and clinical studies on efficacy and safety are ongoing.

Angiogenesis Inducing Agents↗
PubMed1997

Opposing actions of BMP3 and TGF beta 1 in human bone marrow stromal cell growth and differentiation.

BMP3 and TGF beta 1 were found to induce opposite effects on human bone marrow stromal cells both in cell proliferation and cell differentiation and on calcium deposition onto the extracellular matrix. Moreover, BMP3 may exert, in part, the inhibitory effect of TGF beta 1 through decreasing the affinity of TGF-beta for its receptors which are now identified in these human bone cells.

Activin Receptors, Type I↗
PubMed1997

Regulation of the expression of the type-II collagen gene in periosteum-derived cells by three members of the transforming growth factor-beta superfamily.

Although transforming growth factors-beta and bone morphogenetic proteins are both capable of inducing bone formation in vivo, the target cells of their osteoinductive actions may be different. To evaluate periosteal cells as potential targets of the actions of transforming growth factor-beta and bone morphogenetic protein, we investigated the ability of three members of the transforming growth factor-beta superfamily to modulate expression of the gene encoding the alpha 1(II) chain of type-II collagen in periosteum-derived cells in vitro. The results demonstrate that transforming growth factor-beta mRNA is expressed by periosteum-derived cells and that exogenous transforming growth factor-beta 1 acts to upregulate expression of the gene encoding collagen alpha 1(II). This effect was observed as early as 12 hours after administration of transforming growth factor-beta 1 but was not observed in response to bone morphogenetic proteins 3 or 4. No synergy was demonstrated between transforming growth factor-beta 1 and bone morphogenetic protein-3 in the ability to upregulate expression of the collagen alpha 1(II) gene. These results support the hypothesis that committed periosteal mesenchymal cells are cellular targets of the action of transforming growth factor-beta.

Animals↗
PubMed1997

Bone morphogenetic proteins: an unconventional approach to isolation of first mammalian morphogens.

It is conventional to identify morphogens from fly and frog embryos during morphogenesis using gene-screens, subtractive hybridizations, differential displays and expression cloning. This information is then extended to mice and men. The bone morphogenetic proteins (BMPs) are a family of pleiotropic morphogens/cytokines isolated and cloned from the demineralized extracellular matrix of adult bone. Thus, BMPs were isolated from mammalian bone by an unconventional approach. BMPs initiate the sequential developmental cascade of bone morphogenesis in ectopic sites. The pleiotropic effects of BMPs on chemotaxis, mitosis and differentiation are based on concentration-dependent thresholds. Recent work has demonstrated the critical role of BMPs in pattern formation in amphibian and chick limb development. Targeted disruption of gene function by homologous recombination has demonstrated the actions of BMPs beyond bone in such disparate tissues as kidney, eye, testis, teeth, skin and heart. The successful isolation of first mammalian morphogens has laid the foundation for the elucidation of molecular signalling during morphogenesis in bones and beyond.

Adult↗
PubMed1997

Osteogenin-enhanced bone-specific differentiation in hydroxyapatite orbital implants.

Hydroxyapatite orbital implants undergo early ingrowth of fibrovascular tissue after enucleation. This animal study determined whether control and osteogenin-impregnated hydroxyapatite orbital implants vary in their osteogenic response at 6 and 52 weeks. Rabbits underwent enucleation with implantation of control or osteogenin-impregnated hydroxyapatite spheres. Light microscopy determined fibrovascular ingrowth, and histomorphometry quantitated the amount of bone produced. Osteogenin implants vascularized at a faster rate and contained bony foci by 6 weeks that became confluent at 1 year. Spontaneous osteogenesis was not seen in control animals at 6 weeks. After 1 year they contained bone, although less than in the osteogenin implants. Mixed cell inflammation was observed at the hydroxyapatite-tissue interface in both groups. No inflammation was noted at the interface of hydroxyapatite and bone. These are the first controlled observations that bone-specific differentiation occurs in the pores of spherical hydroxyapatite implants within the soft tissues of the socket. This vascularized process can be enhanced with osteogenin to occur earlier and more uniformly in the implants at one year.

Animals↗
PubMed1997

Tissue engineering, morphogenesis, and regeneration of the periodontal tissues by bone morphogenetic proteins.

Tissue engineering is the emerging field of science developing techniques for fabrication of new tissues for replacement based on principles of cell and developmental biology and biomaterials. Morphogenesis is the cascade of pattern formation and the attainment of form of the various organs and the organism as a whole. The periodontium consist of the periodontal ligament, cementum, and alveolar bone. Bone has considerable potential for regeneration and therefore is a prototypic model for tissue engineering. The three main ingredients for tissue engineering are regulatory signals, responding stem cells, and extracellular matrix. Recent advances in molecular biology of the bone morphogenetic proteins (BMPs) have set the stage for tissue engineering of bone and related tissues, including the periodontium. Bone-derived BMPs, with a collagenous matrix as carrier, induced cementum and alveolar bone regeneration in surgically created furcation defects in the primate. It is noteworthy that there was morphogenesis of periodontal ligament and a faithful insertion of Sharpey's fibers into cementum. In the same furcation model, recombinant human osteogenic protein-1 (rhOP-1, also known as BMP-7), in conjunction with the collagenous carrier, induced extensive cementogenesis with insertion of Sharpey's fibers into the newly formed cementum. The observation that BMPs induce cementogenesis and periodontal ligament formation indicates that these proteins may have multiple functions in vivo not limited to cartilage and bone induction. The rapid advances in the molecular biology of BMPs and their receptors bode well for novel strategies to engineer the regeneration of the periodontal tissues.

Alveolar Process↗
PubMed1997

Stimulation of proteoglycan synthesis in explants of porcine articular cartilage by recombinant osteogenic protein-1 (bone morphogenetic protein-7).

UNLABELLED: Osteogenic protein-1 (also known as bone morphogenetic protein-7) is a member of the bone morphogenetic protein family. Bone morphogenetic proteins and related members of the TGF-beta (transforming growth factor-beta) superfamily are involved in the development and repair of bone. Recombinant bone morphogenetic proteins induce the formation of new cartilage and bone at heterotopic sites. We investigated the influence of recombinant osteogenic protein-1 (at doses of three, ten, thirty, or 100 nanograms per milliliter) on the synthesis and release of proteoglycans and the maintenance of a steady-state concentration of proteoglycans in explants of porcine articular cartilage that were maintained in chemically defined serum-free medium. We found a dose-dependent stimulation of proteoglycan synthesis and a concurrent decrease in the rate of release of proteoglycans from the explants. The size of the proteoglycan monomers and the composition of the glycosaminoglycan chains in the untreated articular cartilage were similar to those in the articular cartilage treated with osteogenic protein-1. The capacity of the newly synthesized proteoglycan monomers to form aggregates with exogenous hyaluronic acid was found to be similar to that of proteoglycans in bovine nasal cartilage. Our results demonstrated that osteogenic protein-1 stimulated the synthesis of proteoglycans and diminished the release of proteoglycans from explants of porcine articular cartilage. CLINICAL RELEVANCE: The maintenance and repair of articular cartilage is a formidable challenge in clinical orthopaedics. The stimulation of proteoglycan synthesis by osteogenic protein-1 (bone morphogenetic protein-7) in explants of cartilage maintained in chemically defined serum-free medium implies that recombinant osteogenic protein-1 may play a role in the maintenance of a steady-state concentration of proteoglycans in articular cartilage, a desirable prerequisite for optimum repair of cartilage. Osteogenic protein-1 can initiate the formation of cartilage from mesenchymal cells. Once new cartilage has formed at the site of repair, osteogenic protein-1 also may maintain the synthesis of proteoglycans.

Animals↗
PubMed1996

Identification and cloning of a novel type I serine/threonine kinase receptor of the TGF-beta/BMP superfamily in rat prostate.

A cDNA clone encoding a new member of the type I serine/threonine kinase receptors of the TGF-beta/BMP superfamily was isolated from a rat prostate cDNA library. The predicted sequence of the encoded protein is 493 amino acids with a molecular weight of 55 kDa. It contains a putative cysteine rich extracellular domain, a transmembrane domain, a conserved type I receptor GS domain and a cytoplasmic serine/threonine kinase domain. The kinase domain shares 80% homology with that of ALK-4 and ALK-5 whose ligands are activin and TGF-beta. Northern blot analysis revealed that this prostate serine/threonine kinase receptor I (PSKR-I) is highly expressed in rat dorsolateral prostate, coagulating gland (anterior prostate), cerebellum and adipose tissue.

Amino Acid Sequence↗
PubMed1996

Repair of calvarial defects with flap tissue: role of bone morphogenetic proteins and competent responding tissues.

Bone morphogenetic proteins 2 through 8 have the ability to induce the in vivo transformation of extraskeletal mesenchymal tissue into bone. The aims of this investigation were to determine the optimal responding tissue and the specificity of the inductive effect of bone morphogenetic protein 3. The optimal responding tissue was found to be skeletal muscle. The specificity of this response to bone morphogenetic protein 3 was compared with that of recombinant human basic fibroblast growth factor, recombinant platelet-derived growth factor, and recombinant insulin-like growth factor. Bone morphogenetic protein 3 was the only factor that induced de novo bone formation. This ability to transform muscle into bone was tested in 7 x 7 mm irradiated skull defects in the rat. After 1500 rads of exposure, these defects showed no significant signs of healing by 8 months. When these defects were treated with the microvascular transfer of a nonirradiated muscle flap, they had 8 percent healing at 4 months and 37 percent healing by 8 months. Defects treated with 30 micrograms bone morphogenetic protein 3 (without the muscle flap) achieved 50 percent healing by 4 months and 64 percent healing by 8 months. When the defects were treated with both the muscle flap and bone morphogenetic protein 3, there was 96 percent healing by 4 months and 100 percent healing by 8 months (p < 0.015, compared with bone morphogenetic protein 3 alone at both time points). At 8 months, the transplanted muscle was entirely transformed into bone and healed the skull defect with newly generated bone indistinguishable from the surrounding calvarial tissue. These findings suggest a potential clinical utility of bone morphogenetic protein 3-induced bone formation in skeletal reconstructions. Furthermore, they also show that there is a collaborative requirement for both the osteoinductive factor bone morphogenetic protein 3 and the presence of competent responsive cells in the well-perfused muscle.

Animals↗
PubMed1996

Complete regeneration of bone in the baboon by recombinant human osteogenic protein-1 (hOP-1, bone morphogenetic protein-7).

We examined the efficacy of a single application of recombinant human osteogenic protein-1 (hOP-1, bone morphogenetic protein-7) for its ability to regenerate large calvarial defects in adult male baboons (Papio ursinus). Recombinant hOP-1, in conjunction with baboon or bovine guanidinium-extracted insoluble collagenous bone matrix (0.1, 0.5 and 2.5 mg per g of collagenous matrix as carrier), was implanted in 46 calvarial defects surgically prepared in 14 baboons, whilst 18 defects were implanted with the carrier matrix without hOP-1. Specimens were harvested on d 15, 30, 90 and 365 and subjected to histomorphometry on serial undecalcified sections cut at 7 microm to study the temporal sequence of tissue morphogenesis after the single application of hOP-1. Histological analysis indicated that the induction of new bone formation proceeded from the periphery to the central core of hOP-1 treated specimens after rapid angiogenesis and mesenchymal cell migration in apposition to the collagenous matrix. Whilst chondrogenesis was limited, newly formed bone has already filled with fully differentiated bone marrow elements as early as d 15, even with the 0.1 mg dose of hOP-1. On d 30 and 90, doses of 0.1 and 0.5 mg of hOP-1 showed greater amounts of bone than controls, and on d 90, they induced complete regeneration of the defects. Doses of 2.5 mg hOP-1 per g of matrix induced extensive osteogenesis initially with heterotopic ossification and displacement of the temporalis muscle above the defects. One year after implantation of hOP-1 there was restoration of the internal and external cortices of the calvaria. These results show that hOP-1 induces complete regeneration of calvarial bone in the adult primate, and suggest that the optimal activity of hOP-1 to achieve regeneration is between 100 and 500 microg of hOP-1 per g of matrix. These results in the primate may form the scientific basis for future clinical applications of hOP-1.

Animals↗
PubMed1995

Cartilage morphogenesis: role of bone and cartilage morphogenetic proteins, homeobox genes and extracellular matrix.

Cartilage morphogenesis is one of the central topics in skeletal development. Cartilage geometry determines the future architecture of bones, joints and associated ligaments and tendons. Recent progress in this area has come from purification, cloning and expression of genes encoding bone and cartilage morphogenetic proteins (BMPs and CDMPs). BMPs initiate de novo cartilage and bone differentiation. BMPs are a family of pleiotropic signals for progenitor cell migration by chemotaxis, proliferation, and differentiation. Very recently another class of related morphogenetic proteins, CDMPs have been isolated and cloned. CDMPs may be critical for mesenchymal condensation prior to overt cartilage differentiation, the first step in morphogenesis of both cartilage and bone. The cartilage morphogenetic cascade is a cellular and molecular continuum driven by regulatory signalling molecules such as BMPs and CDMPs and their receptors, homeobox genes, transcription factors, and finally the synthesis and supramolecular assembly of structural macromolecules of the extracellular matrix. BMPs and CDMPs bind to heparin, heparan sulfates, and collagens I and IV. Thus there is a symbiosis of regulatory and structural macromolecules in the morphogenesis of cartilage. An avalanche of recent advances from seemingly disparate areas bodes well for the complete elucidation of the molecular basis of morphogenesis of cartilage, the architectural blue-print for the skeleton.

Animals↗
PubMed1995

Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate.

Prostate cancer is the second most common cause of death from cancer in U.S. men, and advanced, hormone-refractory disease is characterized by painful osteoblastic bone metastases. Endothelin-1, more commonly known as a potent vasoconstrictor, is a normal ejaculate protein that also stimulates osteoblasts. We show here that plasma immunoreactive endothelin concentrations are significantly elevated in men with metastatic prostate cancer and that every human prostate cancer cell line tested produces endothelin-1 messenger RNA and secretes immunoreactive endothelin. Exogenous endothelin-1 is a prostate cancer mitogen in vitro and increases alkaline phosphatase activity in new bone formation, indicating that ectopic endothelin-1 may be a mediator of the osteoblastic response of bone to metastatic prostate cancer.

Adenocarcinoma↗
PubMed1995

Tricalcium phosphate and osteogenin: a bioactive onlay bone graft substitute.

The disadvantages of autogenous bone grafts has prompted a search for a dependable onlay bone graft substitute. A combination of tricalcium phosphate, a resorbable ceramic, and osteogenin, an osteoinductive protein, was evaluated as an onlay bone graft substitute in a rabbit calvarial model. Twenty-eight tricalcium phosphate implants (15 mm diameter x 5 mm; pore size, 100-200 microns) were divided into experimental and control groups and placed on the frontal bone of 14 adult New Zealand White rabbits. In the experimental animals, 185 micrograms of osteogenin was added to each implant. In the control animals, the implants were placed untreated. Implants were harvested at intervals of 1, 3, and 6 months, and evaluated using hematoxylin and eosin histology, microradiography, and histomorphometric scanning electron microscope backscatter image analysis. At 1 month there was minimal bone ingrowth and little tricalcium phosphate resorption in both the osteogenin-treated and control implants. At 3 months, both the osteogenin-treated and control implants showed a modest increase in bone ingrowth (8.85 percent versus 5.87 percent) and decrease in tricalcium phosphate (32.86 percent versus 37.08 percent). At 6 months, however, the osteogenin-treated implants showed a statistically significant increase in bone ingrowth (22.33 percent versus 6.96 percent; p = 0.000) and decrease in tricalcium phosphate (27.25 percent versus 37.80 percent; p = 0.004) compared with the control implants. The bone within the control implants was mostly woven at 6 months, whereas the osteogenin-treated implants contained predominantly mature lamellar bone with well-differentiated marrow. All implants maintained their original volume at each time interval studied. The tricalcium phosphate/osteogenin composite, having the advantage of maintaining its volume and being replaced by new bone as the tricalcium phosphate resorbs, may be applicable clinically as an onlay bone graft substitute.

Animals↗
PubMed1995

Growth/differentiation factor-10: a new member of the transforming growth factor-beta superfamily related to bone morphogenetic protein-3.

We have identified a new member of the transforming growth factor-beta (TGF-beta) superfamily, growth/differentiation factor-10 (GDF-10), which is highly related to bone morphogenetic protein-3 (BMP-3). The nucleotide sequence of GDF-10 encodes a predicted protein of 476 amino acids with a molecular weight of approximately 52,000. The GDF-10 polypeptide contains a potential signal sequence for secretion, a putative RXXR proteolytic processing site, and a carboxy-terminal domain with considerable homology to other known members of the TGF-beta superfamily. In the mature carboxy-terminal domain GDF-10 is more homologous to BMP-3 (83% amino acid sequence identity) than to any other previously identified TGF-beta family member. GDF-10 also shows significant homology to BMP-3 (approximately 30% amino acid sequence identity) in the pro- region of the molecule. Based on these sequence comparisons, GDF-10 and BMP-3 define a new subgroup within the larger TGF-beta superfamily. By Northern analysis, GDF-10 mRNA was detected primarily in murine uterus, adipose tissue, and brain and to a lesser extent in liver and spleen. In addition, GDF-10 mRNA was present in both neonatal and adult bone samples, with higher levels being detected in calvaria than in long bone. These results suggest that GDF10 may play multiple roles in regulating cell differentiation events, including those involved in skeletal morphogenesis. Gdf10 was mapped to the proximal region of mouse chromosome 14 close to a region known to contain a spontaneous recessive mutation that is associated with a craniofacial defect.

Amino Acid Sequence↗