Gianni Rossini - Academia.edu (original) (raw)

Papers by Gianni Rossini

Science, 1999

Osteoporosis and other diseases of bone loss are a major public health problem. Here it is shown ... more Osteoporosis and other diseases of bone loss are a major public health problem. Here it is shown that the statins, drugs widely used for lowering serum cholesterol, also enhance new bone formation in vitro and in rodents. This effect was associated with increased expression of the bone morphogenetic protein–2 (BMP-2) gene in bone cells. Lovastatin and simvastatin increased bone formation when injected subcutaneously over the calvaria of mice and increased cancellous bone volume when orally administered to rats. Thus, in appropriate doses, statins may have therapeutic applications for the treatment of osteoporosis.

INTRODUCTION Normal fracture healing is a complex, multi-step process involving cellular events i... more INTRODUCTION Normal fracture healing is a complex, multi-step process involving cellular events influenced and regulated by local and systemic factors. The most common biological failure in fracture healing involves an improperly formed callus during the first weeks following fracture. Recent advances in understanding the regulatory factors controlling fracture healing have suggested that a number of compounds may be used to stimulate bone growth and initiate and enhance the cascade of events involved in callus formation and maturation. BMPs, particularly BMP2 which is well known for its osteogenic activity, is highly expressed in the healing callus during fracture repair [1] which suggests an important role of these proteins in fracture healing. Statins, a group of natural products widely prescribed for their capacity to inhibit the enzyme HMG Co-A reductase, and therefore decrease cholesterol biosynthesis, have been shown to increase transcription of the BMP-2 gene, and stimulate ...

Osteoporosis International, 2006

Abstract Introduction: Statins are drugs that inhibit HMG Co-A reductase and have been shown to e... more Abstract Introduction: Statins are drugs that inhibit HMG Co-A reductase and have been shown to enhance bone formation in vitro and in vivo in rodents. However, the statins currently used for cholesterol-lowering have been selected for their capacity to target the liver where ...

Enfermedades respir. cir. torac, 1988

Resumo: Se evalúa la utilidad de la determinación de la Adenosin Deaminasa (ADA) sérica en el dia... more Resumo: Se evalúa la utilidad de la determinación de la Adenosin Deaminasa (ADA) sérica en el diagnóstico de la tuberculosis pulmonar activa. Se estudió una serie de enfermos con TBC pulmonar activa confirmada bacteriológicamente y sin tratamiento (n= 19), y se lo ...

Fungal Genomics & Biology, 2017

Annals of the New York Academy of Sciences, 2007

Abstract: We propose that the remodeling process that occurs in localized areas on endosteal bon... more Abstract: We propose that the remodeling process that occurs in localized areas on endosteal bone surfaces and in Haversian canals shares many features in common with the mammalian hair cycle. In both, there are phases of resorption or regeneration, a transition phase, and then a phase of growth, termed anagen in the hair follicle, and formation in the bone remodeling cycle. Furthermore, we suggest that these processes both use the same molecular mechanisms, and specifically the Hedgehog–BMP–Wnt signal transduction cascades. We have found that proteasome inhibitors, which enhance bone formation by effects on these cascades, also stimulate anagen induction and hair growth in the murine and human hair follicle, and propose they do so by effects on similar or identical molecular targets.

Statins are a class of drugs commonly prescribed to decrease cholesterol levels that have recentl... more Statins are a class of drugs commonly prescribed to decrease cholesterol levels that have recently been shown to also stimulate bone formation. Clinical data have emerged in the last few years that suggest statins may reduce the risk of fracture in patients taking these drugs for cholesterol lowering. Red yeast rice (RYR), rice that has been fermented by the red yeast Monascus purpureus, is frequently used in Chinese cuisine to flavor Peking duck and has also been used in traditional medicinal therapy in Asia for centuries. It has been reported that certain strains of RYR produce sufficient levels of lovastatin and other related statins to lower cholesterol levels when ingested by patients with hyperlipidemia. These findings may explain, in part, the suggested benefits of treating heart disease with RYR in conventional Chinese medicine. Because of the bone anabolic effect of statins, we hypothesized that RYR may also be capable of stimulating bone formation. We evaluated several dif...

UNLABELLED In vitro and in vivo assessments suggest that proteasome inhibitors may be useful for ... more UNLABELLED In vitro and in vivo assessments suggest that proteasome inhibitors may be useful for modulating wound healing. METHODS Proteasome Inhibitor I was used to assess the potential utility of proteasome inhibitors in improving wound healing in a standard rat model. Bilateral, 6 cm incisions were made 1 cm lateral to the spine of adult male Sprague Dawley rats. Animals were randomly assigned to 1 of 3 groups: no treatment (n = 15), low concentration (1% w/v, n = 15), or high concentration (5% w/v, n = 15). Treatments were applied to the left side incision at 0 hours, 24 hours, and 48 hours. Right-side incisionsreceived a vehicle, dimethyl sulfoxide, alone and independent of the assigned group, serving as both external and internal controls. Rats were sacrificed at days 7, 14, and 28 (n = 5 per group) and wounds subjected to mechanical testing and histology. RESULTS No significant intergroup difference existed at 7 and 14 days. On day 28, a dosedependent increase in tensile stre...

Osteoporosis International, 2006

Introduction: Statins are drugs that inhibit HMG Co-A reductase and have been shown to enhance bo... more Introduction: Statins are drugs that inhibit HMG Co-A reductase and have been shown to enhance bone formation in vitro and in vivo in rodents. However, the statins currently used for cholesterol-lowering have been selected for their capacity to target the liver where ...

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2008

Statins have been shown to stimulate BMP2 transcription and bone formation. This raises the possi... more Statins have been shown to stimulate BMP2 transcription and bone formation. This raises the possibility that they could be useful for enhancing rates of fracture repair. Observational studies in patients treated with oral statins for lipid-lowering have been controversial. The likely reason for their inconsistent effects is that the statin concentration reaching the periphery was too low after oral administration to produce a reproducible biologic effect. Thus, we examined the effects of lovastatin (LV) given transdermally in a well-described preclinical model of fracture repair. Effects on the healing fracture callus were assessed by biomechanical strength, radiographs, and quantitative morphology. LV was administered transdermally (TD) for 5 days after fracture in several doses (0.1-5 mg/kg/d) and compared with vehicle-treated control rats and rats treated with LV by oral gavage (PO) at 5-25 mg/kg/d for 5 days from the day of fracture. Radiological evaluation of bones treated with...

In vitro and in vivo assessments suggest that proteasome inhibitors may be useful for modulating ... more In vitro and in vivo assessments suggest that proteasome inhibitors may be useful for modulating wound healing. Proteasome Inhibitor I was used to assess the potential utility of proteasome inhibitors in improving wound healing in a standard rat model. Bilateral, 6 cm incisions were made 1 cm lateral to the spine of adult male Sprague Dawley rats. Animals were randomly assigned to 1 of 3 groups: no treatment (n = 15), low concentration (1% w/v, n = 15), or high concentration (5% w/v, n = 15). Treatments were applied to the left side incision at 0 hours, 24 hours, and 48 hours. Right-side incisionsreceived a vehicle, dimethyl sulfoxide, alone and independent of the assigned group, serving as both external and internal controls. Rats were sacrificed at days 7, 14, and 28 (n = 5 per group) and wounds subjected to mechanical testing and histology. No significant intergroup difference existed at 7 and 14 days. On day 28, a dosedependent increase in tensile strength with increasing Proteasome Inhibitor I was observed. Results suggest dimethyl sulfoxide was not the ideal vehicle and additional improvement may be realized by optimizing the delivery method.

Journal of Clinical Investigation, 2003

We have found that the ubiquitin-proteasome pathway exerts exquisite control of osteoblast differ... more We have found that the ubiquitin-proteasome pathway exerts exquisite control of osteoblast differentiation and bone formation in vitro and in vivo in rodents. Structurally different inhibitors that bind to specific catalytic b subunits of the 20S proteasome stimulated bone formation in bone organ cultures in concentrations as low as 10 nM. When administered systemically to mice, the proteasome inhibitors epoxomicin and proteasome inhibitor-1 increased bone volume and bone formation rates over 70% after only 5 days of treatment. Since the ubiquitin-proteasome pathway has been shown to modulate expression of the Drosophila homologue of the bone morphogenetic protein-2 and-4 (BMP-2 and BMP-4) genes, we examined the effects of noggin, an endogenous inhibitor of BMP-2 and BMP-4 on bone formation stimulated by these compounds and found that it was abrogated. These compounds increased BMP-2 but not BMP-4 or BMP-6 mRNA expression in osteoblastic cells, suggesting that BMP-2 was responsible for the observed bone formation that was inhibited by noggin. We show proteasome inhibitors regulate BMP-2 gene expression at least in part through inhibiting the proteolytic processing of Gli3 protein. Our results suggest that the ubiquitin-proteasome machinery regulates osteoblast differentiation and bone formation and that inhibition of specific components of this system may be useful therapeutically in common diseases of bone loss. Article Bone biology Find the latest version: http://jci.me/16198-pdf consequence, osteoblast proliferation and differentiation are enhanced, and a mineralized bone matrix is formed. The precise molecular mechanisms by which bone formation is controlled or how the process can be manipulated therapeutically remain unclear, however. The ubiquitin-proteasomal pathway is recognized as the major intracellular mechanism for degradation of many short-lived proteins (4-6). By this means, the proteasomal mechanism can regulate expression of important genes such as cell cycle regulators and transcription factors. Here, we show that the chymotryptic component of the proteasome is an important regulatory mediator of osteoblast differentiation and bone formation. Different inhibitors of the proteasome increase bone formation in vitro and in vivo, correlating closely with their effects to increase bone morphogenetic protein-2 (BMP-2) gene expression. Methods Compounds. Epoxomicin (7) and eponemycin were synthesized as described previously (8). YU101 (ac-hFLFLepoxide) was synthesized as described previously (9).

Journal of Orthopaedic Research, 2007

Statins stimulate bone formation in vitro and in vivo and, when given in large doses or by prolon... more Statins stimulate bone formation in vitro and in vivo and, when given in large doses or by prolonged infusions, stimulate biomechanical strength of murine long bones with healing fractures. However, administration of statins by large oral doses or prolonged infusions to a fracture site is not a feasible therapeutic approach to hasten healing of human fractures. We administered lovastatin in biodegradable polymer nanobeads of poly(lactic-co-glycolide acid) to determine if lovastatin delivered in low doses in nanoparticles of a therapeutically acceptable scaffold could increase rates of healing in a standard preclinical model of femoral fracture. We found that these nanobeads: (1) stimulated bone formation in vitro at 5 ng/mL, (2) increased rates of healing in femoral fractures when administered as a single injection into the fracture site, and (3) decreased cortical fracture gap at 4 weeks as assessed by microcomputed tomography. These preclinical results suggest that lovastatin administered in a nanobead preparation may be therapeutically useful in hastening repair of human fractures.

Science, 1999

Osteoporosis and other diseases of bone loss are a major public health problem. Here it is shown ... more Osteoporosis and other diseases of bone loss are a major public health problem. Here it is shown that the statins, drugs widely used for lowering serum cholesterol, also enhance new bone formation in vitro and in rodents. This effect was associated with increased expression of the bone morphogenetic protein–2 (BMP-2) gene in bone cells. Lovastatin and simvastatin increased bone formation when injected subcutaneously over the calvaria of mice and increased cancellous bone volume when orally administered to rats. Thus, in appropriate doses, statins may have therapeutic applications for the treatment of osteoporosis.

INTRODUCTION Normal fracture healing is a complex, multi-step process involving cellular events i... more INTRODUCTION Normal fracture healing is a complex, multi-step process involving cellular events influenced and regulated by local and systemic factors. The most common biological failure in fracture healing involves an improperly formed callus during the first weeks following fracture. Recent advances in understanding the regulatory factors controlling fracture healing have suggested that a number of compounds may be used to stimulate bone growth and initiate and enhance the cascade of events involved in callus formation and maturation. BMPs, particularly BMP2 which is well known for its osteogenic activity, is highly expressed in the healing callus during fracture repair [1] which suggests an important role of these proteins in fracture healing. Statins, a group of natural products widely prescribed for their capacity to inhibit the enzyme HMG Co-A reductase, and therefore decrease cholesterol biosynthesis, have been shown to increase transcription of the BMP-2 gene, and stimulate ...

Osteoporosis International, 2006

Abstract Introduction: Statins are drugs that inhibit HMG Co-A reductase and have been shown to e... more Abstract Introduction: Statins are drugs that inhibit HMG Co-A reductase and have been shown to enhance bone formation in vitro and in vivo in rodents. However, the statins currently used for cholesterol-lowering have been selected for their capacity to target the liver where ...

Enfermedades respir. cir. torac, 1988

Resumo: Se evalúa la utilidad de la determinación de la Adenosin Deaminasa (ADA) sérica en el dia... more Resumo: Se evalúa la utilidad de la determinación de la Adenosin Deaminasa (ADA) sérica en el diagnóstico de la tuberculosis pulmonar activa. Se estudió una serie de enfermos con TBC pulmonar activa confirmada bacteriológicamente y sin tratamiento (n= 19), y se lo ...

Fungal Genomics & Biology, 2017

Annals of the New York Academy of Sciences, 2007

Abstract: We propose that the remodeling process that occurs in localized areas on endosteal bon... more Abstract: We propose that the remodeling process that occurs in localized areas on endosteal bone surfaces and in Haversian canals shares many features in common with the mammalian hair cycle. In both, there are phases of resorption or regeneration, a transition phase, and then a phase of growth, termed anagen in the hair follicle, and formation in the bone remodeling cycle. Furthermore, we suggest that these processes both use the same molecular mechanisms, and specifically the Hedgehog–BMP–Wnt signal transduction cascades. We have found that proteasome inhibitors, which enhance bone formation by effects on these cascades, also stimulate anagen induction and hair growth in the murine and human hair follicle, and propose they do so by effects on similar or identical molecular targets.

Statins are a class of drugs commonly prescribed to decrease cholesterol levels that have recentl... more Statins are a class of drugs commonly prescribed to decrease cholesterol levels that have recently been shown to also stimulate bone formation. Clinical data have emerged in the last few years that suggest statins may reduce the risk of fracture in patients taking these drugs for cholesterol lowering. Red yeast rice (RYR), rice that has been fermented by the red yeast Monascus purpureus, is frequently used in Chinese cuisine to flavor Peking duck and has also been used in traditional medicinal therapy in Asia for centuries. It has been reported that certain strains of RYR produce sufficient levels of lovastatin and other related statins to lower cholesterol levels when ingested by patients with hyperlipidemia. These findings may explain, in part, the suggested benefits of treating heart disease with RYR in conventional Chinese medicine. Because of the bone anabolic effect of statins, we hypothesized that RYR may also be capable of stimulating bone formation. We evaluated several dif...

UNLABELLED In vitro and in vivo assessments suggest that proteasome inhibitors may be useful for ... more UNLABELLED In vitro and in vivo assessments suggest that proteasome inhibitors may be useful for modulating wound healing. METHODS Proteasome Inhibitor I was used to assess the potential utility of proteasome inhibitors in improving wound healing in a standard rat model. Bilateral, 6 cm incisions were made 1 cm lateral to the spine of adult male Sprague Dawley rats. Animals were randomly assigned to 1 of 3 groups: no treatment (n = 15), low concentration (1% w/v, n = 15), or high concentration (5% w/v, n = 15). Treatments were applied to the left side incision at 0 hours, 24 hours, and 48 hours. Right-side incisionsreceived a vehicle, dimethyl sulfoxide, alone and independent of the assigned group, serving as both external and internal controls. Rats were sacrificed at days 7, 14, and 28 (n = 5 per group) and wounds subjected to mechanical testing and histology. RESULTS No significant intergroup difference existed at 7 and 14 days. On day 28, a dosedependent increase in tensile stre...

Osteoporosis International, 2006

Introduction: Statins are drugs that inhibit HMG Co-A reductase and have been shown to enhance bo... more Introduction: Statins are drugs that inhibit HMG Co-A reductase and have been shown to enhance bone formation in vitro and in vivo in rodents. However, the statins currently used for cholesterol-lowering have been selected for their capacity to target the liver where ...

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2008

Statins have been shown to stimulate BMP2 transcription and bone formation. This raises the possi... more Statins have been shown to stimulate BMP2 transcription and bone formation. This raises the possibility that they could be useful for enhancing rates of fracture repair. Observational studies in patients treated with oral statins for lipid-lowering have been controversial. The likely reason for their inconsistent effects is that the statin concentration reaching the periphery was too low after oral administration to produce a reproducible biologic effect. Thus, we examined the effects of lovastatin (LV) given transdermally in a well-described preclinical model of fracture repair. Effects on the healing fracture callus were assessed by biomechanical strength, radiographs, and quantitative morphology. LV was administered transdermally (TD) for 5 days after fracture in several doses (0.1-5 mg/kg/d) and compared with vehicle-treated control rats and rats treated with LV by oral gavage (PO) at 5-25 mg/kg/d for 5 days from the day of fracture. Radiological evaluation of bones treated with...

In vitro and in vivo assessments suggest that proteasome inhibitors may be useful for modulating ... more In vitro and in vivo assessments suggest that proteasome inhibitors may be useful for modulating wound healing. Proteasome Inhibitor I was used to assess the potential utility of proteasome inhibitors in improving wound healing in a standard rat model. Bilateral, 6 cm incisions were made 1 cm lateral to the spine of adult male Sprague Dawley rats. Animals were randomly assigned to 1 of 3 groups: no treatment (n = 15), low concentration (1% w/v, n = 15), or high concentration (5% w/v, n = 15). Treatments were applied to the left side incision at 0 hours, 24 hours, and 48 hours. Right-side incisionsreceived a vehicle, dimethyl sulfoxide, alone and independent of the assigned group, serving as both external and internal controls. Rats were sacrificed at days 7, 14, and 28 (n = 5 per group) and wounds subjected to mechanical testing and histology. No significant intergroup difference existed at 7 and 14 days. On day 28, a dosedependent increase in tensile strength with increasing Proteasome Inhibitor I was observed. Results suggest dimethyl sulfoxide was not the ideal vehicle and additional improvement may be realized by optimizing the delivery method.

Journal of Clinical Investigation, 2003

We have found that the ubiquitin-proteasome pathway exerts exquisite control of osteoblast differ... more We have found that the ubiquitin-proteasome pathway exerts exquisite control of osteoblast differentiation and bone formation in vitro and in vivo in rodents. Structurally different inhibitors that bind to specific catalytic b subunits of the 20S proteasome stimulated bone formation in bone organ cultures in concentrations as low as 10 nM. When administered systemically to mice, the proteasome inhibitors epoxomicin and proteasome inhibitor-1 increased bone volume and bone formation rates over 70% after only 5 days of treatment. Since the ubiquitin-proteasome pathway has been shown to modulate expression of the Drosophila homologue of the bone morphogenetic protein-2 and-4 (BMP-2 and BMP-4) genes, we examined the effects of noggin, an endogenous inhibitor of BMP-2 and BMP-4 on bone formation stimulated by these compounds and found that it was abrogated. These compounds increased BMP-2 but not BMP-4 or BMP-6 mRNA expression in osteoblastic cells, suggesting that BMP-2 was responsible for the observed bone formation that was inhibited by noggin. We show proteasome inhibitors regulate BMP-2 gene expression at least in part through inhibiting the proteolytic processing of Gli3 protein. Our results suggest that the ubiquitin-proteasome machinery regulates osteoblast differentiation and bone formation and that inhibition of specific components of this system may be useful therapeutically in common diseases of bone loss. Article Bone biology Find the latest version: http://jci.me/16198-pdf consequence, osteoblast proliferation and differentiation are enhanced, and a mineralized bone matrix is formed. The precise molecular mechanisms by which bone formation is controlled or how the process can be manipulated therapeutically remain unclear, however. The ubiquitin-proteasomal pathway is recognized as the major intracellular mechanism for degradation of many short-lived proteins (4-6). By this means, the proteasomal mechanism can regulate expression of important genes such as cell cycle regulators and transcription factors. Here, we show that the chymotryptic component of the proteasome is an important regulatory mediator of osteoblast differentiation and bone formation. Different inhibitors of the proteasome increase bone formation in vitro and in vivo, correlating closely with their effects to increase bone morphogenetic protein-2 (BMP-2) gene expression. Methods Compounds. Epoxomicin (7) and eponemycin were synthesized as described previously (8). YU101 (ac-hFLFLepoxide) was synthesized as described previously (9).

Journal of Orthopaedic Research, 2007

Statins stimulate bone formation in vitro and in vivo and, when given in large doses or by prolon... more Statins stimulate bone formation in vitro and in vivo and, when given in large doses or by prolonged infusions, stimulate biomechanical strength of murine long bones with healing fractures. However, administration of statins by large oral doses or prolonged infusions to a fracture site is not a feasible therapeutic approach to hasten healing of human fractures. We administered lovastatin in biodegradable polymer nanobeads of poly(lactic-co-glycolide acid) to determine if lovastatin delivered in low doses in nanoparticles of a therapeutically acceptable scaffold could increase rates of healing in a standard preclinical model of femoral fracture. We found that these nanobeads: (1) stimulated bone formation in vitro at 5 ng/mL, (2) increased rates of healing in femoral fractures when administered as a single injection into the fracture site, and (3) decreased cortical fracture gap at 4 weeks as assessed by microcomputed tomography. These preclinical results suggest that lovastatin administered in a nanobead preparation may be therapeutically useful in hastening repair of human fractures.