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Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado
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Josep blanch nuevas perspectivas en el tratamiento faramacológico de la osteoporosis abreviado

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  • The protein encoded by this gene is a lysosomal cysteine protease involved in bone remodeling and resorption. This protein, which is a member of the peptidase C1 protein family, is expressed predominantly in osteoclasts . Cathepsin K is a protease , which is defined by its high specificity for kinins , that is involved in bone resorption . The enzyme's ability to catabolize elastin , collagen , and gelatin allow it to break down bone and cartilage . This catabolic activity is also partially responsible for the loss of lung elasticity and recoil in emphysema . Cathepsin K inhibitors , such as odanacatib , show great potential in the treatment of osteoporosis . Cathepsin K expression is stimulated by inflammatory cytokines that are released after tissue injury.
  • Pycnodysostosis from (from Greek : πυκνός (puknos) meaning "dense") [1] , dys ("defective"), and ostosis ("condition of the bone"), is a lysosomal storage disease of the bone caused by a mutation in the gene that codes the enzyme cathepsin K . This is an autosomal recessive osteochondrodysplasia maps to chromosome 1q21. Cathepsin K, a cysteine protease in osteoclasts, deficiency is known to cause this condition. Interestingly, Cathepsin K became a much sought after drug target in osteoporosis after the etiology of pycnodysostosis was discovered. The disease consistently causes short stature. The height of adult males with the disease is less than 150 cm (59 inches, or 4 feet 11 inches). Adult females with the syndrome are even shorter. The disease has been named Toulouse-Lautrec syndrome, after the French artist Henri de Toulouse-Lautrec , who (it has been surmised) suffered from the disease. In 1996, the defective gene responsible for pycnodysostosis was located, offering accurate diagnosis, carrier testing and a more thorough understanding of this disorder Pycnodysostosis causes the bones to be abnormally dense ( osteopetrosis ); the last bones of the fingers (the distal phalanges ) to be unusually short; and delays the normal closure of the connections (sutures) of the skull bones in infancy, so that the "soft spot" ( fontanel ) on top of the head remains widely open. Those with the syndrome have brittle bones which easily break, especially in the legs and feet. The jaw and collar bone (clavicle) are also particularly prone to fractures. Other abnormalities involve the head and face, teeth, collar bones, skin, and nails. The front and back of the head are prominent. Within the open sutures of the skull, there may be many small bones (called wormian bones). The midface is less full than usual. The nose is prominent. The jaw can be small. The palate is narrow and grooved. The baby teeth are late coming in and may be lost much later than usual. The permanent teeth can also be slow to appear. The permanent teeth are commonly irregular and teeth may be missing (hypodontia). The collar bones are often underdeveloped and malformed. The skin over the back of the fingers is very wrinkled. The nails are flat and grooved. Pycnodysostosis also causes problems that may become evident with time. Aside from the broken bones, the last bones of the fingers (the distal phalanges) and the collar bone can undergo slow progressive deterioration. Vertebral defects may permit the spine to curve laterally (resulting in scoliosis). The tooth problems often require orthodontic care and dental caries are common. [ edit ] Frequency The precise frequency of pycnodysostosis has never been determined. Pycnodysostosis can be classified in the large group of genetic diseases that are individually uncommon, but collectively important because of the sum of their numbers, and their heavy impact upon affected individuals.
  • Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Odanacatib selectively and reversibly inhibited cathepsin K and rapidly decreased bone resorption in preclinical and phase I studies. A 1-year dose-finding trial with a 1-year extension on the same treatment assignment was performed in postmenopausal women with low bone mineral density (BMD) to evaluate the safety and efficacy of weekly doses of placebo or 3, 10, 25, or 50 mg of odanacatib on BMD and biomarkers of skeletal remodeling. Women with BMD T-scores of -2.0 or less but not less than -3.5 at the lumbar spine or femoral sites were randomly assigned to receive placebo or one of four doses of odanacatib; all received vitamin D with calcium supplementation as needed. The primary endpoint was percentage change from baseline lumbar spine BMD. Other endpoints included percentage change in BMD at hip and forearm sites, as well as changes in biomarkers of skeletal remodeling. Twenty-four months of treatment produced progressive dose-related increases in BMD. With the 50-mg dose of odanacatib, lumbar spine and total-hip BMD increased 5.5% and 3.2%, respectively, whereas BMD at these sites was essentially unchanged with placebo (-0.2% and -0.9%). Biochemical markers of bone turnover exhibited dose-related changes. The safety and tolerability of odanacatib generally were similar to those of placebo, with no dose-related trends in any adverse experiences. In summary, 2 years of weekly odanacatib treatment was generally well-tolerated and increased lumbar spine and total-hip BMD in a dose-related manner in postmenopausal women with low BMD.
  • Eisman: The selective cathepsin K inhibitor odanacatib (ODN) progressively increased bone mineral density (BMD) and decreased bone-resorption markers during 2 years of treatment in postmenopausal women with low BMD. A 1-year extension study further assessed ODN efficacy and safety and the effects of discontinuing therapy. In the base study, postmenopausal women with BMD T -scores between −2.0 and −3.5 at the lumbar spine or femur received placebo or ODN 3, 10, 25, or 50 mg weekly. After 2 years, patients ( n  = 189) were rerandomized to ODN 50 mg weekly or placebo for an additional year. Endpoints included BMD at the lumbar spine (primary), total hip, and hip subregions; levels of bone turnover markers; and safety assessments. Continued treatment with 50 mg of ODN for 3 years produced significant increases from baseline and from year 2 in BMD at the spine (7.9% and 2.3%) and total hip (5.8% and 2.4%). Urine cross-linked N -telopeptide of type I collagen (NTx) remained suppressed at year 3 (−50.5%), but bone-specific alkaline phosphatase (BSAP) was relatively unchanged from baseline. Treatment discontinuation resulted in bone loss at all sites, but BMD remained at or above baseline. After ODN discontinuation at month 24, bone turnover markers increased transiently above baseline, but this increase largely resolved by month 36. There were similar overall adverse-event rates in both treatment groups. It is concluded that 3 years of ODN treatment resulted in progressive increases in BMD and was generally well tolerated. Bone-resorption markers remained suppressed, whereas bone-formation markers returned to near baseline. ODN effects were reversible: bone resorption increased transiently and BMD decreased following treatment discontinuation. © 2011 American Society for Bone and Mineral Research.
  • As Americans live longer, degenerative skeletal diseases, such as osteoporosis, become increasingly prevalent. Regardless of cause, osteoporosis reflects a relative enhancement of osteoclast activity. Thus, this unique bone resorptive cell is a prominent therapeutic target. A number of key observations provide insights into the mechanisms by which precursors commit to the osteoclast phenotype and how the mature cell degrades bone. The osteoclast is a member of the monocyte/macrophage family that differentiates under the aegis of two critical cytokines, namely RANK ligand and M-CSF. Tumor necrosis factor (TNF)-α also promotes osteoclastogenesis, particularly in states of inflammatory osteolysis such as that attending rheumatoid arthritis. Once differentiated, the osteoclast forms an intimate relationship with the bone surface via the αvβ3 integrin, which transmits matrix-derived, cytoskeleton-organizing, signals. These integrin-transmitted signals include activation of the associated proteins, c-src, syk, Vav3, and Rho GTPases. The organized cytoskeleton generates an isolated microenvironment between the cell’s plasma membrane and the bone surface in which matrix mineral is mobilized by the acidic milieu and organic matrix is degraded by the lysosomal protease, cathepsin K. This review focuses on these and other molecules that mediate osteoclast differentiation or function and thus serve as candidate anti-osteoporosis therapeutic targets.
  • La vía Wnt es una vía de señalización celular muy conservada a lo largo de la escala filogenética. No es exclusiva del hueso, sino que interviene también de manera importante en otros procesos, incluyendo la embriogénesis, la organogénesis y la tumorigénesis 1,2 . La activación de esta vía induce diversas señales intracelulares que en conjunto se dividen en dos grandes grupos: la vía canónica o clásica y la vía no canónica, de las cuales la primera es la mejor conocida. El acontecimiento clave en la cascada ca nónica es la acumulación de la b-catenina en el citoplasma y su ulterior translocación al núcleo celular, donde modula la transcripción de diferentes genes (fig. 1). Fig. 1. Vía canónica: en ausencia de unión de los ligandos Wnt a su receptor (izquierda), la   b-catenina se degrada y los genes no se transcriben. Sin embargo, cuando se activa la vía (derecha) disminuye la degradación de la   b-catenina, con lo que se acumula en el citoplasma, desde donde puede entrar en el núcleo y activar los factores de transcripción. APC: proteína de la poliposis adenomatosa del colon;   b-cat:   b-catenina; cK: caseína-cinasa; Dsh: dishevelled; GSK3: glucógeno sintasa cinasa 3b; sFRP: proteína soluble similar a  frizzled ; SOST: esclerostina. En condiciones basales, cuando no se encuentra estimulada la vía Wnt, existe en la célula un complejo formado por varias proteínas, incluyendo la axina, la proteína de la poliposis adenomatosa del colon (APC) y la glucógeno sintasa cinasa 3b (GSK3). Esta última fosforila la b-catenina, lo que la hace susceptible de unirse a la ubiquitina y ser posteriormente degradada en los proteasomas. De esta manera, los nive les intracelulares de b-catenina se mantienen relativamente bajos. Sin embargo, cuando se activa la vía Wnt, por la unión de los ligandos Wnt a su receptor, se descompone el complejo axina-APC-GSK3, lo que disminuye la actividad fosforilativa de la GSK3. A su vez, ello disminuye la fosforilación de la b-catenina y en consecuencia su degradación en los proteasomas. La b-catenina hipofosforilada se acumula en el citoplasma y se transloca al núcleo, donde regula la expresión genética a través de la activación de diversos factores de transcripción, como el Tcf-Lef1 ( T cell factor/lymphocyte enhancer factor 1 ) 3 . Los ligandos Wnt actúan a través de la fijación a receptores situados en la membrana celular. Estos tienen dos componentes principales: por un lado, una proteína  frizzled  (familia de receptores transmembrana serpentinados con 7 dominios); por otro, un co-receptor relacionado con el de las LDL ( lipoprotein receptor related peptide  o LRP). Hay dos formas principales de LRP, la 5 y la 6. Es la unión de los ligandos Wnt a este complejo  frizzled -LRP5/6 lo que desencadena la inhibición del complejo axina-APC-GSK3, con el consiguiente aumento de los niveles de b-catenina. Los componentes de la vía Wnt canónica pueden por tanto agruparse de la mane ra siguiente. 1. Ligandos Wnt: son glucoproteínas hidrofóbicas que contienen cadenas de ácido palmítico unido a ciertas citosinas. Estas moléculas son capaces de fijarse al receptor e iniciar la activación de la vía. Hasta la fecha se han descubierto 19, que se denominan con números y letras (por ejemplo Wnt-5a, Wnt-10b, etc.). 2. Receptores de membrana: constituidos por las proteínas  frizzled  (de las que hay diversos tipos) y los co-receptores LRP5 y LRP6. Otra molécula que puede actuar como co-receptor es la llamada kremen. 3. Efectores intracelulares: forman parte de cascadas complejas en las que participan diferentes proteínas. Algunas de ellas ya han sido mencionadas (axina, APC, GSK3, b-catenina, etc.). Otras moléculas implicadas incluyen las proteínas  dishevelled . 4. Antagonistas: se han descrito diversos tipos de moléculas con acción inhibidora sobre la vía Wnt. En algunos casos se trata de moléculas que actúan como señuelos que se fijan a los ligandos Wnt y compiten así por su fijación al receptor. Es el caso de algunas proteínas solubles tipo  frizzled  que son segregadas al medio extracelular. Otra molécula inhibidora es la esclerostina, codificada por el gen SOST, que se expresa en los osteocitos. La esclerostina parece fijarse a LRP5/6, impidiendo la formación del complejo LRP5/6- frizzled -Wnt. Otras moléculas capaces de antagonizar las señales Wnt por unirse a los co-receptores LRP5/6 y kremen son las de la familia  dickkopf.  Hay al menos cuatro miembros de esta familia, de los cuales el tipo 1 (Dkk-1) es especialmente importante en el hueso 4 . La vía Wnt es una vía de señalización celular implicada en múltiples procesos orgánicos. A nivel del esqueleto su papel mejor conocido es la regulación de la actividad osteoblástica (proliferación, funcionamiento y apoptosis), pero también parece tener efectos moduladores de los osteoclastos. El interés en la vía de señalización Wnt continúa expandiéndose rápidamente. Tras ser descubiertas hace 20 años, las proteínas Wnt se mencionan en más de 5.000 artículos incluidos en Medline, la mitad de los cuales se han publicado en los últimos 3 años. Cada vez disponemos de más evidencias de que las modificaciones de la señalización Wnt son un factor contribuyente en muchos trastornos esqueléticos. Por otro lado, la vía Wnt parece estar implicada en la patogenia de otras en fermedades, tan diversas como el cáncer o la esquizofrenia 28 . Además, las proteínas Wnt parece que expanden, o al menos mantienen, ciertas poblaciones de células madre indiferenciadas 29 . Por tanto, la vía Wnt incluye dianas potenciales para agentes terapéuticos frente a diversas enfermedades. Cabe mencionar en esta línea los estudios que muestran que el bloqueo de la esclerostina aumenta la masa ósea en animales de experimentación. No obstante, quedan muchos interrogantes. Algunas de las cuestiones pendientes son: cómo se inicia la señalización tras la unión de Wnt a su receptor, qué mecanismos están implicados en la regulación de la actividad del complejo fosforilador de la b-catenina y, sobre todo, cómo se consi gue la especificidad en la actividad nuclear de la b-catenina y la regulación de genes diana. En cuanto al campo específico de la osteoporosis, es especialmente relevante conocer cuál es el papel real de esta vía en la osteoporosis primaria. Para profundizar en el conocimiento de la vía Wnt, el lector interesado puede consultar la página del profesor Roel Nusse, quien ha efectuado contribuciones notables al estudio de esta vía de señalización
  • En estudios  in vitro  se ha demostrado que la activación de la vía Wnt favorece la diferenciación de los precursores osteoblásticos a través de la inducción de Runx2/Cbaf y otros factores de transcripción 6,7 . Por el contrario, los elementos inhibidores de esta vía, como la proteína soluble frizzled , tienen un efecto negativo sobre la supervivencia de los osteoblastos 8 . Por otro lado, los estudios con animales transgénicos han demostrado importan tes cambios esqueléticos cuando se altera la expresión de algunos genes de esta vía, como Wnt-10b, b-catenina, la proteína soluble frizzled  o las propias LRP5 y LRP6. Las primeras evidencias directas de la importancia de la vía Wnt en la homeostasis esquelética en humanos surgieron a partir del descubrimiento de que dos raros fenotipos óseos estaban causados por mutaciones de la LRP5. Uno de ellos es un tipo muy infrecuente de osteoporosis, el llamado síndrome de pseudoglioma-osteoporosis (cuyas siglas en inglés son OPPG), enfermedad autosómica recesiva que cursa con ceguera por crecimiento vascular anormal, fracturas y deformidades de las extremidades 9 . En contraposición con el síndrome OPPG, se ha descrito el fenotipo de alta densidad ósea (HBM,  high bone mass ), con herencia autosómica dominante, valores de Z $ 5, elevación de los marcadores de formación ósea y resorción normal 10-12 . Tanto el OPPG como el HBM se deben a mutaciones en el gen LRP5, si bien en el primer caso se trata de mutaciones inhibidoras y, en el segundo, de mutaciones activadoras. La enfermedad de Van Buchem y la esclerosteosis son otros trastornos relacionados con la vía Wnt que cursan con aumento de la masa ósea. Se deben a mutaciones en el gen de la esclerostina, un inhibidor de Wnt. Esos casos de mutaciones demuestran fehacientemente la implicación de la vía Wnt en la homeostasis esquelética, pero, dada su rareza, tienen poca relevancia directa en la patogenia de la osteoporosis. No obstante, varios investigadores han analizado si algunos polimorfismos frecuentes de ciertos genes de la vía Wnt se asocian a diferencias en la densidad mineral ósea y podrían, por tanto, desempeñar algún papel en la predisposición genética a la osteoporosis. Así, aunque los resultados no son totalmente concluyentes, se ha sugerido que, efectivamente, ciertos polimorfismos de los genes Wnt10b, LRP5, LRP6 y SOST pueden influir en la masa ósea 13-16 . SOST-related sclerosing bone dysplasia is a disorder of bone development characterized by excessive bone formation (hyperostosis). As a result of hyperostosis, bones throughout the body are denser and wider than normal, particularly the bones of the skull. Affected individuals typically have an enlarged jaw with misaligned teeth. People with this condition may also have a sunken appearance of the middle of the face (midface hypoplasia), bulging eyes with shallow eye sockets (ocular proptosis), and a prominent forehead. People with this condition often experience headaches because increased thickness of the skull bones increases pressure on the brain. The excessive bone formation seen in this condition seems to occur throughout a person's life, so the skeletal features become more pronounced over time. However, the excessive bone growth may only occur in certain areas. Abnormal bone growth can pinch (compress) the cranial nerves, which emerge from the brain and extend to various areas of the head and neck. Compression of the cranial nerves can lead to paralyzed facial muscles (facial nerve palsy), hearing loss, vision loss, and a sense of smell that is diminished (hyponosmia) or completely absent (anosmia). Abnormal bone growth can cause life-threatening complications if it compresses the part of the brain that is connected to the spinal cord (the brainstem). There are two forms of SOST-related sclerosing bone dysplasia: sclerosteosis and van Buchem disease. The two forms are distinguished by the severity of their symptoms. Sclerosteosis is the more severe form of the disorder. People with sclerosteosis are often tall and have webbed or fused fingers (syndactyly), most often involving the second and third fingers. The syndactyly is present from birth, while the skeletal features typically appear in early childhood. People with sclerosteosis may also have absent or malformed nails. Van Buchem disease represents the milder form of the disorder. People with van Buchem disease are typically of average height and do not have syndactyly or nail abnormalities. Affected individuals tend to have less severe cranial nerve compression, resulting in milder neurological features. In people with van Buchem disease, the skeletal features typically appear in childhood or adolescence. SOST-related sclerosing bone dysplasia is caused by mutations in or near the SOST gene. The SOST gene provides instructions for making the protein sclerostin. Sclerostin is produced in osteocytes, which are a type of bone cell. The main function of sclerostin is to stop (inhibit) bone formation. Mutations in the SOST gene that cause sclerosteosis prevent the production of any functional sclerostin. A lack of sclerostin disrupts the inhibitory role it plays during bone formation, causing excessive bone growth. SOST mutations that cause van Buchem disease result in a shortage of functional sclerostin. This shortage reduces the protein's ability to inhibit bone formation, causing the excessive bone growth seen in people with van Buchem disease. Read more about the SOST gene.
  • Sclerostin, the product of the SOST gene, located on chromosome 17, locus q11.2 in humans, was originally believed to be a non-classical  Bone morphogenetic protein  (BMP) antagonist. More recently Sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the  Wnt signalling pathway  . [5]  Wnt pathway inhibition under these circumstances is antagonistic to bone formation (meaning Sclerostin antagonizes bone formation). [6] Although the underlying mechanisms are unclear, it is believed that the antagonism of BMP-induced bone formation by sclerostin is mediated by Wnt signalling, but not BMP signalling pathways. [7] [8] The mechanism of action is likely to be similar for the related protein  DKK1 , which has a broader tissue distribution. Sclerostin production by osteocytes is inhibited by  parathyroid hormone , mechanical loading and cytokines including  oncostatin M ,  cardiotrophin-1  and leukemia inhibitory factor . Sclerostin production is increased by  calcitonin . Thus, osteoblast activity is self regulated by a negative feedback system. [9] [ edit ]Clinical significance Mutations of Sclerostin is associated with the syndrome  Sclerosteosis  in which there is an abnormal increase in the growth of bones due to lack of normal Sclerostin expression by  osteocytes  and a different set of mutations in the non-coding region of sclerostin are associated with Van Buchem's syndrome, a similar high bone mass phenotype. Sclerostin acts upon  osteoblasts  in the bone in a paracrine manner of unknown mechanism. Currently an anti-sclerostin  antibody  for the treatment of  osteoporosis  is being co-developed by  Amgen  and  UCB . [10]  In addition, OsteoGeneX is developing small molecule inhibitors of sclerostin. [11] SOST-related sclerosing bone dysplasia is a disorder of bone development characterized by excessive bone formation (hyperostosis). As a result of hyperostosis, bones throughout the body are denser and wider than normal, particularly the bones of the skull. Affected individuals typically have an enlarged jaw with misaligned teeth. People with this condition may also have a sunken appearance of the middle of the face (midface hypoplasia), bulging eyes with shallow eye sockets (ocular proptosis), and a prominent forehead. People with this condition often experience headaches because increased thickness of the skull bones increases pressure on the brain. The excessive bone formation seen in this condition seems to occur throughout a person's life, so the skeletal features become more pronounced over time. However, the excessive bone growth may only occur in certain areas. Abnormal bone growth can pinch (compress) the cranial nerves, which emerge from the brain and extend to various areas of the head and neck. Compression of the cranial nerves can lead to paralyzed facial muscles (facial nerve palsy), hearing loss, vision loss, and a sense of smell that is diminished (hyponosmia) or completely absent (anosmia). Abnormal bone growth can cause life-threatening complications if it compresses the part of the brain that is connected to the spinal cord (the brainstem). There are two forms of SOST-related sclerosing bone dysplasia: sclerosteosis and van Buchem disease. The two forms are distinguished by the severity of their symptoms. Sclerosteosis is the more severe form of the disorder. People with sclerosteosis are often tall and have webbed or fused fingers (syndactyly), most often involving the second and third fingers. The syndactyly is present from birth, while the skeletal features typically appear in early childhood. People with sclerosteosis may also have absent or malformed nails. Van Buchem disease represents the milder form of the disorder. People with van Buchem disease are typically of average height and do not have syndactyly or nail abnormalities. Affected individuals tend to have less severe cranial nerve compression, resulting in milder neurological features. In people with van Buchem disease, the skeletal features typically appear in childhood or adolescence.
  • Antagosnista de la via Wnt: his gene encodes a protein that is a member of the dickkopf family. It is a secreted protein with two cysteine rich regions and is involved in embryonic development through its inhibition of the WNT signaling pathway. Elevated levels of DKK1 in bone marrow plasma and peripheral blood is associated with the presence of osteolytic bone lesions in patients with  multiple myeloma . [1]
  • GSK-3 is also integrally tied to pathways of cell proliferation and apoptosis. GSK-3 has been shown to phosphorylate  Beta-catenin , thus targeting it for degradation. [13]  GSK-3 is therefore a part of the canonical  Beta-catenin / Wnt  pathway, which signals the cell to divide and proliferate. GSK-3 also participates in a number of apoptotic signaling pathways by phosphorylating transcription factors that regulate apoptosis . [3]  GSK-3 can promote apoptosis by both activating pro-apoptosis factors such as  p53   [14]  and inactivating survival-promoting factors through phosphorylation. [15]  The role of GSK-3 in regulating apoptosis is controversial, however, as some studies have shown that GSK-3β knockout mice are overly sensitized to apoptosis and die in the embryonic stage, while others have shown that overexpression of GSK-3 can induce apoptosis. ecreted frizzled-related protein 1 (SFRP1) is a member of the SFRP family that contains a  cysteine -rich domain homologous to the putative Wnt-binding site of  Frizzled  proteins. SFRPs act as soluble modulators of  Wnt signaling . SFRP1 and SFRP5 may be involved in determining the polarity of photoreceptor cells in the retina. SFRP1 is expressed in several human tissues, with the highest levels in heart. [1] The Secreted frizzled-related protein (SFRP) family consists of five secreted glycoproteins in humans (SFRP1,  SFRP2 ,  SFRP3 , SFRP4, SFRP5) that act as extracellular signaling ligands. Each SFRP is ~300 amino acids in length and contains a cysteine-rich domain (CRD) that shares 30-50% sequence homology with the CRD of Frizzled (Fz) receptors. SFRPs are able to bind Wnt proteins and Fz receptors in the extracellular compartment. The interaction between SFRPs and Wnt proteins prevents the latter from binding the Fz receptors. [2]  SFRPs are also able to downregulate Wnt signaling by the formation of an inhibitory complex with the Frizzled receptors. [3]  The Wnt pathway plays a key role in embryonic development, cell differentiation and cell proliferation. It has been shown that the deregulation of this critical developmental pathway occurs in several human tumor entities. [4] SFRP1 is a 35 kDa prototypical member of the SFRP family. It acts as a biphasic modulator of Wnt signaling, counteracting Wnt-induced effects at high concentrations and promoting them at lower concentrations. [5]  It is located in a chromosomal region (8p12-p11.1) that is frequently deleted in breast cancer and is thought to harbour a tumor suppressor gene. [6]
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    • 1. Nuevas perspectivas en el tratamiento farmacológico de la osteoporosis Dr. Josep Blanch-Rubió Reumatólogo. Consultor 3 Unidad de Metabolismo óseo. Servicio de Reumatología Hospitales Universitarios del Mar i de l’Esperança. Parc de Salut-MarUnitat de Recerca en Fisiopatològia Óssia i Articular (URFOA). Institut Municipal de Investigacions Mèdiques (IMIM) Barcelona
    • 2. Esquema • Los antiosteoporóticos actuales • Cambio de paradigma: “De la química a la biología molecular” Vías de señalización Nuevas dianas terapéuticas • Antirresortivos: Catepsina K Integrina αVβ3 Canal de cloro/ATPasa vacuolar Src-Kinasa
    • 3. Esquema • Terapias anabólicas: Vía de señalización Wnt/ß-Catenina Esclerostina DKK-1 GSK3/sFRP-1 Receptor sensor de calcio PTHrP • Conclusiones
    • 4. Eficacia en la reducción del riesgo de Fx. de los tratamientosantiosteoporóticos actuales. Calidad de la evidencia
    • 5. Biología molecular: Osteocitos, osteoblastos y osteoclastos
    • 6. Antirresortivos Dianas terapéuticas: • Catepsina K • Integrina αvβ3 • Canal de cloro/ATPasa vacuolar • Src-kinasa
    • 7. Inhibidores de la Catepsina K Rachner TD et al. Osteoporosis: now and the future. Lancet 2011; 377: 1276-87 La Catepsina K es el enzima proteolítico más importante del Osteoclasto. Participa en la resorción y remodelado óseo catabolizando elastina, colágeno y gelatina (hueso y cartílago) Inaoka T et al. Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone. Biochem Biophys Res Commun 1995; 206: 89 –96.
    • 8. Inhibidores de la Catepsina K. Sde. de Toulouse-Lautrec La mutación del gen de la Catepsina K causa picnodisostosis Los ratones knock out para Catepsina K presentan osteoesclerosis Saftig P et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci USA 1998; 95: 13453-8.
    • 9. Inhibidores de la Catepsina K: Odanacatib • Los pacientes tratados con Odanacatib, 50 mg/semana, vía oral, presentaron a los 2 años, un aumento significativo de la DMO: – Columna lumbar: 5,3% – Cuello de fémur: 3,8% – Cadera total: 3,2 % • No se evidenciaron efectos adversos relevantes Bone HG et al. Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J Bone Miner Res 2010; 25: 937-47.
    • 10. Inhibidores de la Catepsina K: Odanacatib A los tres años de tratamiento continua aumentando la DMO: - Columna lumbar: 7.9% (2.3%) - Cadera total: 5.8% (2.4%) Si el medicamento se suspende, se empieza a perder DMO Sin efectos secundarios importantesEisman JA et al. Odanacatib in the treatment of postmenopausal women with low bone mineraldensity: three-year continued therapy and resolution of effect. J Bone Miner Res 2011; 26:242-251.
    • 11. Odanacatib: Estudios en marcha A study of MK0822 in postmenopausal women with osteoporosis to assess fracture risk. Fase III. Activo. A study to assess safety and efficacy of odanacatib (MK0822) in men with osteoporosis A study to evaluate the safety, tolerability, and efficacy of odanacatib (MK0822) in postmenopausal women previously treated with bisphosphonate ClinicalTrials.gov (14/6/2012)
    • 12. Inhibición de los canales de cloro y de la ATPasa vacuolar Los canales del cloro y la ATPasa vacuolar acidifican la zona de degradación Teitelbaum SL. Osteoclasts: What do they do and how do they do it ? Am J Pathol 2007; 170: 427-35.
    • 13. Inhibición de los canales de cloro y de la ATPasa vacuolar El déficit funcional de ATPasa vacuolar causa osteopetrosis Frattini A et al. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 2000; 25: 343-6. Mutaciones en el gen CLCN7 producen osteopetrosis Pangrazio A et al. Molecular and clinical heterogeneity in CLCN7- dependent osteopetrosis: report of 20 novel mutations. Human Mutat 2009. DOI: 10.1002/humu.21167 En modelos animales, la administración de un inhibidor de los canales del cloro aumentan la masa ósea Schaller S et al. The chloride channel inhibitor NS3736 prevents bone resorption in ovariectomized rats without changing bone formation. J Bone Miner Res 2004; 19: 1144-53.
    • 14. Inhibidores de la Src-Kinasa Rachner TD et al. Osteoporosis: now and the future. Lancet 2011; 377: 1276-87 La Src-Kinasa es imprescindible para el buen funcionamiento del Osteoclasto al permitir la formación del “borde en cepillo” Horner WC et al. The role of Src kinase and Cb1 proteins in the regulation of osteoclast diffentiation and function. Immunol Res 2005¨; 208: 106-125.
    • 15. Inhibidores de la Src-Kinasa: Saracatinib En modelos animales, la inactivación de Src-Kinasa causa osteopetrosis Horner WC et al. The role(s) of Src kinase and Cb1 proteins in the regulation of osteoclast differentiation and function. Immunol Rev 2005; 208: 106-25. En un ensayo de fase 1, realizado en varones, la administración de saracatinib causó un descenso de los marcadores de resorción, sin que se alteraran los valores de los marcadores de formación. No se produjeron efectos adversos relevantes. Hannon RA et al. Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: a randomized , doubleblind, placebo-controlled, multiple ascending dose phase I trial. J Bone Miner Res 2010; 25: 463-71.
    • 16. Saracatinib: Estudios en marcha A placebo controlled study of saracatinib (AZD0530) in patients with recurrent osteosarcoma localized to the lung Saracatinib in treating patients with prostate cancer Study to evaluate the safety and effects of AZD0530 on prostate and breast cancer subjects with metastasic bone diseases ClinicalTrials.gov
    • 17. Terapias anabólicas: Dianas terapéuticas • Vía de señalización Wnt/ß-Catenina: Esclerostina DKK-1 GSK3/sFRP-1 • Receptor sensor de calcio • PTHrP
    • 18. Modulación de la vía de señalización Wnt/ß-Catenina:Esclerostina, Dkk1, GSK3, sFRP OB no activado Esclerostina OB activado Riancho JA, Velasco J. Rev Esp Enf Met Oseas 2008; 17: 5-9
    • 19. Alteraciones del gen SOST: Déficit de esclerostina La esclerostina frena la formación ósea por su efecto sobre la via WnT/ß-catenina La enfermedad de Van Buchem y la esclerosteosis son consecuencia de una alteración del gen SOST (déficit de esclerostina). Loots GC et al. Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Res 2005; 15: 928-935 Piters E et al. First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function. Hum Mutat 2010; 87: 99-107
    • 20. Ac. antiesclerostina En modelos animales, la administración de anticuerpos frente a la esclerostina causa aumento de la masa ósea. Li X et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 2009; 24: 578- 588. Ominsky MS et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density and bone strengh. J Bone Miner Res 2010; 25: 948 -59. En un ensayo en fase 1, la administración de un anticuerpo frente a esclerostina (AMG-785) produjo un aumento de masa ósea y de los marcadores de formación y un descenso de los marcadores de resorción Padhi D et al. Single-dose, placebo-controlled, randomized study of AMG785, a sclerostin monoclonal antibody. J Bone Miner Res 2011; 26: 19 – 26.
    • 21. Ac. antiesclerostina Phase 2 study of AMG-785 in postmenopausal women with low bone mineral densitiy Study to assess fracture healing with sclerostin antibody Study of AMG-785 in tibial dyaphiseal fractures status post intramedullary nailing ClinicalTrials.gov
    • 22. Ac. anti-Dkk1 En modelos animales, los valores de Dkk-1 se correlacionan de forma inversa con la masa ósea McDonald Bt et al. Bone mass is inversely proportional to Dkk1 levels in mice. Bone 2007; 41: 331-9. En modelo animal, la administración de anticuerpos anti-Dkk1 aumenta los valores de P1NP e induce la formación de masa ósea Glantsching H et al. Fully human anti-Dkk1 antibodies increase bone formation and resolve osteopenia in mouse models of estrogendefiency induced bone loss . J Bone Miner Res 2008; 23(supl1). S60 (resumen ). Potencial papel de los Ac. anti-Dkk1 en la osteolisis por mieloma múltiple Fulciniti M et al. Anti-Dkk1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood 2009; 114: 371 – 9.
    • 23. Modulación de la vía de señalización Wnt/ß-Catenina:Problemas El aumento de la vía de señalización Wnt puede no estar exenta de importantes efectos adversos como: - cáncer colorectal, hepatocarcinoma - Wnt inhibitory factor (inhibidor natural) se constató su ausencia en un 75% de osteosarcomas A largo plazo, el bloqueo con WnT antagonistas, podría provocar importantes efectos adversos esqueléticos y extraexqueléticos Rachner TD et al. Osteoporosis: now and the future. Lancet 2011; 377: 1276-87
    • 24. Receptor sensor del calcio Rachner TD et al. Osteoporosis: now and the future. Lancet 2011; 377: 1276-87 El antagonismo transitorio del RSCa, causa un aumento puntual de la PTH endógena (efecto anabólico sobre el hueso). Trivedi R et al. Recent updates on the calcium-sensing receptor as a drug target. Curr Med Chem 2008; 15: 178-86.
    • 25. Antagonistas del receptor sensor del calcio En un ensayo de fase 1, se observó que la administración de Ronacaleret producía un aumento rápido y transitorio de la PTH y de los marcadores de formación ósea. No se produjeron efectos adversos relevantes En un ensayo de fase 2, realizado en mujeres posmenopáusicas con osteoporosis, no se observó un efecto significativo de Ronacaleret sobre la DMO (suspensión del ensayo por: falta de eficacia y farmacocinética desfavorable) Balan G et al. The discovery of novel calcium-sensing receptor negative allosteric modulators. Bioorg Med Chem Lett 2009; 19: 3328-3332. Kumar S et al. An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation. Bone 2010: 46: 3328-3332.
    • 26. Antagonistas del receptor sensor del calcio: Estudios enmarcha MK5442 in the treatment of osteoporosis in postmenopausal women previously treated with oral bisphosphonate A dose ranging study of MK5442 in postmenpausal women with osteoporosis ClinicalTrials.gov
    • 27. PTHrP: Acciones paracrinas en hueso PTH-rP actúa sobre los progenitores de los OB estimulando la formación de OB maduros y reduce la apoptosis de los OB y OC maduros. En un ensayo Fase 1 demostró incrementos de la DMO. Está en marcha un estudio comparativo contra PTH (1-34) para evaluar eficacia sobre la DMO. Martin TJ. J Clin Invest 2005;115: 2322-2324
    • 28. Conclusiones Los tratamientos antiosteoporóticos actuales han demostrado una razonable eficacia en ensayos clínicos pero, debido a problemas de seguridad y cumplimiento terapéutico, existe la necesidad de desarrollar nuevos fármacos La mejor comprensión de la fisiopatología de la osteoporosis ha permitido la identificación de nuevas dianas terapéuticas y el desarrollo de noveles moléculas moduladoras
    • 29. Conclusiones Entre los antirresortivos, el más avanzado en el desarrollo clínico es el inhibidor de la Catepsina K, Odanacatib De los moduladores de la vía WnT/ß-Catenina ,el Ac. antiesclerostina es el que presenta mejores perspectivas
    • 30. Conclusiones La mejor comprensión de la fisiopatología ósea a nivel molecular, celular y paracrino, va permitir el desarrollo de nuevos fármacos antiosteoporóticos más eficaces, con menores efectos secundarios y con un mejor cumplimiento y adherencia terapéutica Parc de Recerca Biomèdica de Hospital del Mar Barcelona. Institut Municipal de Investigacions Mèdiques

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