F. Jakob

Clinical Aspects of Hypophosphatasia: An Update

Hypophosphatasia (HPP) is a heterogeneous rare inborn error of bone and mineral metabolism caused by mutations in the ALPL gene encoding the isoenzyme, tissue-nonspecific alkaline phosphatase (TNAP). These mutations result in a decreased level of TNAP activity and increased levels of its substrates, including inorganic pyrophosphate, pyridoxal-5′-phosphate and phosphoethanolamine. Clinical presentations are highly variable, ranging from stillbirth and absence of mineralization in severe disease to mild dental problems or osteopenia in adulthood. Further clinical symptoms include defective bone mineralization with bone deformities, recurrent fractures, chronic non-bacterial osteomyelitis, craniosynostosis, neonatal seizures, nephrocalcinosis, muscular hypotonia, failure to thrive and dental abnormalities with premature exfoliation of teeth and caries. Prognosis is very poor in severe perinatal forms with most patients dying from pulmonary complications of their skeletal disease but patients with mild phenotypes (adult form or Odonto-HPP) usually do not have a limitation in their life expectancy. Although TNAP is a ubiquitous enzyme, mostly known for its crucial role during mineralization of bone and teeth, its exact biological role in different human organs is still unclear, and the pathophysiology of symptoms due to TNAP deficiency in HPP are not understood in detail. Since inflammation and tissue destruction of the musculoskeletal system may occur in HPP, TNAP may also play an important role in controlling inflammatory processes. Recent investigations provide evidence that TNAP is also essentially involved in the development of the central nervous system and might contribute to multiple functions of the human brain. HPP can be diagnosed on clinical, biochemical and radiological criteria, and genetic testing confirms the diagnosis and is useful for genetic counseling. Since clinical symptoms are highly variable, patients should be followed up by a multidisciplinary team having experience in HPP treatment. Up to now, no curative treatment of HPP is available. Therefore, symptomatic treatment in particular with regard to pain, seizures and other metabolic phenomena is most important. However, recently, enzyme replacement therapy with a bone-targeted recombinant human TNAP molecule has been reported to improve bone mineralization, respiratory function and physical activity in severely affected infants with HPP, and further clinical trials are ongoing. Hopefully, this and other new therapeutic strategies may improve the prognosis and quality of life of patients with HPP and may contribute to our understanding of bone metabolism in general.

Functional characterization of a novel mutation localized in the start codon of the tissue-nonspecific alkaline phosphatase gene

Hypophosphatasia (HPP) is a rare inborn disease caused by different mutations in the tissue-nonspecific alkaline phosphatase (ALPL) gene. Previous studies showed that gene mutations could exhibit a dominant negative effect leading to a mild HPP phenotype in heterozygous carriers. In the present report we describe the clinical and functional studies of a novel mutation localized in the start codon of transcript variant 1 of the ALPL gene from a female adult heterozygous carrier. The mutation results in translation of an N-terminally truncated protein, which might be identical to the deduced protein from ALPL transcript variant 2. When overexpressed in HEK-293 cells it does not exhibit any enzymatic activity and has no significant effect on the wild type ALPL protein. Furthermore it is not attached to the cell membrane. Due to the loss of the signal peptide an intracellular misrouting and a premature degradation is obvious. Hence the new isoform deposited in the database does not produce an active protein as it is the case in the natural mutation of our patient. Since the mutation does not produce a dominant negative protein in heterozygous carriers, the clinical phenotype in our patient and her relatives is very mild with only unspecific myalgia. However the patient developed bone marrow edema of both femoral heads during lactation after delivery of a healthy child, indicating a risk to develop alterations of bone metabolism in challenge situations. Her sister complains of identical symptoms, her father shows distinct symptoms of odonto-hypophosphatasia. The question if or if not carriers of ALPL mutations in general or only with distinct genotypes can be symptomatic in normal life or in challenge situations requires systematic clinical studies.

Pathophysiology of bone metabolism

Osteoporosis is a multifactorial disease entailing a high risk to sustain fragility fractures. Its susceptibility is determined by genetic and environmental factors and underlying diseases. Bone is rebuilt and regenerated by osteoclasts, osteoblasts and osteocytes. Local and systemic growth and differentiation factors such as Insulin-like growth factors, bone morphogenetic proteins and wnt-proteins confer anabolic signals, while the RANK/RANK-Ligand and Osteoprotegerin (OPG) system regulates bone resorption. The ratio of osteoclast stimulating RANKL and its soluble decoy receptor OPG is modulated by sex hormones, vitamin D, parathyroid hormone, local growth factors and mechanical loading. Osteocytes regulate bone mass via the bone formation inhibitor sclerostin. Bone is tightly interconnected with and regulated by the calcium/phosphate/vitamin D system via the parathyroid gland, the gut, liver and kidneys. Sex hormones are important for bone formation during adolescence and their loss in menopause/andropause exaggerates bone resorption. Basically over-activity of osteoclasts and/or functional deficits of osteoblasts can cause negative bone balance and favor osteoporosis.

Pathophysiologie des Knochenstoffwechsels

Osteoporosis is a multifactorial disease entailing a high risk to sustain fragility fractures. Its susceptibility is determined by genetic and environmental factors and underlying diseases. Bone is rebuilt and regenerated by osteoclasts, osteoblasts and osteocytes. Local and systemic growth and differentiation factors such as Insulin-like growth factors, bone morphogenetic proteins and wnt-proteins confer anabolic signals, while the RANK/RANK-Ligand and Osteoprotegerin (OPG) system regulates bone resorption. The ratio of osteoclast stimulating RANKL and its soluble decoy receptor OPG is modulated by sex hormones, vitamin D, parathyroid hormone, local growth factors and mechanical loading. Osteocytes regulate bone mass via the bone formation inhibitor sclerostin. Bone is tightly interconnected with and regulated by the calcium/phosphate/vitamin D system via the parathyroid gland, the gut, liver and kidneys. Sex hormones are important for bone formation during adolescence and their loss in menopause/andropause exaggerates bone resorption. Basically over-activity of osteoclasts and/or functional deficits of osteoblasts can cause negative bone balance and favor osteoporosis.

[Bone metastases : New aspects of pathogenesis and systemic therapy].

The occurrence of bone metastases, in particular secondary to breast and prostate cancer, represents a complex medical condition that is debilitating for affected patients. In order to provide an efficient and personalized therapy, an interdisciplinary treatment approach is mandatory; therefore, systemic pharmacological therapy represents a core element of the overall treatment concept. In terms of pathophysiology, the cancer cells cause a massive disturbance of the local bone microenvironment, which as a rule leads to activation of bone resorbing osteoclasts. In addition to bisphosphonates, which can be considered classical antiresorptive agents, the monoclonal receptor activator of nuclear factor-kappa B ligand (RANKL) antibody denosumab has been in use in clinical practice since 2011. The alpha-emitting radioisotope Alpharadin was also recently approved for the treatment of metastatic prostate cancer. This article provides a summary of the most recent knowledge on the pathogenesis of how cancer cells alter the bone microenvironment as well as a review of established and future systemic treatment options.

Zelluläre Defekte und Regulationsstörungen bei der Heilung osteoporotischer Frakturen

Osteoporose besteht in einer gestorten Adaptation des Knochens an mechanische Anforderungen des Alltags und resultiert im Auftreten von Fragilitatsfrakturen vorwiegend der Wirbelkorper, des Femur, des Radius und des Humerus. Uber lange Zeit wurde diskutiert, ob die Frakturheilung bei Osteoporose uberhaupt gestort ist, vor allem wegen der Schwierigkeit, geeignete Messparameter fur den Ablauf der Frakturheilung zu finden. In den vergangenen Jahren ist auf der Basis praklinischer und klinischer Daten ein Konsensus dahingehend wahrzunehmen, dass bei Osteoporose die Frakturheilung verzogert ablauft und dass nach operativer Versorgung das Implantatversagen gehauft auftritt. Molekulare Ursachen fur diese gestorte Frakturheilung sind bislang nicht in extenso untersucht. Arbeitshypothesen leiten sich aus den modifizierbaren und nicht modifizierbaren Risikofaktoren fur die Osteoporose ab und betreffen somit hauptsachlich den Mangel an Sexualhormonen, das Alter, die Immobilisation und die gestorte Mechanotransduktion, sowie den genetischen Hintergrund der Osteoporose. Erste praliminare Daten aus mesenchymalen Stammzellen im hoheren Alter und bei Osteoporose weisen darauf hin, dass die gestorte Regeneration und Knochenheilung eine Folge der verminderten Anzahl an kolonieformenden Stammzellen ist, deren Funktion im Sinne der Migration und Rekrutierung gestort ist, deren Mechanosensitivitat vermindert ist und die fruhzeitig autoinhibitorische Proteine exprimieren und in die Seneszenz eintreten. Viele Hinweise konzentrieren sich auf den wnt/frz-Signalweg und dessen Hemmproteine wie „secreted frizzled related proteins“ SFRP und Sclerostin. Die Erforschung der Frakturheilung in monogenetischen Osteoporosemodellen und in menschlichen Zellen mit Regenerationspotential wird sicher spezifische Defekte aufdecken, die es erlauben, gezielte Interventionsstudien zur Verbesserung der Frakturheilung bei Osteoporose praklinisch und klinisch durchzufuhren.

Die Maus als Tiermodell in der Frakturheilungsforschung

Mausmodelle werden mehr und mehr fur die Frakturheilungsforschung eingesetzt. Es stehen zahlreiche verschiedene Mausstamme zur Verfugung. Zu beachten ist jedoch, dass sich die verschiedenen Mausstamme zum Teil erheblich bezuglich Knochenphanotyp und Heilungscharakteristik unterscheiden. Zudem sind auch in der Maus standardisierte und mechanisch kontrollierte Frakturmodelle obligatorisch, da die mechanischen Bedingungen das Versuchsergebnis erheblich beeinflussen. Die standardisierte Frakturfixation ist in der Maus aufgrund der geringen Skelettgrose eine technische Herausforderung. Inzwischen gibt es jedoch eine Reihe kommerziell verfugbarer Osteosynthesesysteme fur das Mausefemur, mit denen kontrollierte Studien moglich sind. Es konnen Marknagel, Platten oder Fixateur externe verwendet werden. Alle Systeme haben verschiedene Vor- und Nachteile, die bei der Auswahl des Versuchsdesigns fur die jeweilige Fragestellung berucksichtigt werden mussen. Durch diese methodischen Fortschritte werden genetisch veranderte Mausmodelle fur die Forschung nutzbar gemacht. Durch Ausschalten, Uber- oder sogar ektopische Expression eines einzelnen Gens in der Maus kann nicht nur seine physiologische bzw. pathologische Bedeutung, sondern auch ein moglicher pharmakologischer Effekt uberpruft werden. Mausmodelle stellen damit ein sehr wertvolles Werkzeug fur die Frakturheilungsforschung dar, wenn auch die Bedeutung der gewonnenen Erkenntnisse im Grostiermodell und im Menschen uberpruft werden muss.

Pathophysiologie des Knochenstoffwechsels@@@Pathophysiology of bone metabolism

Osteoporosis is a multifactorial disease entailing a high risk to sustain fragility fractures. Its susceptibility is determined by genetic and environmental factors and underlying diseases. Bone is rebuilt and regenerated by osteoclasts, osteoblasts and osteocytes. Local and systemic growth and differentiation factors such as Insulin-like growth factors, bone morphogenetic proteins and wnt-proteins confer anabolic signals, while the RANK/RANK-Ligand and Osteoprotegerin (OPG) system regulates bone resorption. The ratio of osteoclast stimulating RANKL and its soluble decoy receptor OPG is modulated by sex hormones, vitamin D, parathyroid hormone, local growth factors and mechanical loading. Osteocytes regulate bone mass via the bone formation inhibitor sclerostin. Bone is tightly interconnected with and regulated by the calcium/phosphate/vitamin D system via the parathyroid gland, the gut, liver and kidneys. Sex hormones are important for bone formation during adolescence and their loss in menopause/andropause exaggerates bone resorption. Basically over-activity of osteoclasts and/or functional deficits of osteoblasts can cause negative bone balance and favor osteoporosis.