Summary Intermittent PTH administration builds bone mass and prevents fractures, but its mechanism of action is unclear. We genetically deleted the PTH/PTHrP Receptor (PTH1R) in mesenchymal stem cells using Prx1Cre and found low bone formation, increased bone resorption and high bone marrow adipose tissue (BMAT). Bone marrow adipocytes traced to Prx1 and expressed classic adipogenic markers and high receptor activator of nuclear factor kappa-B ligand (Rankl) expression. RANKL levels were also elevated in bone marrow supernatant and serum, but undetectable in other adipose depots. By cell sorting, Pref1+RANKL+ marrow progenitors were twice as great in mutant versus control marrow. Intermittent PTH administration to control mice reduced BMAT significantly. A similar finding was noted in male osteoporotics. Thus, marrow adipocytes exhibit osteogenic and adipogenic characteristics, are uniquely responsive to PTH, and secrete RANKL. These studies reveal an important mechanism for PTH’s therapeutic action through its ability to direct mesenchymal cell fate.

Reactive oxygen species such as superoxide anion radicals (O2 (-) ) and hydrogen peroxide (H2 O2 ) have for long time been recognized as undesirable by-products of the oxidative mitochondrial generation of adenosine triphosphate (ATP). Recently, these highly reactive species have been associated to important signaling pathways in diverse physiological conditions such as those activated in hypoxic microenvironments. The molecular response to hypoxia requires fast-acting mechanisms acting within a wide range of partial pressures of oxygen (O2 ). Intracellular O2 sensing is an evolutionary preserved feature, and the best characterized molecular responses to hypoxia are mediated through transcriptional activation. The transcription factor, hypoxia-inducible factor 1 (HIF-1), is a critical mediator of these adaptive responses, and its activation by hypoxia involves O2 -dependent posttranslational modifications and nuclear translocation. Through the induction of the expression of its target genes, HIF-1 coordinately regulates tissue O2 supply and energetic metabolism. Other transcription factors such as nuclear factor κB are also redox sensitive and are activated in pro-oxidant and hypoxic conditions. The purpose of this review is to summarize new developments in HIF-mediated O2 sensing mechanisms and their interactions with reactive oxygen species-generating pathways in normal and abnormal physiology.

Since the 1970s, the establishment and development of the biotech industry has improved exponentially, allowing the commercial production of biopharmaceutical proteins. Nowadays, new recombinant protein production is considered a multibillion-dollar market, in which about 25% of commercial pharmaceuticals are biopharmaceuticals. But to achieve a competitive production process is not an easy task. Any production process has to be highly productive, efficient and economic. Despite that the perfect host is still not discovered, several research groups have chosen Pichia pastoris as expression system for the production of their protein because of its many features. The attempt of this review is to embrace several research lines that have adopted Pichia pastoris as their expression system to produce a protein on an industrial scale in the health care industry.

In the past two decades, Chile has developed intense mining activity in the Andes mountain range, whose altitude is over 4,000 meters above sea level. It is estimated that a workforce population of over 55,000 is exposed to high altitude hypobaric hypoxia. The miners work under shift systems which vary from 4 to 20 days at the worksite followed by rest days at sea level, in a cycle repeated for several years. This Chronic Intermittent Hypoxia (CIH) constitutes an unusual condition for workers involving a series of changes at the physiological, cellular and molecular levels attempting to compensate for the decrease in the environmental partial pressure of oxygen (PO 2 ). The mine worker must become acclimatized to CIH, and consequently undergoes an acute acclimatization process when he reaches the worksite and an acute reverse process when he reaches sea level. We have observed that after a period of 3 to 8 years of CIH exposure workers acclimatize well, and evidence from our studies and those of others indicates that CIH induces acute and chronic multisystem adjustments which are eff ective in off setting the reduced availability of oxygen at high altitudes. The aims of this review are to summarize fi ndings of the physiological responses to CIH exposure, highlighting outstanding issues in the fi eld.