BackgroundSkeletons are formed in a wide variety of shapes, sizes, and compositions of organic and mineral components. Many invertebrate skeletons are constructed from carbonate or silicate minerals, whereas vertebrate skeletons are instead composed of a calcium phosphate mineral known as apatite. No one yet knows why the dynamic vertebrate skeleton, which is continually rebuilt, repaired, and resorbed during growth and normal remodeling, is composed of apatite. Nor is the control of bone and calcifying cartilage mineralization well understood, though it is thought to be associated with phosphate-cleaving proteins. Researchers have assumed that skeletal mineralization is also associated with non-crystalline, calcium- and phosphate-containing electron-dense granules that have been detected in vertebrate skeletal tissue prepared under non-aqueous conditions. Again, however, the role of these granules remains poorly understood. Here, we review bone and growth plate mineralization before showing that polymers of phosphate ions (polyphosphates: (PO3 −)n) are co-located with mineralizing cartilage and resorbing bone. We propose that the electron-dense granules contain polyphosphates, and explain how these polyphosphates may play an important role in apatite biomineralization.Principal Findings/MethodologyThe enzymatic formation (condensation) and destruction (hydrolytic degradation) of polyphosphates offers a simple mechanism for enzymatic control of phosphate accumulation and the relative saturation of apatite. Under circumstances in which apatite mineral formation is undesirable, such as within cartilage tissue or during bone resorption, the production of polyphosphates reduces the free orthophosphate (PO4 3−) concentration while permitting the accumulation of a high total PO4 3− concentration. Sequestering calcium into amorphous calcium polyphosphate complexes can reduce the concentration of free calcium. The resulting reduction of both free PO4 3− and free calcium lowers the relative apatite saturation, preventing formation of apatite crystals. Identified in situ within resorbing bone and mineralizing cartilage by the fluorescent reporter DAPI (4′,6-diamidino-2-phenylindole), polyphosphate formation prevents apatite crystal precipitation while accumulating high local concentrations of total calcium and phosphate. When mineralization is required, tissue non-specific alkaline phosphatase, an enzyme associated with skeletal and cartilage mineralization, cleaves orthophosphates from polyphosphates. The hydrolytic degradation of polyphosphates in the calcium-polyphosphate complex increases orthophosphate and calcium concentrations and thereby favors apatite mineral formation. The correlation of alkaline phosphatase with this process may be explained by the destruction of polyphosphates in calcifying cartilage and areas of bone formation.Conclusions/SignificanceWe hypothesize that polyphosphate formation and hydrolytic degradation constitute a simple mechanism for phosphate accumulation and enzymatic control of biologica...

The menopausal transition in human females, which is driven by a loss of cyclic ovarian function, occurs around age 50 and is thought to underlie the emergence of an array of health problems in aging women. Although mice do not undergo a true menopause, female mice exhibit ovarian failure long before death because of chronological age and subsequently develop many of the same age-associated health complications observed in postmenopausal women. Here we show in mice that inactivation of the proapoptotic Bax gene, which sustains ovarian lifespan into advanced age, extends fertile potential and minimizes many age-related health problems, including bone and muscle loss, excess fat deposition, alopecia, cataracts, deafness, increased anxiety, and selective attention deficit. Further, ovariectomy studies show that the health benefits gained by aged females from Bax deficiency reflect a complex interplay between ovary-dependent and -independent pathways. Importantly, and contrary to popular belief, prolongation of ovarian function into advanced age by Bax deficiency did not lead to an increase in tumor incidence. Thus, the development of methods for postponing ovarian failure at menopause may represent an attractive option for improving the quality of life in aging females.aging ͉ apoptosis ͉ menopause ͉ ovary A lthough the process of aging has been attributed in part to increased apoptosis in various tissues (1), animal models lacking cell death-regulatory genes are rarely subjected to longitudinal aging studies. In females, one of the first organ systems to fail with age is the reproductive axis, which in humans is a principal contributing factor to the onset of menopause (2). Ovarian failure, whether natural (age-related) or induced as a consequence of pathological insults, is driven by depletion of ovarian follicles, the hormonally active support structures that house oocytes, through apoptosis (3). As a consequence, dramatic changes in the endocrine activity of the female gonads ensue, which are thought to underlie the emergence of a spectrum of physiological and psychological health complications in aging females (2). Although it has been shown that aged female mice transplanted with ovaries of young donors live longer than nontransplanted control or ovariectomized females (4), it remains unclear whether postmenopausal health complications arise as a direct result of ovarian failure or simply reflect the aging process.Despite the fact that mice do not undergo a true menopause, female mice exhaust their follicle pool long before death because of chronological age (5), similar to that seen in humans (6). Further, aging female mice exhibit many of the same health complications associated with postmenopausal life in women (see below). In a previous study, we reported that oocyte and follicle loss in female mice lacking the proapoptotic Bax protein is attenuated, leading to a dramatic prolongation of ovarian function into very advanced age (7). To better understand the consequences of Bax deficiency and sustained ovar...