Chronobiology and Chronopharmacology of the Haemopoietic System
The bone marrow, an extremely complex tissue comprising approximately 4.5% of an adult’s body weight (a mass comparable to the liver) (Nathan 1988), is found in the ends of flat bones (sternum, ribs, skull, vertebrae and innominates) and contains the haem
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Chronobiology and Chronopharmacology of the Haemopoietic System R. SMAALAND
A. Outline of Haemopoiesis The bone marrow, an extremely complex tissue compnsmg approximately 4.5% of an adult's body weight (a mass comparable to the liver) (NATHAN 1988), is found in the ends of flat bones (sternum, ribs, skull, vertebrae and innominates) and contains the haemopoietic stem cells, which give rise to the many developing functional blood cell lineages within the marrow spaces. After birth, the bone marrow is the production site for all types of blood cells, which are released through vascular channels into the peripheral blood according to the needs of the body, mediated through different feedback mechanisms. Haemopoiesis is the multi-phase process of cell proliferation and gradual maturation, until the end stage is reached with a population of mature cells that can exert their specialized functions, but are no longer capable of cell proliferation (LAERUM et al. 1989). The continuous, extremely high proliferative capacity of the bone marrow is rivalled only by the skin and the intestinal mucosa, both of which have been shown to exhibit circadian rhythms in humans (SCHEVING 1959; FISHER 1968; BUCHI et al. 1991). It has been estimated that, every second, up to 2 million red cells (ERsLEv 1983; SPIVAK 1984), 2 million platelets (SPIVAK 1984) and 700000-800000 granulocytes are produced in the human bone marrow (DANCEY et al. 1976; Spivak 1984). Thus, being a labile, rapidly proliferating organ system, it is no wonder that haemopoiesis changes with time, both quantitatively and qualitatively. Until recently little recognition has been paid to possible temporal aspects in either experimental or clinical conditions. Most haematologists have assumed that a bone marrow sample taken at one time point of the day represents a constant organ function. Neither in laboratory animals, nor in man, is this true. On the contrary, both circadian and seasonal variations occur in haemopoiesis. Although this phenomenon is not generally recognized, a large, well-documented literature on this topic is now available (for recent reviews, see LAERUM and SMAALAND 1989; LAERUM et al. 1989; SLETVOLD et al. 1991; HAus 1992; SMAALAND and SOTHERN 1994). Accordingly, peripheral blood, while thought of as the mixture of fluid and formed elements which circulate within the cardiovascular system, is also more P. H. Redfern et al. (eds.), Physiology and Pharmacology of Biological Rhythms © Springer-Verlag Berlin Heidelberg 1997
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R. SMAALAND
appropriately considered as a unique organ, with its own anatomy, physiology and developmental history (SPIVAK 1984). In order to understand the biology of the bone marrow, with its temporal organization, as well as the mechanisms and effects of perturbation of the haematopoietic system, a brief overview of the developmental stages of haemopoiesis is necessary. A scheme for haemopoiesis is given in Fig. 1. Of the total haemopoietic cells, less than 0.5% are pluripotent stem cell progenitors (1 in 250 to 1 in 1000 bone
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