The functions of bone (s) are (i) mechanical support of soft tissues,(ii) levers for muscle action,(iii) protection of the central nervous system,(iv) release of calcium and other ions for the maintenance of a constant ionic environment in the extracellular fluid, and (v) housing and support of hemopoiesis. The structure and amount of bone, both at the macroscopic and microscopic level, are determined by the genetic blueprint and by regulatory factors that help carry out bone functions. Genetic information is responsible for the highly conserved anatomical shape of bones and most likely for restoring that shape after fracture. To accomplish its functions, bone undergoes continuous destruction, called resorption, carried out by osteoclasts, and formation by osteoblasts. In the adult skeleton, the two processes are in balance, maintaining a constant, homeostatically controlled amount of bone. This fact, as well as the histological observation that osteoclastic bone resorption is followed by osteoblastic bone formation (1), led to the concept that the two processes are mechanistically ‘‘coupled’’and to the search for ‘‘coupling factors.’’No single factor has been proven to link the two processes. Existing evidence suggests that multiple factors probably are involved in the maintenance of bone homeostasis. Growth factors found in bone (2), such as IGFs or TGFßs, were proposed to be released during resorption and initiate local bone formation (3, 4). Factors deposited on the bone surface by osteoclasts at the end of the resorption phase were proposed to initiate the bone formation that follows (5). Humoral factors, such as parathyroid hormone and prostaglandin E, that stimulate both bone resorption and bone formation, could increase the two processes in tandem. The action of these factors and other hormones and cytokines on osteoclasts was proposed to be mediated by osteoblast-lineage cells, which possess the cognant receptors (6, 7), intimately linking osteoblast–osteoclast interaction to bone turnover. Last, but not least, the ability of bone to change its structure and adapt to mechanical loads implies that mechanical forces can regulate bone resorption and formation: increased loads should increase formation and decrease resorption whereas unloading should have the opposite effect. Indeed, immobilization stimulates resorption and suppresses formation (for review, see ref. 8), providing a clear example of ‘‘uncoupling’’between the two processes. The mechanism for these effects has not been elucidated fully, but, here again, osteoblast lineage cells, osteocytes, and lining cells were proposed to mediate the mechanical signals because their location is best suited to perceive them (9).

The link between bone formation and bone resorption was examined in an elegant study by Corral et al.(10), reported in this issue of the Proceedings, who used a transgenic model to demonstrate clear separation between the two processes in 6-to 14-week-old mice. Using the osteocalcin promoter, responsible for selective expression of this gene in mature osteoblasts, the authors destroyed these cells by expressing thymidylate kinase (tk) and by treating the animals with gancyclovir, a toxin