The functions of bones are mechanical support of soft tissues, leverage for muscle activity, protection of the central nervous system, release of calcium and other ions to maintain a constant ionic environment in the extracellular fluid, and accommodation and support of hematopoiesis. The structure and amount of bone, both at the macroscopic and microscopic levels, are determined by the genetic blueprint and the regulatory factors that help the bones function. Genetic information is responsible for the high conservation of the anatomical shape of the bones and, most likely, for the restoration of this shape after a fracture.
To perform its functions, bone undergoes continuous destruction, called resorption, by osteoclasts and formation by osteoblasts. In the adult skeleton, these two processes are in balance, maintaining a constant, homeostatically controlled amount of bone. This fact, as well as the histological observation that bone resorption by osteoclasts is accompanied by bone formation by osteoblasts, led to the idea that these two processes are mechanistically "linked" and to the search for "linking factors".
It has not been proven that one factor links these two processes. Existing evidence suggests that many factors are likely involved in maintaining bone homeostasis. It has been suggested that growth factors found in bone, such as IGF or TGFβ, are released during resorption and initiate local bone formation. It was assumed that factors deposited on the bone surface by osteoclasts at the end of the resorption phase initiate subsequent bone formation. Humoral factors such as parathyroid hormone and prostaglandin E, which stimulate both bone resorption and bone formation, can simultaneously enhance these two processes. It has been suggested that the effect of these factors and other hormones and cytokines on osteoclasts is mediated by osteoblast cells, which possess cognate receptors that closely link the interaction of osteoblasts and osteoclasts with bone turnover.
Last but not least, the ability of bone to change its structure and adapt to mechanical loading implies that mechanical forces can regulate bone resorption and formation: increased loading should increase formation and decrease resorption, while unloading should have the opposite effect. Indeed, immobilization stimulates resorption and inhibits formation (see reference 8 for a review), providing a clear example of the "decoupling" between the two processes. The mechanism of these effects has not been fully elucidated, but here again it has been proposed that osteoblast cells, osteocytes, and lining cells mediate mechanical signals because their location is best suited for their perception.
The relationship between bone formation and bone resorption was explored in an elegant study by Corral et al. , is reported in this issue of Proceedings, which used a transgenic model to demonstrate a clear separation between the two processes in mice aged 6 to 14 weeks. Using the osteocalcin promoter responsible for the selective expression of this gene in mature osteoblasts, the authors disrupted these cells by expressing thymidylate kinase and treating the animals with ganciclovir, a tk-activated toxin. This study shows that the elimination of bone-forming osteoblasts and the arrest of bone formation does not affect the activity of osteoclasts. The imbalance between the two processes resulted in significant bone loss mimicking the osteoporosis phenotype, which could be completely prevented by treatment with the osteoclast-inhibiting bisphosphonate alendronate. In addition, osteoclasts derived in culture from bone marrow and calvarium cells derived from transgenic animals generally resorb bone in vitro in the presence or absence of ganciclovir, indicating that osteocalcin-expressing cells are not required for differentiation or activity. mouse osteoclasts. in vitro. At first glance, these results seem to defy current dogma and prevailing understanding of bone metabolism and osteoblast/osteoclast interaction, but is it?
The findings raise two important and interrelated questions: what is the nature of the relationship between bone resorption and bone formation, and what osteoblastic cells, if any, influence osteoclast activity? The authors were careful in interpreting the results and only stated that active bone formation and living osteoblasts, at least those that express osteocalcin, are not required for osteoclast activity in these mice. These findings are fully supported by the data.