The Developing Bone: Slave or Master of Its Cells and Molecules?

Abstract

A large number of molecular, cellular, and epidemiologic factors have been implicated in the regulation of bone development. A major unsolved problem is how to integrate these disparate findings into a concept that explains the development of bone as an organ. Often events on the organ level are simply presented as the cumulative effect of all factors that individually are known to influence bone development. In such a cumulative model it must be assumed that each bone cell carries the construction plan of the entire skeletal anatomy in its genes. This scenario is implausible, because it would require an astronomical amount of positional information. We therefore propose a functional model of bone development, which is based on Frost's mechanostat theory. In this model the genome only provides positional information for the basic outline of the skeleton as a cartilaginous template. Thereafter, bone cell action is coordinated by the mechanical requirements of the bone. When mechanical challenges exceed an acceptable level (the mechanostat set point), bone tissue is added at the location where it is mechanically necessary. The main mechanical challenges during growth result from increases in bone length and in muscle force. Hormones, nutrition, and environmental factors exert an effect on bone either directly by modifying the mechanostat system or indirectly by influencing longitudinal bone growth or muscle force. Predictions based on this model are in accordance with observations on prenatal, early postnatal, and pubertal bone development. We propose that future studies on bone development should address topics that can be derived from the mechanostat model. Bone development is one of the key processes of intrauterine and postnatal growth. Indeed, major abnormalities in bone development are incompatible with survival. Elucidating the mechanisms of this process, therefore, is an important task in biology and medicine. Similar to other fields of biomedical investigation, current research in bone biology heavily relies on the reductionist approach, which excludes the physiologic context as far as possible and focuses on the role of individual factors (1). Methods based on this approach have led to spectacular new insights into the molecular and cellular events occurring during bone development. A rapidly increasing number of factors, commonly called determinants or regulators of bone development, have been implicated in this process. To the list of molecular and cellular factors must be added the many environmental and behavioral factors identified by epidemiology, such as nutritional aspects and physical activity.Thus, the reductionist approach has been extremely useful in identifying individual parts of the developing bone's machinery. The problem is how to put the individual pieces back into place. This is an essential task when it comes to explaining bone development on the level that interests patients and physicians most-the organ level. Confronted with a maze of molecular and cellular pathways, one may easily...

Decreased neonatal tibial bone ultrasound velocity in term infants born after breech presentation

“…13 It is also possible that relative lack of motion in large-forgestational-age fetuses, due to reduced space in the uterine cavity, leads to a decrease in bone SOS by a similar mechanism. This explanation is strengthened by the Frost's mechanostat theory, 5,6 which implies that bone cell action is coordinated by the mechanical requirements of the bone. In support of this theory are several recent studies showing that in preterm infants, 4 or 8 weeks of assisted range-of-motion exercise attenuates the postnatal decrease in bone strength 18 or even increases bone mineral content and density; 19,20 results that are consistent with recent reports emphasizing the importance of intrauterine movements on fetal bone development.…”

“…4 Using the mechanostat model, Frost et al 5 established the importance of mechanical loading in the development and maintenance of bone health. 6 Such loading of the fetal skeleton in utero arises from movements against the resistance of the uterine muscle (for example, during extension, flexion and kicking against the uterine wall). 7 We designed a prospective, cross-sectional study to compare bone status, assessed by bone ultrasound velocity, between infants born after breech presentation and those born after vertex presentation.…”

Analysis of the Musculoskeletal System in Children and Adolescents Receiving Anticonvulsant Monotherapy With Valproic Acid or Carbamazepine

“…However, from a more functional perspective, the important question is not whether the bones of a patient are as heavy as the bones of a healthy child but rather whether the bones of a patient are normally adapted to the physiologic loads to which they are exposed. 11,12 The largest physiologic loads on the skeleton are created by the contraction of muscles. 13,14 It therefore could be useful not only to compare bone mass results to an age-specific reference range but also to test whether bone strength (as reflected by bone mass) is adequately adapted to muscle force.…”

The effect of body composition and serum inflammatory markers on the functional muscle–bone unit in premenopausal women

“…Moreover, a higher F m1LH in conjunction with lower bone mass and strength would contradict the theoretical mechanisms of bone accretion during childhood and adolescence, 2,20,21 which posit that during childhood and adolescence, joint size adapts to maximum voluntary muscle force and gravitational force. [22][23][24] After closure of growth plates, joint size and hyaline cartilage material properties cannot, under normal conditions, be further increased. 21,25,26 Therefore, the higher F m1LH in women with higher body fat percentage as compared with women with lower body fat percentage might be indicative of a larger joint size and, consequently, higher absolute bone mass and strength would be expected.…”