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The Jackson Laboratory and St. Joseph Hospital Bangor, Maine 04401
Address all correspondence and requests for reprints to: Clifford J. Rosen, M.D., Maine Center for Osteoporosis Research and Education, St. Joseph Hospital, 900 Broadway, Building 2, Bangor, Maine 04401. E-mail: rofe{at}aol.com.
Calcium balance is absolutely essential for mammalian life. In the conversion from marine- to land-based existence, various pathways evolved to promote mineral homeostasis; these included an elaborate and multifaceted system for regulating bone turnover and the generation of a bihormonal mechanism for controlling divalent availability in the gut and kidney. Calcium homeostasis is particularly tested during two phases of life–puberty and aging. At one end, skeletal development and maturation require the orchestration of multiple endocrine and paracrine systems, finely tuned for optimal longitudinal growth, volumetric expansion, and mineralization. The GH/IGF-I regulatory network, primed by pituitary-hypothalamic mediators and interfacing at the hard-tissue level with gonadal steroids, calciotropic hormones, and local growth factors, mediates linear and volumetric growth (1). Less certain, however, is the control over skeletal mineralization after deposition of organic matrix.
At the other extreme, preservation of bone mass with advanced age, especially after sex steroid deficiency and reduced calcium intake, places mineral balance and bone strength in a different but even more tenuous position. Compensatory changes in PTH and 1,25-dihydroxyvitamin D production maintain calcium homeostasis through their respective actions on the kidney and gut, but only at the expense of the skeleton, where significant and prolonged endosteal resorption occurs. Bone dissolution can continue indefinitely to preserve calcium balance, but how the skeleton maintains its mechanical properties under these conditions remains uncertain.
Recent studies employing genetically engineered mice offer some insight into these questions. In fact, emerging evidence has challenged conventional thinking about skeletal growth at any age as well as the interdependence of the GH/IGF-I and PTH/1,25-dihydroxyvitamin D pathways for skeletal health. The work of Kasukawa et al. (2) featured in this issue of the journal highlights such progress.
During rapid mammalian growth, i.e. puberty, there is a marked increase in the magnitude and frequency of GH release. This induces IGF-I expression in the liver and other tissues including the skeleton; in turn, systemic and local IGF-I mediates longitudinal growth via chondrocytes and expansion of the outer cortical envelope via periosteal osteoblasts. GH-induced expression of IGF-I in the trabecular compartment of the skeleton may also be important for the recruitment of stromal cells into the bone lineage and the terminal differentiation of endosteal osteoblasts. Despite common endocrine signaling through GH, each of these three skeletal components (i.e. the growth plate, the periosteum, and the endosteum) responds in a distinct and tissue-specific manner. Eventually, newly formed bone matrix becomes fully mineralized, signaling the end of skeletal maturation but the beginning of lifelong adult remodeling.
In their current work, Kasukawa et al. (2) suggest that systemic and tissue changes in IGF-I are directly tied to the 1,25-dihydroxyvitamin D/PTH axis and therefore represent a major link between calcium homeostasis and skeletal growth. At first glance, some of their findings are not surprising, because others have reported that IGF-I can induce 1
-hydroxylase activity in the kidney (3, 4); and investigators have previously noted an inverse relationship between PTH concentrations and GH secretion in animals and humans (5, 6). However, using a calcium-deficiency paradigm and the IGF-I-knockout mouse as a model, the authors provide functional support for an intimate relationship between these two pathways. More importantly, by studying IGF-I-null mice that have very high GH levels, their experimental evidence suggests that IGF-I, not GH, is essential for activation of 1,25-dihydroxyvitamin D.
The link proposed by Kazukawa et al. (2) between GH/IGF-I and PTH/1,25-dihydroxyvitamin D is also sound from an evolutionary perspective. Growth and maturation of the adult skeleton mandates that bone must be mineralized. That would require increased calcium availability from other sites. Systemic IGF-I, through its actions on the 1,25-dihydroxyvitamin D system, could enhance calcium absorption in the gut and promote greater renal conservation during puberty (Table 1
). But how calcium then becomes available to the skeleton for mineralization is still unknown. Recently, Weaver and colleagues (7) demonstrated that during rodent puberty, but not at the time of weaning nor during adult life, calcium entry into the skeletal compartment (as calculated by isotope studies and measured by mineral ash) is directly and markedly enhanced by administration of IGF-I complexed to IGFBP-3. Alternatively, IGF-I produced by osteoblasts could orchestrate mineralization through its influence on phosphate transport. This was first postulated by Caverzasio et al. (8) and more recently by Zhang et al. (9) using a conditional knockout of the IGF-I receptor. Several other putative pathways linking IGF-I to calcium balance are likely to be important and certainly deserve further study (Table 1).
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Aging in humans is associated with a marked increase in endosteal resorption as a function of secondary hyperparathyroidism due to reduced calcium availability, loss of gonadal steroids, and a general increase in stromal cell generation of cytokines. In response, the periosteal envelope expands to compensate for loss of endosteal bone surface. This compensatory mechanism, although not complete, allows the skeleton to maintain some structural integrity in the face of rapid bone loss. As such, skeletal growth coincident with skeletal loss represents an important evolutionary adaptation to longevity and its consequences. What regulates this unique phenomenon is not known, although there is a growing body of circumstantial evidence, partially supported by this paper, suggesting that circulating IGF-I, which may influence the differentiation of periosteal osteoblasts, regulates this component of skeletal expansion (1, 11) If so, then with aging, those individuals that have lower circulating IGF-I concentrations and higher PTH levels would be less likely to preserve mechanical strength in the face of sustained endosteal bone loss. Eventually, the absence of a compensatory response in the periosteum would result in a lower bone mineral density, a mechanically compromised host, and a greater fracture risk with even minimal trauma.
Evolution is a long and tricky business. For the skeleton of mammals, major adaptations evolve to maintain calcium balance in the face of pressures related to growth, calcium availability, gonadal steroid loss, and longevity. The paper by Kazukawa et al. (2) adds to our knowledge of the ever-evolving skeleton, particularly in respect to the pathogenesis of osteoporosis. Even more exciting work lies ahead.
Received August 11, 2003.
Accepted for publication August 12, 2003.
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, 25(OH)2D3 on receptor expression and growth stimulation in rat growth plate chondrocytes. Kidney Int 53:1152–1161[CrossRef][Medline]
B ligand in vitro and OPG in vivo. J Clin Endocrinol Metab 87:4273–4279
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