Age- and gender-related changes in the distribution of osteocalcin in the extracellular matrix of normal male and female bone. Possible involvement of osteocalcin in bone remodeling.

Abstract

IntroductionWith increasing age, bone undergoes changes in remodeling that ultimately compromise the structural integrity ofthe skeleton. The presence of osteocalcin in bone matrix may alter bone remodeling by promoting osteoclast activity. Whether ageand/or gender-related differences exist in the distribution of osteocalcin within individual bone remodeling units is not known. In this study, we determined the immunohistochemical distribution of osteocalcin in the extracellular matrix of iliac crest bone biopsies obtained from normal male and female volunteers, 20-80 yr old. Normal bone metabolism is the result of a highly integrated relationship between bone resorption and formation. With age, the structural integrity of the skeleton declines along with the functional capacity of various organ systems. Although overall bone mass decreases with age in females and males, the rate of bone loss in females is greater than males ( 1-3). The mechanisms by which bone remodeling is altered with age and gender are poorly understood. The organic phase of normal bone consists of 90% type I collagen and the remaining 10% is composed of noncollagenous proteins (NCPs).' NCPs are synthesized and secreted by bone cells, and their expression is regulated, in part, by local growth factors and hormones (4-7). Accumulating evidence suggests that the extracellular matrix of bone exerts profound effects on cellular activity by retaining NCPs and growth factors that influence both immediate and long-term cell-matrix interactions (8-13). Reduced recruitment of osteoclasts to devitalized particles of bone from human donors of increasing age suggests that bone matrix components may be partially responsible for impaired skeletal remodeling associated with aging (9).Osteocalcin is a 6.5-kD vitamin K-dependent, gamma-carboxyglutamic acid-containing NCP secreted by osteoblasts and odontoblasts. Due to its high affinity for calcium and hydroxyapatite, osteocalcin is incorporated into the extracellular matrix of bone ( 14-16). A growing body of evidence suggests that this matrix protein is involved in bone remodeling. Significant differences in the concentration ofextractable osteocalcin between cortical and trabecular bone in humans provides evidence of distinct regulatory mechanisms among these areas (10). Osteocalcin-deficient bone particles obtained from warfarn-treated rats recruit fewer osteoclasts and are resorbed less than normal particles using in vivo assays ( 1 1, 17, 18). Osteopetrotic rat bone contains low concentrations of osteocalcin, and osteoclast activity in these animals is reduced ( 19).The possibility that NCPs are involved in regulating sitespecific cell-matrix interactions is supported by studies that have immunolocalized NCPs within the extracellular matrix of bone from several species (13,(20)(21)(22). Presently, it is not known whether age or gender differences exist in the microanatomical distribution of NCPs within bone remodeling units. In this study, the immunohistochemical distribution of osteocalcin in ...

Diffuse calcification in human coronary arteries. Association of osteopontin with atherosclerosis.

“…An additional calcium-binding Gla-containing protein named plaque Gla protein (PGP) was isolated from human calcified plaque (30). Osteocalcin plays an essential role in normal skeleton development, and genderrelated differences in skeletal tissue suggest that this phosphorylated glycoprotein may play an important role in the pathogenesis of several disorders (31 ). Gamma carboxyglutamate, or Gla, is an amino acid residue with a high affinity for binding hydroxy-apatite.…”

Effects of rhIGF-I administration on bone turnover during short-term fasting.

“…Glomerular filtration rate (GFR), calcium filtration and fractional tubular reabsorption of calcium were calculated on days 5, 8, and 11 to determine the effects of rhIGF-I on renal calcium handling (see Appendix) (31). Weight was measured daily and percent ideal body weight (%IBW) was calculated at baseline and days 5 and 11. Laboratory methods Serum total and ionized calcium, phosphorus, electrolytes, PTH, 25 hydroxyvitamin D, 1,25 dihydroxyvitarmin D and insulin levels were measured using published methods (32). Serum IGF-I was measured after an acid-alcohol extraction using a RIA kit with an intra-assay coefficient of variation 2.4-3.0% (Corning Nichols Institute).…”

“…We hypothesized that in the fasting state, IGF-I levels would decline significantly and would establish a model in which we could investigate the effects of IGF-I administration on bone turnover. We therefore studied 14 normal women ages [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] 24±4 [SD] years) during a complete 10-d fast. After 4 d of fasting, subjects were randomized to receive rhIGF-I or placebo subcutaneously twice a day for 6 d. Bone turnover was assessed using specific markers of formation (osteocalcin and type I procollagen carboxyl-terminal propeptide [PICP]) and resorption (pyridinoline, deoxypyridinoline, type I collagen crosslinked N-telopeptide [N-telopeptide] and hydroxyproline).…”

“…In severe chronic undernutrition, IGF-I concentrations decrease in association with low bone turnover and significant bone loss (19)(20)(21)(22)(23). Similarly, bone turnover is diminished in other pathologic states in which IGF-I levels are deficient because of an inherited resistance to the action of GH or in association with decreased GH secretion (24)(25)(26)(27)(28). These data suggest that IGF-I is an important modulator of normal bone metabolism and that a deficiency of IGF-I at systemic and/or tissue levels may contribute to abnormal bone metabolism in undernutrition.…”

Osteocalcin: an emerging biomarker for bone turnover

“…10 The distribution of osteocalcin in human osteons (the basic unit of structure of compact bone) changes with sex and age, and local reductions of osteocalcin in bone are associated with reduced cortical remodeling. 11 Since, OC is useful in the diagnosis and follow-up of high turnover osteoporosis, it can be considered as an important and highly sensitive marker of bone turnover.…”