Tetracycline administration restores osteoblast structure and function during experimental diabetes

Abstract

Osteopenia is a recognized complication of diabetes mellitus in humans and experimental animals. We recently found that tetracyclines prevent osteopenia in the streptozotocin-induced diabetic rat and that this effect was associated with a restoration of defective osteoblast morphology (Golub et al., 1990). The present study extends these initial ultrastructural observations by assessing osteoblast function in the untreated and tetracycline-treated diabetic rats. After a 3-week protocol, non-diabetic control and diabetic rats, including those orally administered a tetracycline, minocycline (MC), or a non-antimicrobial tetracycline analog (CMT), were perfusion-fixed with an aldehyde mixture; the humeri were dissected and processed for ultracytochemical localization of alkaline phosphatase (ALPase) and Ca-ATPase activities. Some rats from each experimental group received an intravenous injection of 3H-proline as a radioprecursor of procollagen, and the humeri were processed for light microscopic autoradiography. In addition, the osteoid volume in each experimental group was quantitatively examined by morphometric analysis of electron micrographs. During the diabetic state, active cuboidal osteoblasts in the endosteum of control rats were replaced by flattened bone-lining cells that contained few cytoplasmic organelles for protein synthesis (Golgi-RER system), and active transport (mitochondria). Treating diabetic rats with MC, and even more so with CMT, appeared to "restore" osteoblast structure. During diabetes, bone-lining cells incorporated little 3H-proline or secreted little labeled protein and produced only a very thin osteoid layer. Tetracycline administration to the diabetics increased both the incorporation of 3H-proline by osteoblasts and their secretion of labeled protein toward the osteoid matrix, in a pattern similar to that seen in the non-diabetic controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic hyperglycemia modulates osteoblast gene expression through osmotic and non‐osmotic pathways

“…For example, in the streptozotocin induced mouse model of IDDM, we demonstrated through serum marker analyses and histology that osteoclast number and activity is not influenced by IDDM [Botolin et al, 2005] similar to reports by others [Verhaeghe et al, 1990;Sasaki et al, 1991]. In contrast, osteoblast function/maturation is suppressed and marrow adiposity is increased in IDDM mice.…”

Osteogenic Protein-1 Overcomes Inhibition of Fracture Healing in the Diabetic Rat: A Pilot Study

“…Type I diabetes mellitus alters the mechanical and biologic properties of bone [3,22]. Impairment of histomorphometric, cellular, and biochemical indicators of bone formation, like osteocalcin have been linked to diabetes mellitus [15,27,32]. One study suggests delayed fracture healing in an animal model of diabetes is attributable in part to reduced cellular proliferation associated with decreased levels of platelet-derived growth factor (PDGF) [31].…”

Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues

“…In a number of T1DM animal studies, histomorphometric analyses have shown that, irrespective of the model used, insulindeficient rats may exhibit reduced or absent bone formation and this decline is appreciated in relation to all bone surfaces examined, i.e., trabecular, periosteal, and endocortical (132)(133)(134). The major deficits in these insulin-deficient models appear to be related to a deficit in mineralized surface area, a decrement in the rate of mineral apposition, deceased osteoid surface, depressed osteoblast activity, and decreased numbers of osteoclasts (34,104,112,135), leading to an overall depression in remodeling of bone in the untreated insulin-deficient state. These data are supported by surrogate markers, such as the osteoblast marker osteocalcin, which is also generally depressed in the untreated diabetic rat (20,131), as is urinary deoxypyridinoline, an index of bone resorption (136).…”