Matrix Regulation of Skeletal Cell Apoptosis

Abstract

Previously, we noted that inorganic phosphate (P i ), a major component of bone extracellular matrix, induced osteoblast apoptosis (Meleti, Z., Shapiro, I. M., and Adams, C. S. (2000 Bone adapts to mechanical and physiological stress by a unique form of tissue replacement contained within discrete structures defined as basic multicellular units (2). Within each of these units, the actual process of bone removal is carried out by osteoclasts; replacement bone matrix is synthesized and mineralized by cells of stromal origin, osteoblasts. Examination of resorbing sites in developing skeletal tissues indicates that many of the cells are apoptotic (3). Thus, there is evidence of DNA fragmentation in osteoclasts, osteoblasts, and osteocytes (4, 5). In contrast, in mature skeletal tissues, only about 1-2% of all bone cells are dying or dead. In both the developing and mature skeleton, most of the apoptotic cells are confined to bone remodeling sites or locales of high bone turnover (5-8).How osteoclasts communicate with and regulate the life history of other cells of the basic multicellular unit is a topic of intense debate. It is clear that osteoclast differentiation and activation are dependent on paracrine signals received from stromal cells in the multicellular unit (9). Within the past four years, chemical modulators of these processes have been identified, and recent evidence indicates that growth factors provide survival signals that result in bone cell proliferation and depression of the apoptotic process (5, 6, 10). In addition, it has been demonstrated that a number of pharmacological agents can induce osteoblast apoptosis in vitro (5, 10 -12). Surprisingly, however, little is known of events that promote osteoblast death in situ.Although the resorption process may generate agents that stimulate osteoblast proliferation, it is probable that products of the resorbing bone may also stimulate bone cell death. Recent work from this laboratory has clearly demonstrated that one of the ions present in the bone matrix, inorganic phosphate (P i ), induces apoptosis of cultured human osteoblasts and chondrocytes (1, 13). Since Ca 2ϩ as well as P i are released from the bone apatite lattice during the resorption process, the possibility exists that Ca 2ϩ may influence P i -mediated bone cell apoptosis. To test the hypothesis that this ion pair may trigger the death program, we examine the effect of P i and Ca 2ϩ on human osteoblast-like cells. We ask the questions, Can Ca 2ϩ modulate P i -induced cell death, and, if so, is death mediated by apoptosis? Using a cell culture system, we demonstrate that Ca 2ϩ accentuates the apoptogenic effect of P i . In addition, we provide evidence for the involvement of mitochondria and intracellular Ca 2ϩ in the apoptotic pathway activated by the ion pair. MATERIALS AND METHODSCell Culture-Specimens of human bone were obtained during dental surgery performed at the Hospital of the University of Pennsylvania and during spinal surgery performed at the Children's Hospital of Philadelphia...

Matrix remodeling during endochondral ossification

“…In addition to the regulation of growth factor bioavailability by MMPs, ECM remodeling also induces variations in calcium and phosphate ion concentrations. Interestingly, Adams and coworkers [58] demonstrated that, depending upon their extracellular concentrations, these ions could also regulate chondrocyte and osteoblast apoptosis. Thus, growth factors and ions might be involved in closely related molecular pathways that govern the equilibrium between survival and apoptosis of skeletal cells.…”

The Relationship Between Fetuin-A and Bone Mineral Density in Postmenopausal Osteoporosis

“…Studies with fetuin-A gene-ablated mice showed an irregularity of bone mineralization that reinforced the role of fetuin-A in this process. [6,30] Moreover, in patients with end-stage renal failure with fetuin-A deficiency, decreased concentrations of Ca and P against increased osteoblast apoptosis have been suggested to have a negative effect on bone structure. [6] A study by Binkert et al [21] showed that in bone marrow cultures of rats treated with a high dose of dexamethasone, fetuin-A and TNF-β suppressed bone alkaline phosphatase, osteopontin, type I collagen, and bone sialoprotein.…”

“…[4] Studies have also shown that fetuin-A can inhibit transforming growth factor beta (TGF-β)/bone morphogenic protein (BMP) activity. [6] In the absence of fetuin-A, inhibition of TGF-β/BMP occurs, and osteogenesis is subsequently stimulated. [7] Thus, the decrease in fetuin-A serum levels with respect to the metabolism of bone through osteoblast apoptosis and the TGF-β/BMP system can lead to osteo-inductive effects.…”

Biocompatibility, Bioactivity and Mechanical Properties of Portland Cement and Portland Cement-Metakaolin Blends for Bone Tissue Engineering Applications

“…Metals exhibit susceptibility to corrosion, poor osseointegration, and stress shielding [2,5]. Ceramics tend to be brittle, present low mechanical strength (in a porous configuration), and unpredictable in vivo degradation/dissolution rates [1,2,6,7]. Polymers on the other hand show reduced osseointegration capabilities, decreased cell-material interactions due to surface hydrophobicity, and excessive ductility for hard tissue replacement applications [1,2,8].…”