Osteoblastic Bone Metastases

There are many challenges to determining the mechanisms that contribute to the selective development of CaP in bone (80-82). These include mechanisms of homing and attachment to bone and invasion into bone. However, once in the bone, CaP tumors have pathobiology that seems to be somewhat unique to cancer skeletal metastases. Specifically, CaP skeletal metastases are most often radiographically characterized as osteoblastic (i.e., increased mineral density at the site of the lesion) as opposed to osteolytic. Other tumors, such as breast cancer, can form osteoblastic lesions; however, these occur less frequently (83,84). Despite the radiographic osteoblastic appearance, it is clear from histological evidence that CaP metastases form a heterogeneous mixture of osteolytic and osteoblas-tic lesions, although osteoblastic lesions predominate (85-88). Recent evidence shows that osteo-

Osteoblastic Lesion

Fig. 2. Bone remodeling. Osteoclast initiation of bone resorption creating a leading edge, termed the cutting cone. Mononuclear cells behind the osteoclasts create a cement line that delimits the area of resorption. This is termed the reversal phase, which is then followed by osteoblasts that create new bone in the formation zone, followed by a resting phase in which the osteoblasts appear as flattened cells, termed lining cells.

Fig. 2. Bone remodeling. Osteoclast initiation of bone resorption creating a leading edge, termed the cutting cone. Mononuclear cells behind the osteoclasts create a cement line that delimits the area of resorption. This is termed the reversal phase, which is then followed by osteoblasts that create new bone in the formation zone, followed by a resting phase in which the osteoblasts appear as flattened cells, termed lining cells.

blastic metastases form on trabecular bone at sites of previous osteoclastic resorption, and that such resorption may be required for subsequent osteoblastic bone formation (89,90). These findings suggest that CaP induces bone production through an overall increase in bone remodeling, which, in the nonpathological state, is a balance between osteoclast resorption of bone, followed by osteoblast-mediated replacement of resorbed bone (reviewed in refs. 91-93). In the case of CaP, it seems the induction of osteoblast-mediated mineralization outweighs the increase in osteoclast resorption, resulting in an overall formation of osteoblastic lesions. The osteoblastic lesions result in overall weakening of the bone because of the production of woven bone and hypermineralization (22,81,94). Thus, the combination of underlying osteolysis and production of weak bone leads to a predisposition to fracture. The mechanisms through which CaP cells promote bone mineralization remain poorly understood.

CaP cells produce a variety of factors that have direct or indirect osteogenic properties (Table 1) (reviewed in refs. 95-97). Some of these factors, such as BMP (98-100) and endothelin (ET)-1 (101) may directly stimulate differentiation of osteoblast precursors to mature mineral-producing osteoblasts. Other factors, such as PTH-related protein (PTHrP) may work through inhibition of osteoblast apoptosis (102,103). Additionally, there are proteins that may work indirectly to enhance bone production, such as the serine proteases, prostate-specific antigen (PSA), and urinary plasminogen activator, which can activate latent forms of osteogenic proteins, such as transforming growth factor (TGF)-P (104,105). Finally, some molecules, such as OPG (50,106,107) and ET-1 (in a dual role with its osteoblast-stimulating activity) (108) can enhance osteosclerosis through inhibiting osteoclastogenesis. Despite this gamut of putative mediators of CaP-induced osteosclerosis, we are unaware of in vivo studies that unequivocally demonstrate their role in this process. Other tumor types, such as osteosarcoma, are also known to produce a variety of osteoblastic factors (109-111). With such a large number of factors, it is difficult to determine which is the most appropriate one to evaluate, and, in fact, several of these osteogenic factors most likely work in concert to produce maximal bone production.

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