To examine the local actions of IGF signaling in skeletal tissue in a physiological context, we have used Cremediated recombination to disrupt selectively in mouse osteoblasts the gene encoding the type 1 IGF receptor (Igf1r). Mice carrying this bone-specific mutation were of normal size and weight but, in comparison with normal siblings, demonstrated a striking decrease in cancellous bone volume, connectivity, and trabecular number, and an increase in trabecular spacing. These abnormalities correlated with a striking decrease in the rate of mineralization of osteoid that occurred despite an unexpected osteoblast and osteoclast hyperactivity, detected from the significant increments in both osteoblast and erosion surfaces. Our findings indicate that IGF1 is essential for coupling matrix biosynthesis to sustained mineralization. This action is likely to be particularly important during the pubertal growth spurt when rapid bone formation and consolidation are required.Body size and linear bone growth in mammals is affected by cellular signaling pathways controlled by growth factors and hormones (1). In this regard, a major growth-promoting signaling system consisting of the insulin-like growth factors (IGF, 1 IGF1 and IGF2) and the type 1 IGF receptor (IGF1R) regulates embryonic growth, as shown by gene knockout experiments in mice (1). IGF1 acting through IGF1R also plays central roles in postnatal growth either independently or by mediating growth hormone functions (2). Signaling through the IGF1R tyrosine kinase receptor not only promotes cell proliferation, but also mediates anti-apoptotic actions (3, 4). The IGF system includes a second receptor (IGF2R) devoid of signaling properties, but serving IGF2 turnover, and at least six IGF-binding proteins (IGFBPs) of obscure functional significance (single and also some double mouse mutations ablating IGFBPs have not revealed as yet significant consequences in growth impairment). 2 The IGFs are produced locally in various tissues, including bones, and exert autocrine/paracrine functions, but they are also present in serum, mostly associated with IGFBPs. Whether the circulating IGFs act systemically as hormones is currently controversial (5, 6).A number of in vitro and in vivo studies are progressively unraveling the significance of the IGF system for skeletal development and metabolic control (for a review see Ref. 7). IGF1, by stimulating the proliferation of chondrocytes in the growth plate, plays an essential role in longitudinal bone growth (2) and is also involved in the formation of trabecular bone. In fact, chondrocytes and bone cells produce IGFs and express IGF1R (see for example Refs. 8 and 9). Studies using osteoblast culture systems have shown that IGF1 stimulates osteoblast proliferation, accelerates their differentiation, and enhances bone matrix production (10, 11). In addition, IGF1 is being recognized as a critical factor for bone cell survival (12)(13)(14). Finally, IGF1 also appears to regulate bone resorption, either directly or through its actio...

There is considerable evidence that osteoclasts are involved in the pathogenesis of focal bone erosion in rheumatoid arthritis. Tumor necrosis factor-related activation-induced cytokine, also known as receptor activator of nuclear factor-kappaB ligand (TRANCE/RANKL) is an essential factor for osteoclast differentiation. In addition to its role in osteoclast differentiation and activation, TRANCE/RANKL also functions to augment T-cell dendritic cell cooperative interactions. To further evaluate the role of osteoclasts in focal bone erosion in arthritis, we generated inflammatory arthritis in the TRANCE/RANKL knockout mouse using a serum transfer model that bypasses the requirement for T-cell activation. These animals exhibit an osteopetrotic phenotype characterized by the absence of osteoclasts. Inflammation, measured by clinical signs of arthritis and histopathological scoring, was comparable in wild-type and TRANCE/RANKL knockout mice. Microcomputed tomography and histopathological analysis demonstrated that the degree of bone erosion in TRANCE/RANKL knockout mice was dramatically reduced compared to that seen in control littermate mice. In contrast, cartilage erosion was present in both control littermate and TRANCE/RANKL knockout mice. These results confirm the central role of osteoclasts in the pathogenesis of bone erosion in arthritis and demonstrate distinct mechanisms of cartilage destruction and bone erosion in this animal model of arthritis.

The operative treatment of fractures of the proximal humerus can be complicated by poor bone quality. Our aim was to evaluate a new method which allows prediction of the bone quality of the proximal humerus from radiographs. Anteroposterior radiographs were taken of 19 human cadaver humeri. The cortical thickness was measured at two levels of the proximal humeral diaphysis. The bone mineral density (BMD) was determined for the humeral head (HH), the surgical neck (SN), the greater tuberosity (GT) and lesser tuberosity (LT) using dual-energy x-ray absorptiometry. The mean cortical thickness was 4.4 +/- 1.0 mm. Specimens aged 70 years or less had a significantly higher cortical thickness than those aged over 70 years. A significant positive correlation was found between cortical thickness and the BMD for each region of interest. The cortical thickness of the proximal diaphysis is a reliable predictor of the bone quality of the proximal humerus.

Preventing nontraumatic fractures in millions of patients with osteoporosis or metastatic cancer may significantly reduce the associated morbidity and reduce health-care expenditures incurred by these fractures. Predicting fracture occurrence requires an accurate understanding of the relationship between bone structure and the mechanical properties governing bone fracture that can be readily measured. The aim of this study was to test the hypothesis that a single analytic relationship with either bone tissue mineral density or bone volume fraction (BV/TV) as independent variables could predict the strength and stiffness of normal and pathologic cancellous bone affected by osteoporosis or metastatic cancer. After obtaining institutional review board approval and informed consent, 15 patients underwent excisional biopsy of metastatic prostate, breast, lung, ovarian, or colon cancer from the spine and/or femur to obtain 41 metastatic cancer specimens. In addition, 96 noncancer specimens were excised from 43 age- and site-matched cadavers. All specimens were imaged using micro-computed tomography (micro-CT) and backscatter emission imaging and tested mechanically by uniaxial compression and nanoindentation. The minimum BV/TV, measured using quantitative micro-CT, accounted for 84% of the variation in bone stiffness and strength for all cancellous bone specimens. While relationships relating bone density to strength and stiffness have been derived empirically for normal and osteoporotic bone, these relationships have not been applied to skeletal metastases. This simple analytic relationship will facilitate large-scale screening and prediction of fracture risk for normal and pathologic cancellous bone using clinical CT systems to determine the load capacity of bones altered by metastatic cancer, osteoporosis, or both.