Andreas Sommer

Treatment of ovariectomized rats with the complex of rhIGF-I/IGFBP-3 Increases cortical and cancellous bone mass and improves structure in the femoral neck

Sixteen-week-old Sprague-Dawley rats were ovariectomized (Ovx) or sham-operated and housed for 8 weeks to develop osteopenia prior to systemic administration of rhIGF-I (0.9 and 2.6 mg/kg) alone or the rhIGF-I/IGFBP-3 (0.9, 2.6 and 7.5 mg/kg) complex. After 8 weeks of treatment, proximal femurs were fixed, embedded, and cut through the midneck region. Structural and dynamic histomorphometric analyses were performed using standard techniques. Ovx increased endocortical resorption and modeling-dependent periosteal formation which resulted in decreased cortical bone area. Despite increased bone formation, trabecular number, thickness, and area were all reduced due to increased resorption. Structural changes following Ovx included fewer struts and nodes, a higher percentage of the simpler strut forms, and reduced endocorticotrabecular cnnnectivity. Eight weeks of treatment with rhIGF-I or rhIGF-I/IGFBP-3 promoted periosteal and endocortical bone formation and reduced the endocortical resorption induced by Ovx. Both rhIGF-I formulations stimulated bone formation on existing trabecular surfaces which increased trabecular thickness and area but not trabecular number. These treatments prevented further deterioration of the trabecular network caused by Ovx and preserved endocortico-trabecular connectivity. In summary, changes in the femoral neck following Ovx appear to be similar in rats and humans. The highest dose of rhIGF-I/IGFBP-3 used in this study showed the best results in promoting cortical and cancellous bone formation, and appears to be promising therapy for human osteopenias.

Systemic administration of rhIGF-I or rhIGF-I/IGFBP-3 increases cortical bone and lean body mass in ovariectomized rats

The purpose of this study was to compare dose-related effects on cortical bone and lean body mass following subcutaneous administration of rhIGF-I alone, or bound to an equimolar amount of rhIGFBP-3 to adult Ovx rats. At the age of 16 weeks, rats were ovariectomized or sham-operated and were allowed 8 weeks to develop osteopenia. After being divided into control (saline treated) or treatment groups, rats were injected daily during an 8-week period with 0.9 and 2.6 mg/kg of rhIGF-I, or with 0.9, 2.6, and 7.5 mg/kg of rhIGF-I bound to rhIGFBP-3. Fluorescent bone markers were given 9 and 2 days prior to necropsy. Body weights and lean body mass were monitored throughout the experiment. Cortical bone histomorphometry was performed on tibial cross-sections at the tibiofibular junction, and endochondral bone growth was measured at the distal femoral metaphysis. All rats treated with rhIGF-I or the rhIGF-I/IGFBP-3 complex had increased body weights, corresponding to a dose-dependent increase in lean body mass. Endochondral growth was slightly increased in all experimental groups, but was not dose-dependent. A dramatic increase in periosteal, modeling-dependent formation, coupled with decreased or unchanged resorption on the endocortical envelope resulted in a dose-dependent increase in cortical thickness and cross-sectional area in groups treated with the complex of rhIGF-I/IGFBP-3. This complex appeared to be more effective in promoting positive musculoskeletal changes than rhIGF-I alone.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of systemically administered rhIGF-I/IGFBP-3 complex on cortical bone strength and structure in ovariectomized rats.

The action of systematically administered recombinant human insulinlike growth factor-I (rhIGF-I) complexed to its natural binding protein-3 (rhIGFBP-3) on cortical bone dynamic, structural, and mechanical properties was tested in previously ovariectomized (Ovx) rats. Bilateral ovariectomy or sham surgery was performed on 16-week-old female Sprague-Dawley rats. Eight weeks after surgery basal Sham and Ovx rats were killed to establish baseline cortical bone values before the initiation of treatment with rhIGF-I/IGFBP-3 complex. At that time, Ovx rats had increased body weight and body fat mass with reduced femoral BMC and BMD relative to basal Shams. Bone formation rates in Ovx rats were increased on both cortical envelopes relative to time-matched controls. The thickness of the inner lamellar bone layer and average cortical width were reduced due to increased endocortical erosion. A similar ratio between Sham and Ovx rats in body mass and composition and femoral BMC and BMD continued throughout the experiment. Sixteen weeks after surgery bone formation rates at both cortical envelopes in Ovx rats were reduced relative to Shams, but endocortical erosion remained high causing a further decrease in thickness of the inner lamellar layer. As a result of periosteal bone modeling. Ovx rats exhibited a larger femoral cross-sectional area and periosteal perimeter, as well as a thicker outer lamellar layer. Newly deposited periosteal bone increased ultimate torque values in the Ovx rats relative to Shams at 16 weeks. Treatment of Ovx rats with the rhIGF-I/IGFBP-3 complex increased body weight, lean body mass, and femoral BMC and BMD.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of IGF-I Therapy by IGFBP-3: Potential Utility in Wound Healing

Insulin-like growth factor-I (IGF-I) is one of the most abundant growth factors in circulation (~200 ng/ml); however, very little of it exists in its free form. Normally, IGF-I is bound to one of its six known binding proteins designated as IGFBPs1–6 (1, 2). These IGFBPs exhibit variable tissue distributions and are believed to be involved in modulation of IGF activity (3–7). In circulation, IGF-I exists primarily as part of a ternary complex comprised of equimolar ratios of IGF-I, IGFBP-3, and a protein known as acid labile subunit (ALS) (1, 8). IGFBP-3 is by far the most abundant IGF binding protein and the only form that can bind to ALS to form the large 150-kd ternary complex. This complex found in serum greatly extends the circulating time of IGF-I and is believed to modulate the availability of free IGF-I (1, 9).