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The ectodomains of numerous proteins are released from cells by proteolysis to yield soluble intercellular regulators. The responsible protease, tumor necrosis factor-α converting enzyme (TACE), has been identified only in the case when tumor necrosis factor-α (TNFα) is released. Analyses of cells lacking this metalloproteinase-disintegrin revealed an expanded role for TACE in the processing of other cell surface proteins, including a TNF receptor, thel-selectin adhesion molecule, and transforming growth factor-α (TGFα). The phenotype of mice lacking TACE suggests an essential role for soluble TGFα in normal development and emphasizes the importance of protein ectodomain shedding in vivo.

Background Sclerostin antibody (Scl-Ab) increases bone formation, bone mass, and bone strength in rodents and cynomolgus monkeys (cynos) in studies of up to 10 weeks duration. Objectives To investigate the effects of 6 months of Scl-Ab treatment on cynos bone formation. Methods Adolescent (age 3-5 years) cynos were treated for 6 months with weekly subcutaneous injections of vehicle, 3, 10, or 100 mg/kg Scl-Ab (n=4/sex/group). Results The bone formation marker serum osteocalcin peaked within the first 3 months of Scl-Ab treatment and returned toward baseline levels at month 6, at which time the L2 vertebra bone formation rate per bone surface (BFR/BS) was similar across all treatment groups. At the tibia diaphysis, endocortical BFR/BS remained dose-dependently elevated. Despite the normalization of cancellous BFR/BS at month 6, Scl-Ab dose-dependently increased DXA bone mineral density (BMD) by 15-30% at the lumbar spine compared with vehicle (Table). By ex vivo microCT, Scl-Ab resulted in dose-dependent increases in BMD at L3 vertebral bodies and L6 cancellous cores, bone area, cortical thickness (Ct.Th), trabecular bone volume (BV/TV), and trabecular thickness (Tb.Th) (Table). Improvements in bone microarchitecture resulted in increased yield load for all dose levels at both L3 (+33-92%) and L6 (+83-142%) compared with vehicle. Stiffness and energy to failure also increased dose-dependently after Scl-Ab treatment at both sites. Strength properties were normalized to BV/TV to approximate material properties, and no group differences were found in yield strength, modulus, or toughness. Positive correlations between BMD and yield load were observed across all groups for both vertebral specimens, further supporting the maintenance of material properties. No group differences were found in the ratio of ash to dry weight in vertebral samples, reflecting normal matrix mineralization during Scl-Ab treatment. Data reported here are from male cynos; similar results were observed in females. Conclusions Six months of Scl-Ab treatment in cynos markedly increased vertebral BMD, trabecular microarchitecture, and bone strength, with maintenance of bone material properties. These data also highlight the unique mode of action of Scl-Ab, which temporally increases cancellous bone formation, resulting in a rapid increase in bone volume of normal quality that is maintained after indices of trabecular bone formation return to baseline. Disclosure of Interest M. Ominsky Shareholder of: Amgen Inc., Employee of: Amgen Inc., R. Samadfam Employee of: Charles River Laboratories, J. Jolette Employee of: Charles River Laboratories, S. Smith Employee of: Charles River Laboratories, H. Z. Ke Shareholder of: Amgen Inc., Employee of: Amgen Inc., R. Boyce Shareholder of: Amgen Inc., Employee of: Amgen Inc.

Postmenopausal osteoporosis is a chronic, disabling disease. The high prevalence of osteoporosis in elderly people, particularly women, is becoming increasingly important as baby boomers are reaching retirement age and life expectancy in industrialized countries is increasing.1,2 In addition to the reduced quality of life suffered by affected people, osteoporosis is a substantial contributor to the burden of health care costs frequently due to prolonged treatment and hospitalization from osteoporotic fractures.1,2 Although risk factors contributing to osteoporotic fractures, such as gonadal failure following menopause, lower peak bone mass, lack of physical activity, genetic and nutrition, are well identified, the deficit in understanding of osteoporosis pathogenesis makes the search for therapeutic agents difficult.3,4

1. It was investigated whether an extract of Tripterygium wilfordii Hook f (TW) inhibits IL-1 production by monocytes and suppresses the development of IL-1-dependent arthritis induced in rats with streptococcal cell wall and adjuvant. 2. TW preferentially inhibited IL-1 alpha and IL-1 beta production by bacterial lipopolysaccharide (LPS)-stimulated human monocytes with IC50 of approximately 1 microgram/ml. 3. Oral administration of TW dose-dependently suppressed joint swelling and structural damage in streptococcal cell wall-induced arthritis (ED50 = 20 mg/kg/day) and in adjuvant-induced arthritis (ED50 = 46 mg/kg/day for developing and 8 mg/kg/day for established arthritis).