Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
A Combined Fc-OPG/hPTH(134) Therapy to Restore Impaired Skeletal Growth and Bone Loss in a Mouse Model of IL-6 Dependent Juvenile Inflammatory Diseases.
Del Fatore1, Andrea, Capannolo2, Marta, Peruzzi2, Barbara, Cappariello1, Alfredo, Rucci2, Nadia, De Benedetti1, Fabrizio, Teti2, Anna
Premature osteoporosis and stunted growth are common complications of childhood chronic inflammatory diseases and have a significant impact on patients' quality of life. Presently no treatment regimens are available for these defects in juvenile diseases. To test a new therapeutic approach, growing mice overexpressing the pro-inflammatory cytokine IL-6 (TG) showing a generalized bone loss and stunted growth were used. Since TG mice present increased bone resorption and impaired bone formation, we hypothesized that a combined therapy with the antiresorptive modified osteoprotegerin, Fc-OPG, and the anabolic PTH could counteract their skeletal alterations and improve growth.
We therefore treated TG mice with Fc-OPG 0.25 mg/Kg once at the 4th day of life and with 80 mg/Kg hPTH(134) everyday from the 16th to the 30th day of age. No toxic effects were observed on vital organs.
The treated mice presented a complete rescue of growth, as showed by a body weight of 93% and a tibia length of 92% of WT mice (p<0.05 vs TG vehicle), and of bone phenotype (BV/TV %; WT vehicle 6.38+2.46; TG vehicle 3.12+0.82; TG Fc-OPG/hPTH 5.24+0.66#; #p<0.02 vs TG vehicle), with a normalization of osteoclast and osteoblast parameters. Restoring of normal bone turnover was confirmed by RT-PCR on femurs of Fc-OPG/hPTH-treated mice that showed normalization of TRAcP, ALP and RUNX2 expression compared to vehicle-treated TG mice, with levels similar to WT mice. In vitro cultures from Fc-OPG/hPTH-treated mice confirmed the full rescue of osteoclast number and bone resorption and an increase of osteoblast ALP staining to levels similar to cultures from WT mice, with normal osteoblast progenitors determined by CFU-F-ALP assay. The phenotypic rescue of TG mice was due to the combined treatment, because TG mice treated once at the 4th day of life with Fc-OPG 0.25 mg/Kg alone showed an increase of body weight (WT vehicle 14.61+1.72 g; TG vehicle 7.64+0.7 g*; TG Fc-OPG 10.4+1.12 g*; *p<0.03 vs WT vehicle), tibia length (WT vehicle 1.59+0.14 cm; TG vehicle 1.30+0.05 cm*; TG Fc-OPG 1.40+0.04 cm*; *p<0.05 vs WT vehicle) and bone volume to intermediate levels between those observed in WT and in TG vehicle-treated mice. Similar intermediate rescue was observed treating TG mice with hPTH alone since the 16th day of life. Moreover, intermittent injections of hPTH since the 4th day of age caused distress of the mice with no effects on the somatic growth.
In conclusion, our results identified the sequential Fc-OPG/hPTH as a treatment regimen to rescue the somatic growth and bone disorder in TG mice, thus providing the proof of principle for a new therapeutic approach to correct these defects in juvenile inflammatory diseases.
To cite this abstract, please use the following information:
Del Fatore, Andrea, Capannolo, Marta, Peruzzi, Barbara, Cappariello, Alfredo, Rucci, Nadia, De Benedetti, Fabrizio, et al; A Combined Fc-OPG/hPTH(134) Therapy to Restore Impaired Skeletal Growth and Bone Loss in a Mouse Model of IL-6 Dependent Juvenile Inflammatory Diseases. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1589