An experimental therapy to improve skeletal growth and prevent bone loss in a mouse model overexpressing IL-6.
Premature osteoporosis and stunted growth are common complications of childhood chronic inflammatory disease. Presently, no treatment regimens are available for these defects in juvenile diseases. We identified the sequential Fc-OPG/hPTH treatment as an experimental therapy that improves the skeletal growth and prevents the bone loss in a mouse model overexpressing IL-6.


BACKGROUND
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, we used growing mice overexpressing the pro-inflammatory cytokine IL-6 (TG), which show a generalized bone loss and stunted growth.


METHODS
Since TG mice present increased bone resorption and impaired bone formation, we tested a combined therapy with the antiresorptive modified osteoprotegerin, Fc-OPG, and the anabolic PTH. We injected TG mice with Fc-OPG once at the 4th day of life and with hPTH(1-34) everyday from the 16th to the 30th day of age.


RESULTS
A complete prevention of growth and bone defects was observed in treated mice due to normalization of osteoclast and osteoblast parameters. Re-establishment of normal bone turnover was confirmed by RT-PCR analysis and by in vitro experiments that revealed the full rescue of osteoclast and osteoblast functions. The phenotypic recovery of TG mice was due to the sequential treatment, because TG mice treated with Fc-OPG or hPTH alone showed an increase of body weight, tibia length, and bone volume to intermediate levels between those observed in vehicle-treated WT and TG mice.


CONCLUSIONS
Our results identified the sequential Fc-OPG/hPTH treatment as an experimental therapy that improves the skeletal growth and prevents the bone loss in IL-6 overexpressing mice, thus providing the proof of principle for a therapeutic approach to correct these defects in juvenile inflammatory diseases.
Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00165, Rome, Italy, andrea.delf@gmail.com.
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Del Fattore
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Cappariello
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Capulli
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Rucci
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Muraca
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De Benedetti
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Teti
D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004359:Drug Therapy, Combination; D005260:Female; D006130:Growth Disorders / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010024:Osteoporosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053244:Osteoprotegerin / Q000627:therapeutic use; D019379:Teriparatide / Q000627:therapeutic use; D055114:X-Ray Microtomography / Q000379:methods
D050071:Bone Density Conservation Agents; D015850:Interleukin-6; D053244:Osteoprotegerin; C577686:interleukin-6, mouse; D019379:Teriparatide