Bone morphogenetic protein pathway activation, compositions for ossification, and methods related thereto

Abstract

The disclosure relates to compounds and compositions for bone formation, fracture treatment, bone grafting, bone fusion, cartilage maintenance and repair and methods related thereto. In certain embodiments, the disclosure relates to compositions comprising one or more compound(s) disclosed herein, such as clotrimazole, honokiol, magnolol, tacrolimus, pimecrolimus, sirolimus, everolimus, temsirolimus, spironolactone, fluticasone, fluticasone propionate, fluticasone furoate, linezolid, telmisartan, chlorambucil, retinol, isotretinoin, acitretin, etretinate, retinoic acid (tretinoin), teniposide, mitomycin C, cytarabine, decitabine, vinblastine, vincristine, vindesine, vinorelbine, valrubicin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, pixantrone, plicamycin, pazopanib, topotecan, camptothecin, irinotecan, sunitinib, derivatives, or salt thereof, for use in bone growth processes. In a typical embodiment, a bone graft composition is implanted in a subject at a site of desired bone growth or enhancement.

1 . A bone graft composition comprising clotrimazole, honokiol, magnolol, tacrolimus, pimecrolimus, sirolimus, everolimus, temsirolimus, spironolactone, fluticasone, fluticasone propionate, fluticasone furoate, linezolid, telmisartan, chlorambucil, retinol, isotretinoin, acitretin, etretinate, retinoic acid (tretinoin), teniposide, mitomycin C, cytarabine, decitabine, vinblastine, vincristine, vindesine, vinorelbine, valrubicin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, pixantrone, plicamycin, pazopanib, topotecan, camptothecin, irinotecan, sunitinib, derivatives, or salts thereof. 
     
     
         2 . The bone graft composition of  claim 1 , further comprising a growth factor. 
     
     
         3 . The bone graft composition of  claim 2 , wherein the growth factor is a bone morphogenetic protein. 
     
     
         4 . The bone graft composition of  claim 3 , wherein the bone morphogenetic protein is BMP-2, BMP-5, BMP-6, BMP-7, or BMP-9. 
     
     
         5 . The bone graft composition of  claim 1 , further comprising calcium phosphates. 
     
     
         6 . The bone graft composition of  claim 5 , wherein said calcium phosphates are hydroxyapatite and tricalcium phosphate. 
     
     
         7 . The bone graft composition of  claim 1 , further comprising a collagen or hydrogel matrix. 
     
     
         8 . A kit comprising a clotrimazole, honokiol, magnolol, tacrolimus, pimecrolimus, sirolimus, everolimus, temsirolimus, spironolactone, fluticasone, fluticasone propionate, fluticasone furoate, linezolid, telmisartan, chlorambucil, retinol, isotretinoin, acitretin, etretinate, retinoic acid (tretinoin), teniposide, mitomycin C, cytarabine, decitabine, vinblastine, vincristine, vindesine, vinorelbine, valrubicin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, pixantrone, plicamycin, pazopanib, topotecan, camptothecin, irinotecan, sunitinib, derivatives, or salt thereof and a graft composition. 
     
     
         9 . The kit of  claim 8 , further comprising a bone morphogenetic protein. 
     
     
         10 - 25 . (canceled) 
     
     
         26 . A bone graft comprising more than 10, 15, 20, 25, 30, 35 mM of a compound disclosed herein per about 100 mm 3 , or about 150 mm 3 , or 50 to 200 mm 3 , or about 100 to 200 mm 3  of bone graft volume. 
     
     
         27 . The bone graft of  claim 26 , wherein the compound is tacrolimus, pimecrolimus, sirolimus, everolimus, or temsirolimus