We have demonstrated that synovial MSCs derived from the knee joints of aging human donors possess chondrogenic potential. Under serum-free culturing conditions and in the absence of dexamethasone, BMP-2 and BMP-7 were the most potent inducers of this transformation process.

We randomly assigned 17 patients with scaphoid non-union at the proximal pole to three treatment groups: (1) autologous iliac graft (n=6), (2) autologous iliac graft + osteogenic protein-1 (OP-1; n=6), and (3) allogenic iliac graft + OP-1 (n=5). Radiographic, scintigraphic, and clinical assessments were performed throughout the follow-up period of 24 months. OP-1 improved the performance of both autologous and allogenic bone implants and reduced radiographic healing time to 4 weeks compared with 9 weeks in group 1. Helical CT scans and scintigraphy showed that in OP-1-treated patients sclerotic bone was replaced by well-vascularised bone. The addition of OP-1 to allogenic bone implant equalised the clinical outcome with the autologous graft procedure. Consequently the harvesting of autologous graft can be avoided.Résumé Nous avons réparti 17 malades avec une pseudarthrose du pôle proximal du scaphoide en trois groupes aléatoires de traitement: (1) greffe autologue iliaque (n=6), (2) greffe autologue iliaque + protéine osteogenique-1 (OP-1; n=6), et (3) greffe allogène iliaque + OP-1 (n=5). L'estimation radiographique, scintigraphique et clinique a été exécutée pendant une période de suivi de 24 mois. L'OP-1 a amélioré la performance des autogreffes et des allogreffes osseuses et a réduit le temps curatif radiographique à 4 semaines, comparé à 9 semaines dans le groupe traité uniquement avec de l'os autologues. Chez les malades traités avec l'OP-1, la tomodensitométrie hélicoïdale et la scintigraphie ont montré que l'os scléreux était remplacé par de l'os bien vascularisé. L'addition d'OP-1 à la greffe allogène a égalisé le résultat clinique avec la procédure de greffe autologue et a permis de supprimer le temps de prise de greffe.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-beta) gene superfamily of growth and differentiation factors. Members of the BMP family were originally cloned and characterized by their ability to induce ectopic bone formation. Of the various BMPs cloned, the bone inductive ability of BMP-7 (OP-1) and BMP-2 has been well characterized. Both BMP-7 and -2 have been shown to have clinical utility in the healing of non-union fractures. However, in spite of the various advances in BMP research, the physiological regulation of BMPs is not well understood. Here we studied the expression of BMP-7 by cloning a 4.6-kB fragment of the human BMP-7 promoter (hBMP-7p) and placing it upstream of a luciferase reporter. The promoter reporter construct was stably transfected into different cell backgrounds and its regulation by various factors was investigated. We show that retinoic acid (RA) treatment results in an upregulation of the hBMP-7p reporter activity. This regulation of the hBMP-7p was further confirmed by Northern blot, PCR, and Western blot analyses, which showed an increase in both BMP-7 mRNA and protein expression upon treatment with RA. We further show that RA specifically upregulates expression of osteocalcin via activation of BMP-7 mRNA and protein in vitro. Similarly, prostaglandin E(2) (PGE(2)) treatment increases BMP-7 mRNA and protein levels, but does not transcriptionally activate the hBMP-7p. Additionally, in vivo expression of BMP-7 in bone was increased upon PGE(2) treatment. In conclusion, RA and PGE(2) upregulate BMP-7 protein expression both in vitro and in vivo.

The requirement of a bone morphogenetic protein for the maintenance and stimulation of an osteoblast phenotype was examined using mouse MC3T3-E1 cell cultures. Cells expressed BMP-4 mRNA, which correlated with the stimulation of the osteoblast phenotype. The addition of a BMP-4 specific antibody reduced bone nodules, suggesting that BMP-4 is required for the osteogenic activity of osteoblasts in an autocrine manner. Exogenously added BMP-7 gradually decreased the expression of BMP-4 with a concurrent stimulation of the osteoblast phenotype. Exogenous BMP-7 can therefore substitute for endogenously produced BMP-4 acting as a paracrine factor on osteoblasts. The addition of 17beta estradiol decreased BMP-4 expression but initiated synthesis of BMP-6 mRNA, an endocrine signal for osteoblasts, which also substituted for the lack of endogenous BMP-4, as evidenced by normal bone nodule formation. The addition of dexamethasone and parathyroid hormone did not affect the BMP-4 expression but induced transcripts for BMP-2 and BMP-3, respectively, suggesting that their effects on bone can be in part achieved via the BMP signaling. These experiments support the requirement of a BMP for osteoblast differentiation and function, demonstrating for the first time that a BMP can functionally substitute for another BMP in an autocrine/paracrine manner or mediate a response to an endocrine action on osteoblasts.

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