In principle, transplantation of mesenchymal progenitor cells would attenuate or possibly correct genetic disorders of bone, cartilage and muscle, but clinical support for this concept is lacking. Here we describe the initial results of allogeneic bone marrow transplantation in three children with osteogenesis imperfecta, a genetic disorder in which osteoblasts produce defective type I collagen, leading to osteopenia, multiple fractures, severe bony deformities and considerably shortened stature. Three months after osteoblast engraftment (1.5-2.0% donor cells), representative specimens of trabecular bone showed histologic changes indicative of new dense bone formation. All patients had increases in total body bone mineral content ranging from 21 to 29 grams (median, 28), compared with predicted values of 0 to 4 grams (median, 0) for healthy children with similar changes in weight. These improvements were associated with increases in growth velocity and reduced frequencies of bone fracture. Thus, allogeneic bone marrow transplantation can lead to engraftment of functional mesenchymal progenitor cells, indicating the feasibility of this strategy in the treatment of osteogenesis imperfecta and perhaps other mesenchymal stem cell disorders as well.

Preclinical models have shown that transplantation of marrow mesenchymal cells has the potential to correct inherited disorders of bone, cartilage, and muscle. The report describes clinical responses of the first children to undergo allogeneic bone marrow transplantation (BMT) for severe osteogenesis imperfecta (OI), a genetic disorder characterized by defective type I collagen, osteopenia, bone fragility, severe bony deformities, and growth retardation. Five children with severe OI were enrolled in a study of BMT from human leukocyte antigen (HLA)-compatible sibling donors. Linear growth, bone mineralization, and fracture rate were taken as measures of treatment response. The 3 children with documented donor osteoblast engraftment had a median 7.5-cm increase in body length (range, 6.5-8.0 cm) 6 months after transplantation compared with 1.25 cm (range, 1.0-1.5 cm) for age-matched control patients. These patients gained 21.0 to 65.3 g total body bone mineral content by 3 months after treatment or 45% to 77% of their baseline values. With extended follow-up, the patients' growth rates either slowed or reached a plateau phase. Bone mineral content continued to increase at a rate similar to that for weight-matched healthy children, even as growth rates declined. These results suggest that BMT from HLA-compatible donors may benefit children with severe OI. IntroductionBone marrow mesenchymal cells can differentiate to a variety of tissues including bone, cartilage, muscle, and fat. 1-7 Thus, in principle, bone marrow transplantation (BMT) could provide effective therapy for disorders that involve cells derived from mesenchymal precursors. 8 One attractive candidate is osteogenesis imperfecta (OI) or "brittle bone disease," a genetic disorder caused by defects in type I collagen, the major structural protein of the extracellular matrix of bone. [9][10][11] Patients with severe OI have numerous painful fractures, progressive deformities of the limbs and spine, retarded bone growth, and short stature. There is no cure for OI, and only one class of drugs, the bisphosphonates, which can reduce or prevent bone resorption, appear to have therapeutic potential. [12][13][14] Ideally, therapy for OI should be directed toward improving bone strength by improving the structural integrity of collagen and thereby the quality of the bone. 15,16 Although the existence of circulating osteoblast progenitors is controversial, 17 preclinical studies have demonstrated that whole bone marrow contains cells that can engraft and become competent osteoblasts after transplantation. 18 Moreover, because collagen is a secreted product, even a low level of osteoblast engraftment might be beneficial to OI patients. 6,19 Guided by this rationale, we undertook a pilot study to demonstrate the feasibility of transplanting bone marrow-derived mesenchymal cells in children with OI.Although providing a basis for continued testing of this strategy, our initial analysis 20 included only 6 months of clinical follow-up and did not directly compare resul...