Are bone morphogenetic proteins effective inducers of cartilage repair? Ex vivo transduction of muscle-derived stem cells.

Bone morphogenetic proteins (BMPs), together with other growth and differentiation factors, orchestrate the complex process of chondrogenesis during embryonic development and postnatal growth plate formation that sets the stage for endochondral ossification and bone growth. In vitro and in vivo studies have shown that BMP signaling is required both for the formation of precartilaginous condensations from the mesenchymal precursors and for the differentiation of precursors into chondrocytes (1). BMPs coordinately regulate the patterning of limb elements within cartilage condensations, depending upon the temporal and spatial expression of BMP receptors, signaling molecules and transcription factors, including Smads, and BMP antagonists, such as noggin and chordin (2). Among other activities, BMPs regulate the expression of sex-determining region Y–type high mobility group box (SOX) proteins, which are required for expression of type II collagen during chondrogenesis in vivo, as well as the Runx-2 transcription factor, which regulates hypertrophic chondrocyte maturation and osteogenesis (for review, see ref. 3). During development, embryonic mesenchymal stem cells (MSCs) have the potential to differentiate into a variety of cell lineages, including those that form muscle, adipose tissue, cartilage, and bone. The fates of these cells and patterning within tissues are determined by specific cell–cell and cell–matrix interactions that are controlled by extracellular signaling molecules, their receptors, and intracellular events that control gene transcription in a cell lineage–specific manner. The BMP, fibroblast growth factor, and Wnt pathways predominate in the pathways that control cartilage and bone formation (Figure 1). The discovery of MSCs that remain in adult tissues has promoted investigations to determine the potential of these cells to participate in the repair of skeletal tissues. The capacity of several BMPs, including BMPs 2, 4, 6, 7, 9, and 13, to stimulate the synthesis of the cartilage matrix constituents, type II collagen, and aggrecan by adult articular chondrocytes provides the basis for their use to promote cartilage repair. In this issue of Arthritis & Rheumatism, Kuroda et al (4) report that local delivery of BMP-4 by genetically engineered muscle-derived stem cells (MDSCs) enhances chondrogenesis and improves the repair of the articular cartilage in rats. Although bone marrow– derived stem cells have been investigated extensively for the repair of bone and cartilage defects, enriched stem cells from muscle, which have been suggested as potential sources of cartilage and bone progenitors, have not been investigated previously in this context. MDSCs isolated from skeletal muscles of 3-week-old mice were cultured in vitro for 2 weeks, mixed with fibrin glue, and applied to fresh full-thickness defects in the trochlear groove of femurs of 12-week-old athymic rats. The crucial factor for cartilage repair appeared to be not only the expression of BMP-4 by retroviral induction, but also the culture of the cells prior to injection in a chondrogenic medium that contained a serum substitute of insulin, transferrin, and selenium, dexamethasone, and ascorbate, which are standard additives for inducing chondrogenesis in vitro. The initial report on autologous chondrocyte transplantation for repairing small cartilage defects in humans subsequently led to the search for less invasive approaches for cell-based therapy, since the donor site, although not load-bearing, often undergoes significant morbidity and osteoarthritic changes (5). Many studies that address alternative cellular sources for cartilage repair have aimed at exploiting the capacity of bone marrow–derived MSCs to undergo endochondral ossification whereby a cartilage intermediate is formed (6,7). The initial driving force for the application of BMPs to Mary B. Goldring, PhD: New England Baptist Bone and Joint Institute and Harvard Medical School, Boston, Massachusetts. Address correspondence and reprint requests to Mary B. Goldring, PhD, Harvard Institutes of Medicine, HIM 246, 4 Blackfan Circle, Boston, MA 02115-5713. E-mail: mgoldrin@bidmc. harvard.edu. Submitted for publication October 17, 2005; accepted in revised form November 10, 2005.