Mesenchymal stem cells (MSCs) have been demonstrated as an attractive cell source for tissue-engineering applications because of their ability to be easily isolated and expanded from adult bone marrow aspirates and their versatility for pluripotent differentiation into mesenchymal tissues. This review highlights advances and progress in bone reconstruction techniques for both the repair of site-specific bone defects and the attenuation of musculoskeletal disease symptoms associated with osteoporosis and osteogenesis imperfecta. Despite the enormous potential benefits of MSCs within these approaches, conventional tissue culture methods limit the clinical utility of these cells because of the gradual loss of both their proliferative and differentiation potential during ex vivo expansion. Novel strategies to overcome these limitations are discussed including cultivation in the presence of basic fibroblastic growth factor 2, induction of ectopotic telomerase expression, and ex vivo expansion on various collagenous biomaterials. In addition, this review also outlines mechanistic theories on the potential role of MSC-extracellular matrix interactions in mediating the retention of MSC proliferative and differentiation capacity after ex vivo expansion on collagenous biomaterials.