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Background Mice with a loss of function mutation in Wdpcp were described previously to display severe birth defects in the developing heart, neural tube, and limb buds. Further characterization of the skeletal phenotype of Wdpcp null mice was limited by perinatal lethality. Results We utilized Prx1-Cre mice to generate limb bud mesenchyme specific deletion of Wdpcp. These mice recapitulated the appendicular skeletal phenotype of the Wdpcp null mice including polydactyl and limb bud signaling defects. Examination of late stages of limb development demonstrated decreased size of cartilage anlagen, delayed calcification, and abnormal growth plates. Utilizing in vitro assays, we demonstrated that loss of Wdpcp in skeletal progenitors lead to loss of hedgehog signaling responsiveness and associated proliferative response. In vitro chondrogenesis assays showed this loss of hedgehog and proliferative response was associated with decreased expression of early chondrogenic marker N-Cadherin. E14.5 forelimbs demonstrated delayed ossification and expression of osteoblast markers Runx2 and Sp7. P0 growth plates demonstrated loss of hedgehog signaling markers and expansion of the hypertrophic zones of the growth plate. In vitro osteogenesis assays demonstrated decreased osteogenic differentiation of Wdpcp null mesenchymal progenitors in response to hedgehog stimulation. Conclusions These findings demonstrate how Wdpcp and associated regulation of the hedgehog signaling pathway plays an important role at multiple stages of skeletal development. Wdpcp is necessary for positive regulation of hedgehog signaling and associated proliferation is key to the initiation of chondrogenesis. At later stages, Wdpcp facilitates the robust hedgehog response necessary for chondrocyte hypertrophy and osteogenic differentiation.

Cartilage defects of the patellofemoral joint are commonly found in association with patellar instability owing to abnormal biomechanics. Strategies to address chondral defects of the patellofemoral joint secondary to instability should first address causes of recurrent instability. Most patellofemoral chondral defects associated with instability are less than 2 cm2 and do not generally require intervention beyond chondroplasty. Larger defects of the patella and/or the trochlea can be repaired with osteochondral or surface cartilage repair.

Musculoskeletal disorders constitute a substantial disease burden. Neither conservative management nor surgical intervention provides adequate treatment for several pathologies. As an element of regenerative medicine, stem cell therapies may overcome the poor innate healing capacity of several musculoskeletal tissues. This review highlights promising results of preclinical studies in which stem cell therapies have been applied to individual tissues of the musculoskeletal system (bone, articular cartilage, tendon and ligament, meniscus, intervertebral disc, and skeletal muscle) as well as transitions between tissues (osteochondral interfaces and tendon–bone interfaces). Clinical studies, although limited in number, are also reviewed. Challenges to the translation of stem cell therapies from bench to bedside are discussed and possible solutions are highlighted.

Injuries of tendon, ligament, and meniscus affect more than 10 million people in the United States annually. Unfortunately, most of the current clinical reparative interventions do not adequately address the requirements of the tissue junction sites, resulting in high failure rates of surgery and readmission upon overuse. This chapter reviews the nature and current treatments for such injuries and summarizes selected clinical trials in specific categories. Adult stem cells, or mesenchymal stem cells, are of particular therapeutic interest for these skeletal soft tissues in part because of the relative ease of isolation and enrichment, and freedom from ethical issues. Successful cell-based therapies will require the use of biomimetic biomaterial scaffolds to support and promote cell differentiation and tissue regeneration. The challenges and promises of combining stem/progenitor cells, scaffolds, and bioactive factors, for ligament, tendon, and meniscus tissue engineering and regenerative medicine approaches are highlighted in this review.

The bones and connective tissues of the body are derived from two embryonic origins, the mesoderm and neural crest. The appendicular skeleton arises from the lateral plate mesoderm, the axial skeleton from the paraxial mesoderm, and the craniofacial skeleton from a combination of cephalic paraxial mesoderm and neural crest cells. Bones are formed through one of two processes: Endochondral ossification involves the formation of primordial cartilaginous anlagen that are subsequently replaced by bone via the growth plates. Intramembranous ossification is characterized by the direct differentiation of mesenchymal cells to osteogenic tissue. The growth plate can be divided into a resting zone, a proliferating zone, a pre-hypertrophic zone, and a hypertrophic zone, reflecting a gradient of chondrocyte differentiation that is regulated by antagonism between bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) signaling pathways and gradients of IHH and PTHrP. Replacement of cartilage by osteoblasts is dependent upon prior mineralization of the cartilage matrix and vascular invasion. The activities of the hypertrophic chondrocytes and of the osteoblasts are regulated by RUNX2. Osteoclasts are of hematopoietic origin (monocyte), and with osteoblasts, they remodel bone throughout an individual’s lifetime to adapt to mechanical demands. Joints and intra-articular structures arise from a cohort of progenitor cells distinct from those of the bones and are labeled by GDF5 and TGFBRII expression. Somites are formed from the segmental plate through the interaction of a cell-autonomous oscillator and a morphogenetic wave that coordinates somite boundary formation via the Notch-Delta juxtacrine system and epithelialization via WNT paracrine system and cadherin activity. Dysregulation of this developmental process leads to congenital scoliosis. The axial skeleton is derived from the ventro-medial sclerotome of somites. Differentiation of the somite is regulated by paracrine factors from surrounding tissues and the sclerotome in particular is induced by SHH. Tendons and ligaments develop from the interaction of mesodermal mesenchyme with myoblasts. The nucleus pulposus of the intervertebral disc is initially derived from the notochord. The gradual loss of “embryonic cells” from the disc may be related to disc degeneration and back pain.