Proximal Junctional Kyphosis: Inter- and Intraobserver Reliability of Radiographic Measurements in Adult Spinal Deformity.

STUDY DESIGN: Reliability study of radiographic measures of proximal junctional kyphosis (PJK) in patients with adult spinal deformity (ASD). OBJECTIVE: To assess impacts of level of proximal endpoint and vertebral fracture on reliability of measurement of junctional kyphosis. SUMMARY OF BACKGROUND DATA: Radiographic assessment is important in determining management of patients with PJK or proximal junctional failure (PJF). No study to date has evaluated the reliability of radiographic measurement of the junctional kyphotic angle after surgery for ASD. METHODS: Postoperative radiographs from 52 patients with ASD were divided into four categories based on the level of the upper instrumented vertebra (UIV) and the presence or absence of PJF: upper thoracic without failure (UT), thoracolumbar without failure (TL), upper thoracic with PJF (UTF), and thoracolumbar with PJF (TLF). Nine surgeon reviewers performed radiographic measurements of kyphosis between UIV+2 and UIV twice at least 4 weeks apart. Intraclass correlation coefficients (ICC) were calculated to determine inter- and intraobserver reliability. RESULTS: Interobserver reliability for measurements of UT, TL, UTF, and TLF were all "almost perfect" with ICC scores of 0.917, 0.965, 0.956, and 0.882, and 0.932, 0.975, 0958, and 0.989, for sessions 1 and 2, respectively. Similarly, ICCs for kyphosis measurements for the TL and TLF group had "almost perfect" agreement with means of 0.898 (range: 0.817-0.969) and 0.976 (range: 0.931-0.995), respectively. ICCs for measurements for the UT and UTF groups all had "substantial" or "almost perfect" agreement with means of 0.801 (range: 0.662-0.942) and 0.879 (range: 0.760-0.988), respectively. CONCLUSION: The present study demonstrates high inter- and intraobserver reliability of PJK measurement following instrumented fusion for ASD, independent of the presence or absence of PJF. Although slightly lower for upper thoracic than for thoracolumbar proximal endpoints, all ICCs consistently reached at least "substantial agreement" and "near perfect agreement" for most. LEVEL OF EVIDENCE: 4.

Inter- and Intra-rater Reliability of the Hart-ISSG Proximal Junctional Failure Severity Scale.

STUDY DESIGN: Reliability/external validation study. OBJECTIVE: Investigate inter- and intrarater reliability of the Hart-International Spine Study Group (ISSG) Proximal Junctional Failure Severity Scale (PJFSS) and its correlation with operative revision in patients with proximal junctional failure (PJF). SUMMARY OF BACKGROUND DATA: The Hart-ISSG PJFSS is a validated classification system for PJF. Reliability of the PJFSS has not been assessed. METHODS: Sixteen detailed clinical scenarios were assessed using the ISSG PJFSS classification in six categories: neurologic status, axial pain, instrumentation issue, proximal kyphotic angle, level of upper instrumented vertebrae (UIV), and severity of UIV/UIV+1 fracture. Eleven spine surgeons evaluated each case in all six categories during two different assessments, and provided recommendations regarding operative revision or observation for each case. Inter- and intrarater reliability were calculated based on intraclass correlation coefficients. RESULTS: All intraclass correlation coefficients demonstrated "almost perfect"' (0.817-0.988) inter-rater agreement for both assessments, except UIV/UIV+1 fracture severity during the second assessment, which demonstrated "substantial" agreement' (0.692). Five of six categories had "almost perfect" mean intrarater reliability (0.805-0.981), while "instrumentation issue" demonstrated "substantial" mean agreement (0.757). Inter-rater reliability for recommendation of surgical intervention was "almost perfect" during both assessments (0.911 and 0.922, respectively). Mean PJFSS scores between the two assessments were significantly higher for cases recommended for operative revision (8.43 ±â€Š0.90) versus cases recommended for observation (P < 0.0001). CONCLUSION: The ISSG PJFSS is a reliable and repeatable classification system for assessing patients with PJF. Higher PJFSS scales correlate with recommendation for operative revision, extending prior external validation of the PJFSS. LEVEL OF EVIDENCE: 3.

Hospital charges associated with "never events": comparison of anterior cervical discectomy and fusion, posterior lumbar interbody fusion, and lumbar laminectomy to total joint arthroplasty.

OBJECTIVE Beginning in 2008, the Centers for Medicare and Medicaid Service (CMS) determined that certain hospital-acquired adverse events such as surgical site infection (SSI) following spine surgery should never occur. The following year, they expanded the ruling to include deep vein thrombosis (DVT) and pulmonary embolism (PE) following total joint arthroplasty. Due to their ruling that "never events" are not the payers' responsibility, CMS insists that the costs of managing these complications be borne by hospitals and health care providers, rather than billings to health care payers for additional care required in their management. Data comparing the expected costs of such adverse events in patients undergoing spine and orthopedic surgery have not previously been reported. METHODS The California State Inpatient Database (CA-SID) from 2008 to 2009 was used for the analysis. All patients with primary procedure codes indicating anterior cervical discectomy and fusion (ACDF), posterior lumbar interbody fusion (PLIF), lumbar laminectomy (LL), total knee replacement (TKR), and total hip replacement (THR) were analyzed. Patients with diagnostic and/or treatment codes for DVT, PE, and SSI were separated from patients without these complication codes. Patients with more than 1 primary procedure code or more than 1 complication code were excluded. Median charges for treatment from primary surgery through 3 months postoperatively were calculated. RESULTS The incidence of the examined adverse events was lowest for ACDF (0.6% DVT, 0.1% PE, and 0.03% SSI) and highest for TKA (1.3% DVT, 0.3% PE, 0.6% SSI). Median inpatient charges for uncomplicated LL was $51,817, compared with $73,432 for ACDF, $143,601 for PLIF, $74,459 for THR, and $70,116 for TKR. Charges for patients with DVT ranged from $108,387 for TKR (1.5 times greater than index) to $313,536 for ACDF (4.3 times greater than index). Charges for patients with PE ranged from $127,958 for TKR (1.8 times greater than index) to $246,637 for PLIF (1.7 times greater than index). Charges for patients with SSI ranged from $168,964 for TKR (2.4 times greater than index) to $385,753 for PLIF (2.7 times greater than index). CONCLUSIONS Although incidence rates are low, adverse events of spinal procedures substantially increase the cost of care. Charges for patients experiencing DVT, PE, and SSI increased in this study by factors ranging from 1.8 to 4.3 times those for patients without such complications across 5 common spinal and orthopedic procedures. Cost projections by health care providers will need to incorporate expected costs of added care for patients experiencing such complications, assuming that the cost burden of such events continues to shift from payers to providers.

Adverse Event Recording and Reporting in Clinical Trials Comparing Lumbar Disk Replacement with Lumbar Fusion: A Systematic Review.

Study Design Systematic review. Objectives (1) To compare the quality of adverse event (AE) methodology and reporting among randomized trials comparing lumbar fusion with lumbar total disk replacement (TDR) using established AE reporting systems; (2) to compare the AEs and reoperations of lumbar spinal fusion with those from lumbar TDR; (3) to make recommendations on how to report AEs in randomized controlled trials (RCTs) so that surgeons and patients have more-detailed and comprehensive information when making treatment decisions. Methods A systematic search of PubMed, the Cochrane collaboration database, and the National Guideline Clearinghouse through May 2015 was conducted. Randomized controlled trials with at least 2 years of follow-up comparing lumbar artificial disk replacement with lumbar fusion were included. Patients were required to have axial or mechanical low back pain of ≥3 months' duration due to degenerative joint disease defined as degenerative disk disease, facet joint disease, or spondylosis. Outcomes included the quality of AE acquisition methodology and results reporting, and AEs were defined as those secondary to the procedure and reoperations. Individual and pooled relative risks and their 95% confidence intervals comparing lumbar TDR with fusion were calculated. Results RCTs demonstrated a generally poor description of methods for assessing AEs. There was a consistent lack of clear definition or grading for these events. Furthermore, there was a high degree of variation in reporting of surgery-related AEs. Most studies lacked adequate reporting of the timing of AEs, and there were no clear distinctions between acute or chronic AEs. Meta-analysis of the pooled data demonstrated a twofold increased risk of AEs in patients having lumbar fusion compared with patients having lumbar TDR at 2-year follow-up, and this relative risk was maintained at 5 years. Furthermore, the pooled data demonstrated a 1.7 times greater relative risk of reoperation in the fusion group compared with lumbar TDR, although this risk decreased to 1.1 at 5-year follow-up. However, given the lack of quality and consistency in the methods of recording and reporting of AEs, we are unable to make a clear recommendation of one treatment over the other. Conclusions Based on the currently available literature, lumbar TDR appears to be comparable in safety to lumbar fusion. However, due to lack of consistency in reporting of AEs, it is difficult to make conclusions regarding the true safety profile of lumbar TDR. Standardization in AE reporting will significantly improve the reliability of the current literature.

Characterization of Reversibly Immortalized Calvarial Mesenchymal Progenitor Cells.

BACKGROUND: Bone morphogenetic proteins (BMPs) play a sentinel role in osteoblastic differentiation, and their implementation into clinical practice can revolutionize cranial reconstruction. Preliminary data suggest a therapeutic role of adenoviral gene delivery of BMPs in murine calvarial defect healing. Poor transgene expression inherent in direct adenoviral therapy prompted investigation of cell-based strategies. OBJECTIVE: To isolate and immortalize calvarial cells as a potential progenitor source for osseous tissue engineering. MATERIALS AND METHODS: Cells were isolated from murine skulls, cultured, and transduced with a retroviral vector bearing the loxP-flanked SV40 large T antigen. Immortalized calvarial cells (iCALs) were evaluated via light microscopy, immunohistochemistry, and flow cytometry to determine whether the immortalization process altered cell morphology or progenitor cell profile. Immortalized calvarial cells were then infected with adenoviral vectors encoding BMP-2 or GFP and assessed for early and late stages of osteogenic differentiation. RESULTS: Immortalization of calvarial cells did not alter cell morphology as demonstrated by phase contrast microscopy. Mesenchymal progenitor cell markers CD166, CD73, CD44, and CD105 were detected at varying levels in both primary cells and iCALs. Significant elevations in alkaline phosphatase activity, osteocalcin mRNA transcription, and matrix mineralization were detected in BMP-2 treated iCALs compared with GFP-treated cells. Gross and histological analyses revealed ectopic bone production from treated cells compared with controls in an in vivo stem cell implantation assay. CONCLUSION: We have established an immortalized osteoprogenitor cell line from juvenile calvarial cells that retain a progenitor cell phenotype and can successfully undergo osteogenic differentiation upon BMP-2 stimulation. These cells provide a valuable platform to investigate the molecular mechanisms underlying intramembranous bone formation and to screen for factors/small molecules that can facilitate the healing of osseous defects in the craniofacial skeleton.

Distinct effects of platelet-rich plasma and BMP13 on rotator cuff tendon injury healing in a rat model.

BACKGROUND: Although platelet-rich plasma (PRP) is used clinically to augment tendon healing, bone morphogenetic protein-13 (BMP13) may provide a better therapeutic avenue to improve early tendon healing and repair. HYPOTHESIS: Exogenous expression of BMP13 in tenocytes will up-regulate genes involved in tendon healing. Direct delivery of adenovirus-mediated BMP13 (AdBMP13) into the injured rat supraspinatus tendon will increase biomechanical properties. STUDY DESIGN: Controlled laboratory study. METHODS: Exogenous expression of BMP13 and the major growth factors in PRP (transforming growth factor-ß1 [TGF-ß1], vascular endothelial growth factor-A [VEGF-A], and platelet-derived growth factor-BB [PDGF-BB]) was accomplished by using recombinant adenoviral vectors. The expression of tendon- and matrix-associated genes in growth factor-treated tenocytes was analyzed by use of semiquantitative reverse-transcription polymerase chain reaction. A total of 32 rats with supraspinatus defect were divided into 4 groups and injected with adenovirus-containing green fluorescent protein (AdGFP; negative control), PRP, AdBMP13, or PRP+AdBMP13. All rats were sacrificed at 2 weeks after surgery, and tendons were harvested for biomechanical testing and histologic analysis. RESULTS: BMP13 up-regulated type III collagen expression compared with AdGFP control and PRP growth factors (P < .01). BMP13 and PRP growth factors each up-regulated fibronectin expression (P < .01). There was an increase in stress to failure in each of the 3 treatment groups (P < .05 for PRP; P < .01 for AdBMP13 or PRP+AdBMP13) compared with AdGFP control. AdBMP13 demonstrated higher stress to failure than did the PRPs (P < .01). The addition of PRP did not increase the BMP13-enhanced stress to failure or stiffness. The biomechanical results were further supported by histologic analysis of the retrieved samples. CONCLUSION: Exogenous expression of BMP13 enhances tendon healing more effectively than PRP as assessed by tendon- and matrix-associated gene expression, biomechanical testing, and histologic analysis. CLINICAL RELEVANCE: While PRP is used in the clinical setting, BMP13 may be explored as a superior biofactor to improve rotator cuff tendon healing and reduce the incidence of retears.

The therapeutic potential of the Wnt signaling pathway in bone disorders.

The Wnt pathway plays a critical role in development and differentiation of many tissues, such as the gut, hair follicles, and bone. Increasing evidence indicates that Wnts may function as key regulators in osteogenic differentiation of mesenchymal stem cells and bone formation. Conversely, aberrant Wnt signaling is associated with many osteogenic pathologies. For example, genetic alterations in the Wnt signaling pathway lead to osteoporosis and osteopenia, while inactivating mutations of Wnt inhibitors result in a hyperostotic skeleton with increased bone mineral density. Hyperparathyroidism causes osteopenia via induction of the Wnt signaling pathway. Lithium, often used to treat bipolar disorder, blocks a Wnt antagonist, decreasing the patient's risk of fractures. Thus, manipulating the Wnt pathway may offer plenty therapeutic opportunities in treating bone disorders. In fact, induction of the Wnt signaling pathway or inhibition of Wnt antagonists has shown promise in treating bone metabolic disorders, including osteoporosis. For example, antibodies targeting the Wnt inhibitor Sclerostin lead to increased bone mineral density in post-menopausal women. However, such therapies targeting the Wnt pathway are not without risk, as genetic alternations may lead to over-activation of Wnt/ß-catenin and its association with many tumors. It is conceivable that targeting Wnt inhibitors may predispose the individuals to tumorigenic phenotypes, at least in bone. Here, we review the roles of Wnt signaling in bone metabolic and pathologic processes, as well as the therapeutic potential for targeting Wnt pathway and its associated risks in bone diseases.

Lysophosphatidic acid acyltransferase ß (LPAATß) promotes the tumor growth of human osteosarcoma.

BACKGROUND: Osteosarcoma is the most common primary malignancy of bone with poorly characterized molecular pathways important in its pathogenesis. Increasing evidence indicates that elevated lipid biosynthesis is a characteristic feature of cancer. We sought to investigate the role of lysophosphatidic acid acyltransferase ß (LPAATß, aka, AGPAT2) in regulating the proliferation and growth of human osteosarcoma cells. LPAATß can generate phosphatidic acid, which plays a key role in lipid biosynthesis as well as in cell proliferation and survival. Although elevated expression of LPAATß has been reported in several types of human tumors, the role of LPAATß in osteosarcoma progression has yet to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Endogenous expression of LPAATß in osteosarcoma cell lines is analyzed by using semi-quantitative PCR and immunohistochemical staining. Adenovirus-mediated overexpression of LPAATß and silencing LPAATß expression is employed to determine the effect of LPAATß on osteosarcoma cell proliferation and migration in vitro and osteosarcoma tumor growth in vivo. We have found that expression of LPAATß is readily detected in 8 of the 10 analyzed human osteosarcoma lines. Exogenous expression of LPAATß promotes osteosarcoma cell proliferation and migration, while silencing LPAATß expression inhibits these cellular characteristics. We further demonstrate that exogenous expression of LPAATß effectively promotes tumor growth, while knockdown of LPAATß expression inhibits tumor growth in an orthotopic xenograft model of human osteosarcoma. CONCLUSIONS/SIGNIFICANCE: Our results strongly suggest that LPAATß expression may be associated with the aggressive phenotypes of human osteosarcoma and that LPAATß may play an important role in regulating osteosarcoma cell proliferation and tumor growth. Thus, targeting LPAATß may be exploited as a novel therapeutic strategy for the clinical management of osteosarcoma. This is especially attractive given the availability of selective pharmacological inhibitors.

Retinoic acids potentiate BMP9-induced osteogenic differentiation of mesenchymal progenitor cells.

BACKGROUND: As one of the least studied bone morphogenetic proteins (BMPs), BMP9 is one of the most osteogenic BMPs. Retinoic acid (RA) signaling is known to play an important role in development, differentiation and bone metabolism. In this study, we investigate the effect of RA signaling on BMP9-induced osteogenic differentiation of mesenchymal progenitor cells (MPCs). METHODOLOGY/PRINCIPAL FINDINGS: Both primary MPCs and MPC line are used for BMP9 and RA stimulation. Recombinant adenoviruses are used to deliver BMP9, RARalpha and RXRalpha into MPCs. The in vitro osteogenic differentiation is monitored by determining the early and late osteogenic markers and matrix mineralization. Mouse perinatal limb explants and in vivo MPC implantation experiments are carried out to assess bone formation. We find that both 9CRA and ATRA effectively induce early osteogenic marker, such as alkaline phosphatase (ALP), and late osteogenic markers, such as osteopontin (OPN) and osteocalcin (OC). BMP9-induced osteogenic differentiation and mineralization is synergistically enhanced by 9CRA and ATRA in vitro. 9CRA and ATRA are shown to induce BMP9 expression and activate BMPR Smad-mediated transcription activity. Using mouse perinatal limb explants, we find that BMP9 and RAs act together to promote the expansion of hypertrophic chondrocyte zone at growth plate. Progenitor cell implantation studies reveal that co-expression of BMP9 and RXRalpha or RARalpha significantly increases trabecular bone and osteoid matrix formation. CONCLUSION/SIGNIFICANCE: Our results strongly suggest that retinoid signaling may synergize with BMP9 activity in promoting osteogenic differentiation of MPCs. This knowledge should expand our understanding about how BMP9 cross-talks with other signaling pathways. Furthermore, a combination of BMP9 and retinoic acid (or its agonists) may be explored as effective bone regeneration therapeutics to treat large segmental bony defects, non-union fracture, and/or osteoporotic fracture.

Insulin-like growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation.

Efficient osteogenic differentiation and bone formation from mesenchymal stem cells (MSCs) should have clinical applications in treating nonunion fracture healing. MSCs are adherent bone marrow stromal cells that can self-renew and differentiate into osteogenic, chondrogenic, adipogenic, and myogenic lineages. We have identified bone morphogenetic protein 9 (BMP-9) as one of the most osteogenic BMPs. Here we investigate the effect of insulin-like growth factor 2 (IGF-2) on BMP-9-induced bone formation. We have found that endogenous IGF-2 expression is low in MSCs. Expression of IGF-2 can potentiate BMP-9-induced early osteogenic marker alkaline phosphatase (ALP) activity and the expression of later markers. IGF-2 has been shown to augment BMP-9-induced ectopic bone formation in the stem cell implantation assay. In perinatal limb explant culture assay, IGF-2 enhances BMP-9-induced endochondral ossification, whereas IGF-2 itself can promote the expansion of the hypertropic chondrocyte zone of the cultured limb explants. Expression of the IGF antagonists IGFBP3 and IGFBP4 leads to inhibition of the IGF-2 effect on BMP-9-induced ALP activity and matrix mineralization. Mechanistically, IGF-2 is further shown to enhance the BMP-9-induced BMPR-Smad reporter activity and Smad1/5/8 nuclear translocation. PI3-kinase (PI3K) inhibitor LY294002 abolishes the IGF-2 potentiation effect on BMP-9-mediated osteogenic signaling and can directly inhibit BMP-9 activity. These results demonstrate that BMP-9 crosstalks with IGF-2 through PI3K/AKT signaling pathway during osteogenic differentiation of MSCs. Taken together, our findings suggest that a combination of BMP-9 and IGF-2 may be explored as an effective bone-regeneration agent to treat large segmental bony defects, nonunion fracture, and/or osteoporotic fracture.

Synergistic antitumor effect of the activated PPARgamma and retinoid receptors on human osteosarcoma.

PURPOSE: Osteosarcoma is the most common primary malignancy of bone. The long-term survival of osteosarcoma patients hinges on our ability to prevent and/or treat recurrent and metastatic lesions. Here, we investigated the activation of peroxisome proliferator-activated receptor gamma (PPARgamma) and retinoid receptors as a means of differentiation therapy for human osteosarcoma. EXPERIMENTAL DESIGN: We examined the endogenous expression of PPARgamma and retinoid receptors in a panel of osteosarcoma cells. Ligands or adenovirus-mediated overexpression of these receptors were tested to inhibit proliferation and induce apoptosis of osteosarcoma cells. Osteosarcoma cells overexpressing the receptors were introduced into an orthotopic tumor model. The effect of these ligands on osteoblastic differentiation was further investigated. RESULTS: Endogenous expression of PPARgamma and isotypes of retinoic acid receptor (RAR) and retinoid X receptor (RXR) is detected in most osteosarcoma cells. Troglitazone, 9-cis retinoic acid (RA), and all-trans RA, as well as overexpression of PPARgamma, RARalpha, and RXRalpha, inhibit osteosarcoma cell proliferation and induce apoptosis. A synergistic inhibitory effect on osteosarcoma cell proliferation is observed between troglitazone and retinoids, as well as with the overexpression pairs of PPARgamma/RARalpha, or PPARgamma/RXRalpha. Overexpression of PPARgamma, RARalpha, RXRalpha, or in combinations inhibits osteosarcoma tumor growth and cell proliferation in vivo. Retinoids (and to a lesser extent, troglitazone) are shown to promote osteogenic differentiation of osteosarcoma cells and mesenchymal stem cells. CONCLUSIONS: Activation of PPARgamma, RARalpha, and RXRalpha may act synergistically on inhibiting osteosarcoma cell proliferation and tumor growth, which is at least partially mediated by promoting osteoblastic differentiation of osteosarcoma cells.

Therapeutic Implications of PPARgamma in Human Osteosarcoma.

Osteosarcoma (OS) is the most common nonhematologic malignancy of bone in children and adults. Although dysregulation of tumor suppressor genes and oncogenes, such as Rb, p53, and the genes critical to cell cycle control, genetic stability, and apoptosis have been identified in OS, consensus genetic changes that lead to OS development are poorly understood. Disruption of the osteogenic differentiation pathway may be at least in part responsible for OS tumorigenesis. Current OS management involves chemotherapy and surgery. Peroxisome proliferator-activated receptor (PPAR) agonists and/or retinoids can inhibit OS proliferation and induce apoptosis and may inhibit OS growth by promoting osteoblastic terminal differentiation. Thus, safe and effective PPAR agonists and/or retinoid derivatives can be then used as adjuvant therapeutic drugs for OS therapy. Furthermore, these agents have the potential to be used as chemopreventive agents for the OS patients who undergo the resection of the primary bone tumors in order to prevent local recurrence and/or distal pulmonary metastasis.

Mesenchymal Progenitor Cells and Their Orthopedic Applications: Forging a Path towards Clinical Trials.

Mesenchymal progenitor cells (MPCs) are nonhematopoietic multipotent cells capable of differentiating into mesenchymal and nonmesenchymal lineages. While they can be isolated from various tissues, MPCs isolated from the bone marrow are best characterized. These cells represent a subset of bone marrow stromal cells (BMSCs) which, in addition to their differentiation potential, are critical in supporting proliferation and differentiation of hematopoietic cells. They are of clinical interest because they can be easily isolated from bone marrow aspirates and expanded in vitro with minimal donor site morbidity. The BMSCs are also capable of altering disease pathophysiology by secreting modulating factors in a paracrine manner. Thus, engineering such cells to maximize therapeutic potential has been the focus of cell/gene therapy to date. Here, we discuss the path towards the development of clinical trials utilizing BMSCs for orthopaedic applications. Specifically, we will review the use of BMSCs in repairing critical-sized defects, fracture nonunions, cartilage and tendon injuries, as well as in metabolic bone diseases and osteonecrosis. A review of www.ClinicalTrials.gov of the United States National Institute of Health was performed, and ongoing clinical trials will be discussed in addition to the sentinel preclinical studies that paved the way for human investigations.

Mesenchymal stem cells: Molecular characteristics and clinical applications.

Mesenchymal stem cells (MSCs) are non-hematopoietic stem cells with the capacity to differentiate into tissues of both mesenchymal and non-mesenchymal origin. MSCs can differentiate into osteoblastic, chondrogenic, and adipogenic lineages, although recent studies have demonstrated that MSCs are also able to differentiate into other lineages, including neuronal and cardiomyogenic lineages. Since their original isolation from the bone marrow, MSCs have been successfully harvested from many other tissues. Their ease of isolation and ex vivo expansion combined with their immunoprivileged nature has made these cells popular candidates for stem cell therapies. These cells have the potential to alter disease pathophysiology through many modalities including cytokine secretion, capacity to differentiate along various lineages, immune modulation and direct cell-cell interaction with diseased tissue. Here we first review basic features of MSC biology including MSC characteristics in culture, homing mechanisms, differentiation capabilities and immune modulation. We then highlight some in vivo and clinical evidence supporting the therapeutic roles of MSCs and their uses in orthopedic, autoimmune, and ischemic disorders.