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Degenerative changes of the intervertebral disc (IVD) are a leading cause of disability affecting humans worldwide and has been attributed primarily to trauma and the accumulation of pathology during aging. While genetic defects have also been associated with disc degeneration, the precise mechanisms driving the initiation and progression of disease have remained elusive due to a paucity of genetic animal models. Here, we discuss a novel conditional mouse genetic model of endplate-oriented disc herniations in adult mice. Using conditional mouse genetics, we show increased mechanical stiffness and reveal dysregulation of typical gene expression profiles of the IVD in adhesion G-protein coupled receptor G6 (Adgrg6) mutant mice prior to the onset of endplate-oriented disc herniations in adult mice. We observed increased STAT3 activation prior to IVD defects and go on to demonstrate that treatment of Adgrg6 conditional mutant mice with a small molecule inhibitor of STAT3 activation ameliorates endplate-oriented herniations. These findings establish ADGRG6 and STAT3 as novel regulators of IVD endplate and growth plate integrity in the mouse, and implicate ADGRG6/STAT3 signaling as promising therapeutic targets for endplate-oriented disc degeneration.

Emerging immune therapy, such as with the anti-programmed cell death-1 (anti-PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 ([Pd1.sup.-/-]) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, [Pd1.sup.-/-] mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in [Pd1.sup.-/-] mice. Consistently, these beneficial effects in [Pd1.sup.-/-] mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti-PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis., Introduction Cancer pain is experienced by 70% of patients with advanced stage cancer; more than 80% of this pain is attributed to metastatic cancer-induced bone pain (1-3). Generally, bone metastasis [...]

Background: Atrophy of the rotator cuff is a negative prognostic indicator after rotator cuff repair. Although full-thickness rotator cuff tears accompanied by tendon retraction are commonly associated with decreased muscle cross-sectional area (CSA) on magnetic resonance imaging (MRI), it is unclear whether this is accompanied by histologic atrophy of rotator cuff myofibers. Purpose: To evaluate the effect of supraspinatus tendon retraction and myofiber size on supraspinatus atrophy on MRI. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Supraspinatus muscle biopsy specimens were obtained from consecutive patients undergoing arthroscopic shoulder surgery. Rotator cuff tears were classified according to size. Preoperative MRI was used to measure tendon retraction and CSA of the supraspinatus muscle in the Y-shaped view. The occupation ratio of the supraspinatus was calculated by dividing the supraspinatus CSA by the supraspinatus fossa CSA. Muscle biopsy specimens were examined using laminin to quantify myofiber CSA. The association between supraspinatus tear size and measures of histologic and MRI muscle atrophy were compared using standard statistical tests. Multivariable logistic regression analysis was used to identify independent predictors of muscle atrophy on MRI. Results: A total of 38 patients were included: 8 with no tear, 14 with a partial-thickness tear, and 16 with a full-thickness tear. Increasing tear size was associated with greater distance of tendon retraction (P <.001), smaller mean histologic myofiber size (P =.004), lower mean supraspinatus CSA on MRI (P <.001), and lower occupation ratio: 0.73 (control), 0.66 (partial tear), 0.53 (small to medium full-thickness tear), and 0.38 (large to massive full-thickness) (P <.001). On Pearson correlation analysis, tendon retraction demonstrated strong correlation with occupation ratio (–0.725; P <.001) and weak correlation with myofiber size (–0.437; P =.006), while occupation ratio showed moderate correlation with myofiber size (0.593; P <.001). Multivariable linear regression analysis demonstrated that increasing tendon retraction (P <.001), age (P =.034), and smaller histologic myofiber CSA (P =.047) were independently associated with greater supraspinatus atrophy on MRI. Conclusion: Supraspinatus muscle atrophy appreciated on MRI is independently associated with patient age, tendon retraction, and atrophy of the supraspinatus myofibers at the histologic level. [ABSTRACT FROM AUTHOR]

Fracture nonunions develop in 10%-20% of patients with fractures, resulting in prolonged disability. Current data suggest that bone union during fracture repair is achieved via proliferation and differentiation of skeletal progenitors within periosteal and soft tissues surrounding bone, while bone marrow stromal/stem cells (BMSCs) and other skeletal progenitors may also contribute. The NOTCH signaling pathway is a critical maintenance factor for BMSCs during skeletal development, although the precise role for NOTCH and the requisite nature of BMSCs following fracture is unknown. Here, we evaluated whether NOTCH and/or BMSCs are required for fracture repair by performing nonstabilized and stabilized fractures on NOTCH- deficient mice with targeted deletion of RBPjk in skeletal progenitors, maturing osteoblasts, and committed chondrocytes. We determined that removal of NOTCH signaling in BMSCs and subsequent depletion of this population result in fracture nonunion, as the fracture repair process was normal in animals harboring either osteoblast- or chondrocyte-specific deletion of RBPjk. Together, this work provides a genetic model of a fracture nonunion and demonstrates the requirement for NOTCH and BMSCs in fracture repair, irrespective of fracture stability and vascularity., Introduction Although most fractures progress to union, 10% to 20% result in nonunions and are often associated with morbidity, prolonged hospitalization, and increased expenses (1-3). Risk factors for fracture nonunion [...]