Differential efficacy of two small molecule PHLPP inhibitors to promote nucleus Pulposus cell health.

Background: Intervertebral disc (IVD) degeneration is associated with chronic back pain. We previously demonstrated that the phosphatase pleckstrin homology domain and leucine-rich repeat protein phosphatase (PHLPP) 1 was positively correlated with IVD degeneration and its deficiency decelerated IVD degeneration in both mouse IVDs and human nucleus pulposus (NP) cells. Small molecule PHLPP inhibitors may offer a translatable method to alleviate IVD degeneration.

PHLPP1 deficiency protects against age-related intervertebral disc degeneration.

Background: Intervertebral disc (IVD) degeneration is strongly associated with low back pain and is highly prevalent in the elderly population. Hallmarks of IVD degeneration include cell loss and extracellular matrix degradation. The PH domain leucine-rich-repeats protein phosphatase (PHLPP1) is highly expressed in diseased cartilaginous tissues where it is linked to extracellular matrix degradation.

Development of a standardized histopathology scoring system for human intervertebral disc degeneration: an Orthopaedic Research Society Spine Section Initiative.

Background: Histopathological analysis of intervertebral disc (IVD) tissues is a critical domain of back pain research. Identification, description, and classification of attributes that distinguish abnormal tissues form a basis for probing disease mechanisms and conceiving novel therapies. Unfortunately, lack of standardized methods and nomenclature can limit comparisons of results across studies and prevent organizing information into a clear representation of the hierarchical, spatial, and temporal patterns of IVD degeneration.

Advanced glycation end products cause RAGE-dependent annulus fibrosus collagen disruption and loss identified using in situ second harmonic generation imaging in mice intervertebral disk in vivo and in organ culture models.

Aging and diabetes are associated with increased low-back pain and intervertebral disk (IVD) degeneration yet causal mechanisms remain uncertain. Advanced glycation end products (AGEs), which accumulate in IVDs from aging and are implicated in diabetes-related disorders, alter collagen and induce proinflammatory conditions. A need exists for methods that assess IVD collagen quality and degradation in order to better characterize specific structural changes in IVDs due to AGE accumulation and to identify roles for the receptor for AGEs (RAGE).