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Cells isolated from moderately and severely degenerated human intervertebral disks (IVDs) cultured in an alginate scaffold.

We sought to determine whether risedronate can preserve cortical bone mass and mechanical properties during long‐term disuse in dogs, assessed by histomorphometry and biomechanics on metacarpal diaphyses. Risedronate slowed cortical thinning and partially preserved mechanical properties, but it was unable to suppress bone loss to the degree seen in other osteoporoses.

We sought to determine whether risedronate can preserve cortical bone mass and mechanical properties during long‐term disuse in dogs, assessed by histomorphometry and biomechanics on metacarpal diaphyses. Risedronate slowed cortical thinning and partially preserved mechanical properties, but it was unable to suppress bone loss to the degree seen in other osteoporoses.Introduction:Disuse induces dramatic bone loss resulting from greatly elevated osteoclastic resorption. Targeting osteoclasts with antiresorptive agents, such as bisphosphonates, should be an effective countermeasure for preventing disuse osteoporosis.Materials and Methods:Single forelimbs from beagles (5–7 years old, n= 28) were immobilized (IM) for 12 months. Age‐matched, non‐IM dogs served as controls. One‐half the animals received either risedronate (RIS, 1 mg/kg) or vehicle daily. Histomorphometry was performed on second metacarpal mid‐diaphyses. Cortical mechanical properties were determined by testing third metacarpal diaphyses in four‐point bending.Results:IM caused marked reduction in cortical area (−42%) and cortical thinning (−40%) through endocortical resorption, extensive intracortical tunneling, and periosteal resorption; both bone resorption and formation were significantly elevated over control levels on all envelopes. IM also decreased maximum load and stiffness by ∼80% compared with controls. RIS reduced both periosteal bone loss and marrow cavity expansion; however, cortical area remained significantly lower in RIS‐treated IM animals than in untreated non‐IM controls (−16%). RIS also increased resorption indices in all envelopes compared with nontreated IM, indicating that RIS suppressed osteoclast activity but not osteoclast recruitment. RIS did not affect bone formation. RIS treatment conserved some whole bone mechanical properties, but they were still significantly lower than in controls. There were no significant differences in tissue level material properties among the groups.Conclusion:RIS treatment reduces cortical bone loss at periosteal and endocortical surfaces caused by long‐term immobilization, thus partially conserving tissue mechanical properties. This modest effect contrasts with more dramatic actions of the bisphosphonate in other osteoporoses. Our results suggest that risedronate impairs osteoclastic function but cannot completely overcome the intense stimulus for osteoclast recruitment during prolonged disuse.

The role of axonopathy in myelin disorders recently has been examined. To investigate axonal pathologic changes in vacuolar myelopathy (VM), semiquantitative immunohistochemical stains for inflammation, axonal damage, and gliosis were performed on spinal cord sections from patients with AIDS with and without VM and from HIV-negative controls. Significant axonal damage was present in only moderate to severe VM, despite inflammation at all stages. The authors conclude that axonal damage is not present in early disease; it is present in moderate to severe vacuolar myelopathy and may contribute to clinical deficits in late stages of this disorder.

Back pain is a leading cause of disability and is strongly associated with intervertebral disc (IVD) degeneration. Reducing structural disruption and catabolism in IVD degeneration remains an important clinical challenge. Pro-oxidant and structure-modifying advanced glycation end-products (AGEs) contribute to obesity and diabetes, which are associated with increased back pain, and accumulate in tissues due to hyperglycemia or ingestion of foods processed at high heat. Collagen-rich IVDs are particularly susceptible to AGE accumulation due to their slow metabolic rates, yet it is unclear whether dietary AGEs can cross the endplates to accumulate in IVDs. A dietary mouse model was used to test the hypothesis that chronic consumption of high AGE diets results in sex-specific IVD structural disruption and functional changes. High AGE diet resulted in AGE accumulation in IVDs and increased IVD compressive stiffness, torque range and failure torque, particularly for females. These biomechanical changes were likely caused by significantly increased AGE crosslinking in the annulus fibrosus, measured by multiphoton imaging. Increased collagen damage measured with collagen hybridizing peptide did not appear to influence biomechanical properties and may be a risk factor as these animals age. The greater influence of high AGE diet on females is an important area of future investigation that may involve AGE receptors known to interact with estrogen. We conclude that high AGE diets can be a source for IVD crosslinking and collagen damage known to be important in IVD degeneration. Dietary modifications and interventions that reduce AGEs warrant further investigation and may be particularly important for diabetics, in whom AGEs accumulate more rapidly.

Mesenchymal stem cell (MSC)-based treatments have shown promise for improving tendon healing and repair. MSCs have the potential to differentiate into multiple lineages in response to select chemical and physical stimuli, including into tenocytes. Cell elongation and cytoskeletal tension have been shown to be instrumental to the process of MSC differentiation. Previous studies have shown that inhibition of stress fiber formation leads MSCs to default toward an adipogenic lineage, which suggests that stress fibers are required for MSCs to sense the environmental factors that can induce differentiation into tenocytes. As the Rho/ROCK signal transduction pathway plays a critical role in both stress fiber formation and in cell sensation, we examined whether the activation of this pathway was required when inducing MSC tendon differentiation using rope-like silk scaffolds. To accomplish this, we employed a loss-of-function approach by knocking out ROCK, actin and myosin (two other components of the pathway) using the specific inhibitors Y-27632, Latrunculin A and blebbistatin, respectively. We demonstrated that independently disrupting the cytoskeleton and the Rho/ROCK pathway abolished the expression of tendon differentiation markers and led to a loss of spindle morphology. Together, these studies suggest that the tension that is generated by MSC elongation is essential for MSC teno-differentiation and that the Rho/ROCK pathway is a critical mediator of tendon differentiation on rope-like silk scaffolds.

Some male camel spiders (Arachnida: Solifugae) in the families Eremobatidae, Karschiidae, and Solpugidae have clusters of specialized conical or acuminate setae called papillae, on the ventral surface of the metatarsus of the pedipalps. We compared the overall structure of the papillae found on representatives of the three families using scanning electron microscopy (SEM). We examined the ultrastructure of these setae using transmission electron microscopy (TEM). We also used extracellular electrophysiological recording techniques to examine the electrical properties of these sensory structures and test the hypotheses that they function as mechanoreceptors, olfactory receptors, and chemoreceptors. We found similarities in the structure of papillae among genera within a family or distinct family-level differences in structure. Thus, the papillae are phylogenetically informative; similar within family but differing between families. TEM results demonstrated the cuticular wall of a papilla is divided into three sublayers: endo-, meso-, and exocuticle. Mechanoreceptive dendrites are evident at the base of the setal shaft. Other dendrites innervate the shaft of the papilla and penetrate through the cuticular layers near the setal apex. Two SEM images show what appear to be pores on the branches of the papillae, and we found what appears to be a pore tubule extending from the distal portion of the dendrites through the exocuticular layer. Electrophysiological data support the hypothesis that the papillae function as mechanoreceptors and provide no support for chemosensory, thermoregulatory, or hygroreceptive functions. Our data suggest that the papillae function as mechanoreceptors and may also function as chemoreceptors.

Notochordal cells (NCs) pattern aneural and avascular intervertebral discs (IVDs), and their disappearance, is associated with onset of IVD degeneration. This study induced and characterized the maturation of nucleus pulposus (NP) tissue from a gelatinous NC-rich structure to a matrix-rich structure populated by small NP cells using dynamic pressurization in an ex vivo culture model, and also identified soluble factors from NCs with therapeutic potential.