Teriparatide and abaloparatide are parathyroid hormone receptor 1 (PTHR1) analogs with unexplained differential efficacy for the treatment of osteoporosis. Therefore, we compared the effects of abaloparatide and teriparatide on bone structure, turnover, and levels of receptor activator of nuclear factor‐kappa B ligand (RANKL) and osteoprotegerin (OPG). Wild‐type (WT) female mice were injected daily with vehicle or 20–80 µg/kg/day of teriparatide or abaloparatide for 30 days. Femurs and spines were examined by microcomputed tomography scanning and serum levels of bone turnover markers, RANKL, and OPG, were measured by ELISA. Both analogs similarly increased the distal femoral fractional trabecular bone volume, connectivity, and number, and reduced the structure model index (SMI) at 20–80 µg/kg/day doses. However, only abaloparatide exhibited a significant increase (13%) in trabecular thickness at 20 µg/kg/day dose. Femoral cortical evaluation showed that abaloparatide caused a greater dose‐dependent increase in cortical thickness than teriparatide. Both teriparatide and abaloparatide increased lumbar 5 vertebral trabecular connectivity but had no or modest effect on other indices. Biochemical analysis demonstrated that abaloparatide promoted greater elevation of procollagen type 1 intact N‐terminal propeptide, a bone formation marker, and tartrate‐resistant acid phosphatase 5b levels, a bone resorption marker, and lowered the RANKL/OPG ratio. Furthermore, PTHR1 signaling was compared in cells treated with 0–100 nmol/L analog. Interestingly, abaloparatide had a markedly lower EC50 for cAMP formation (2.3‐fold) and β‐arrestin recruitment (1.6‐fold) than teriparatide. Therefore, abaloparatide‐improved efficacy can be attributed to enhanced bone formation and cortical structure, reduced RANKL/OPG ratio, and amplified Gs‐cAMP and β‐arrestin signaling.

Immobilization, as a result of motor‐complete spinal cord injury (SCI), is associated with severe osteoporosis. Whether parathyroid hormone (PTH) administration would reduce bone loss after SCI remains unclear. Thus, female mice underwent sham or surgery to produce complete spinal cord transection. PTH (80 μg/kg) or vehicle was injected subcutaneously (SC) daily starting on the day of surgery and continued for 35 days. Isolated tibias and femurs were examined by microcomputed tomography scanning (micro‐CT) and histology and serum markers of bone turnover were measured. Micro‐CT analysis of tibial metaphysis revealed that the SCI‐vehicle animals exhibited 49% reduction in fractional trabecular bone volume and 18% in trabecular thickness compared to sham‐vehicle controls. SCI‐vehicle animals also had 15% lower femoral cortical thickness and 16% higher cortical porosity than sham‐vehicle counterparts. Interestingly, PTH administration to SCI animals restored 78% of bone volume, increased connectivity to 366%, and lowered structure model index by 10% compared to sham‐vehicle animals. PTH further favorably attenuated femoral cortical bone loss to 5% and prevented the SCI‐associated cortical porosity. Histomorphometry evaluation of femurs of SCI‐vehicle animals demonstrated a marked 49% and 38% decline in osteoblast and osteoclast number, respectively, and 35% reduction in bone formation rate. In contrast, SCI‐PTH animals showed preserved osteoblast and osteoclast numbers and enhanced bone formation rate. Furthermore, SCI‐PTH animals had higher levels of bone formation and resorption markers than either SCI‐ or sham‐vehicle groups. Collectively, these findings suggest that intermittent PTH receptor activation is an effective therapeutic strategy to preserve bone integrity after severe immobilization.

No abstract

Direct current electrical fields have been shown to be a major factor in the regulation of cell proliferation, differentiation, migration, and survival, as well as in the maturation of dividing cells during development. During adulthood, spinal cord cells are continuously produced in both animals and humans, and they hold great potential for neural restoration following spinal cord injury. While the effects of direct current electrical fields on adult-born spinal cells cultured ex vivo have recently been reported, the effects of direct current electrical fields on adult-born spinal cells in vivo have not been characterized. Here, we provide convincing findings that a therapeutic form of transspinal direct current stimulation (tsDCS) affects the migration and proliferation of adult-born spinal cells in mice. Specifically, cathodal tsDCS attracted the adult-born spinal cells, while anodal tsDCS repulsed them. In addition, both tsDCS polarities caused a significant increase in cell number. Regarding the potential mechanisms involved, both cathodal and anodal tsDCS caused significant increases in expression of brain-derived neurotrophic factor, while expression of nerve growth factor increased and decreased, respectively. In the spinal cord, both anodal and cathodal tsDCS increased blood flow. Since blood flow and angiogenesis are associated with the proliferation of neural stem cells, increased blood flow may represent a major factor in the modulation of newly born spinal cells by tsDCS. Consequently, we propose that the method and novel findings presented in the current study have the potential to facilitate cellular, molecular, and/or bioengineering strategies to repair injured spinal cords. Our results indicate that transspinal direct current stimulation (tsDCS) affects the migratory pattern and proliferation of adult newly born spinal cells, a cell population which has been implicated in learning and memory. In addition, our results suggest a potential mechanism of action regarding the functional effects of applying direct current. Thus tsDCS may represent a novel method by which to manipulate the migration and cell number of adult newly born cells and restore functions following brain or spinal cord injury.

Bone loss is one of the most common complications of immobilization after spinal cord injury (SCI). Whether TGF-β signaling plays a role in SCI-induced disuse bone loss has not been determined. Thus, 16-week-old male mice underwent sham or spinal cord contusion injury to cause complete hindlimb paralysis. Five days later, 10 mg/kg/day control (IgG) or anti-TGF-β1,2,3 neutralizing antibody (1D11) was administered twice weekly for 4 weeks. Femurs were examined by micro-computed tomography scanning (micro-CT) and histology. Bone marrow (BM) supernatants were analyzed by ELISA for levels of procollagen type 1 intact N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase (TRAcP-5b), receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin (OPG), and prostaglandin E2 (PGE2). Distal femoral micro-CT analysis showed that SCI-1D11 mice had significantly (P<0.05) attenuated loss of trabecular fractional bone volume (123% SCI-1D11 vs 69% SCI-IgG), thickness (98% vs 81%), and connectivity (112% vs 69%) and improved the structure model index (2.1 vs 2.7). Histomorphometry analysis revealed that osteoclast numbers were lower in the SCI-IgG mice than sham-IgG sham control. Biochemically, SCI-IgG mice had higher levels of P1NP and PGE2 but similar TRAcP-5b and RANKL/OPG ratio to the sham-IgG group. SCI-1D11 group exhibited higher levels of P1NP and RANKL/OPG ratio but similar TRAcP-5b and PGE2 to the sham-1D11 group. Furthermore, 1D11 treatment prevented SCI-induced hyperphosphorylation of tau protein in osteocytes, an event that destabilizes the cytoskeleton. Together, inhibition of TGF-β signaling after SCI protects trabecular bone integrity, likely by balancing bone remodeling, inhibiting PGE2 elevation, and preserving the osteocyte cytoskeleton.