NELL-1 Injection Maintains Long-Bone Quantity and Quality in an Ovariectomy-Induced Osteoporotic Senile Rat Model

Abstract

Over 10 million Americans have osteoporosis, and is the predominant cause of fractures in the elderly. Treatment of fractures in the setting of osteoporosis is complicated by a suboptimal bone regenerative response due to a decline in the number of osteoblasts, their function, and survival. Consequently, an osteogenic therapeutic to prevent and treat fractures in patients with osteoporosis is needed. Nel-like molecule-1 (NELL-1), a novel osteoinductive growth factor, has been shown to promote bone regeneration. In this study, we aim to demonstrate the capacity of recombinant NELL-1 to prevent ovariectomy (OVX)-induced osteoporosis in a senile rat model. Ten-month-old female Sprague-Dawley rats underwent either sham surgery or OVX. Subsequently, 50 μL of 600 μg/mL NELL-1 lyophilized onto a 0-50-μm tricalcium phosphate (TCP) carrier was injected into the femoral bone marrow cavity while phosphate-buffered saline (PBS) control was injected into the contralateral femur. Our microcomputed tomography results showed that OVX+PBS/TCP control femurs showed a continuous decrease in the bone volume (BV) and bone mineral density (BMD) from 2 to 8 weeks post-OVX. In contrast, OVX+NELL-1/TCP femurs showed resistance to OVX-induced bone resorption showing BV and BMD levels similar to that of SHAM femurs at 8 weeks post-OVX. Histology showed increased endosteal-woven bone, as well as decreased adipocytes in the bone marrow of NELL-1-treated femurs compared to control. NELL-1-treated femurs also showed increased immunostaining for bone differentiation markers osteopontin and osteocalcin. These findings were validated in vitro, in which addition of NELL-1 in OVX bone marrow stem cells resulted in increased osteogenic differentiation. Thus, NELL-1 effectively enhances in situ osteogenesis in the bone marrow, making it potentially useful in the prevention and treatment of osteoporotic fractures.

Effects of Administration of Amlodipine and Lacidipine on Inflammation-Induced Bone Loss in the Ovariectomized Rat

“…We showed the highest OP levels occurred in OVX and OVX+INF groups compared to sham groups and amlodipine and lacidipine reduced levels of OP in both OVX and OVX+INF groups. The result of our study is similar to others, which proved an increased level of OP in osteoporosis models [54]. Amlodipine and lacidipine ameliorated elevated OP levels in both OVX and OVX+INF groups.…”

Effect of NELL1 gene overexpression in iPSC-MSCs seeded on calcium phosphate cement

“…The BMP2 gene-modified iPSC-MSCs enhanced osteogenic differentiation and bone mineral production, compared to iPSC-MSCs without gene modification [10]. Besides BMPs, NEL-like protein 1 (NELL1) is another key osteoinductive growth factor to promote bone regeneration [11–14]. Compared to BMPs which participate in multiple developmental processes during embryogenesis, NELL1 is highly specific to the osteochondral lineage with less adverse effects, such as ectopic bone formation [12,15].…”

NELL-1 induces Sca-1+ mesenchymal progenitor cell expansion in models of bone maintenance and repair

“…Sample size calculations are as follows: for experiments presented in Figures 1-3, initial animal numbers were based on an α = 0.05, power = 0.8, and an anticipated effect size of 3.73 (based on our previously published data in sheep spinal fusion) (27). For experiments presented in Figures 5 and 6, initial animal numbers were based on an α = 0.05, power = 0.8, and an anticipated effect size of 2.69 (based on our previously published data in local rhNELL-1 injection in ovariectomized rats) (44). In vitro experiments were performed in biological triplicate, unless otherwise described.…”