Intraperitoneally Administered PEGylated NELL-1 Treatment for Osteoporosis, in Mice
Michael D. Uyeda, MD.
UCLA, Los Angeles, CA, USA.
PURPOSE: Osteoporosis affects over 200 million people worldwide. Current antiresorptive treatments have significant limitations due to systemic side-effects. NELL-1 is a potent cytokine with combined pro-osteogenic and anti-osteoclastic effects. Previous systemic administration studies using PEGylated NELL-1(NELL-PEG) showed increased bone quality and quantity in healthy mice given 1.25mg/kg intravenously every 7 days. This study aims to reduce NELL-PEG injection frequency to 14 days while using more patient-friendly intraperitoneal(IP) administration route to recover bone in OVX-induced osteoporotic mice.
METHODS: Three-month-old female BALB/c mice underwent ovariectomy(OVX; n=10) or Sham operation(n=10). Osteoporosis induction was confirmed using dual-energy x-ray absorptiometry(DEXA) and ex vivo micro-CT scans. Twelve 5-weeks-post-OVX BALB/c mice underwent NELL-PEG treatment every two weeks with dosages of (1)5mg/kg intraperitoneally(IP) or (2)10mg/kg IP, and harvested at 8 weeks. Serum as analyzed at 0, 4, and 8 weeks. Dynamic BMD was measured by DEXA. Ex vivo micro-CT, colony forming unit assay(CFU), and histology were performed post-harvest.
RESULTS: Ovariectomy was confirmed by decreased BMD(7%) and BV/TV(39.3%). Systemic NELL-PEG at 10 mg/kg IP increased BMD in distal femur(13%), proximal tibia(14%), and lumbar vertebrae(15%). Micro-CT data showed the same trend in BMD, BV/TV, and trabecular structures. CFU assay confirmed greater osteogenesis in BMSCs flushed from 10mg/kg delivery than 5mg/kg group, and histology confirmed increased bone formation in both treatment groups.
CONCLUSIONS: Systemic NELL-PEG therapy regenerates bone in osteoporotic mice when administered at 10mg/kg dosage via IP administration every 2 weeks. Systemic NELL-PEG may be applied to improve overall bone architecture, and potentially enhance post-surgical craniofacial and alveolar bone healing.
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