Blockade of the OGF-OGFr pathway in diabetic bone

ABSTRACT

Purpose: This research investigated the presence and integrity of the opioid growth factor (OGF)—opioid growth factor receptor (OGFr) regulatory pathway in type 1 diabetic (T1D) rats, and investigated whether modulation of this axis by naltrexone (NTX) altered the composition of normal bone or fractured femurs.

Materials and Methods: Diabetes was induced by streptozotocin; controls rats received buffer. Hyperglycemic animals were subjected to femur osteotomy, with randomized cohorts receiving either topical NTX or sterile saline in calcium carbonate. In experiment 2, hyperglycemic rats were injected daily for 3 weeks with either 30 mg/kg NTX or sterile saline. Expression levels of OGF and OGFr were measured by immunohistochemistry, bone composition was assessed by histomorphometry, and bone integrity was evaluated by µCT and 3-point bending.

Results: Relative to normoglycemic bones, OGF and OGFr expression levels were increased 95% and 84%, respectively, in T1D bone; serum levels of OGF in T1D rats were elevated 23%. Hyperglycemia decreased the strength (26%), osteocalcin expression (17%), and number of proliferative (Ki67+) cells (32%) in intact femur. Topical NTX treatment of fractured femurs reduced the percentage of granulation tissue and increased cartilage. Systemic NTX treatment of diabetic rats increased strength by 21% and energy absorbed by105% in bone relative to measurements in saline-treated diabetic rats.

Conclusions: The OGF-OGFr pathway appears to be dysregulated in the bone of T1D rats. Topical NTX treatment of T1D fractured bone accelerated some aspects of delayed diabetic fracture repair, and systemic NTX protected against some elements of compromised bone composition.

KEYWORDS:

• Naltrexone
• OGFr
• OGF
• type 1 diabetes
• bone composition

Acknowledgments

Special thanks to Dr. Michael D. Ludwig for providing help throughout the surgeries and to Hwa Bok Wee for assistance with μCT scanning.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Research was supported in part by discretionary gift funds to ISZ and PJM.