Authors: Cawley NX, Yanik T, Woronowicz A, et. al
Carboxypeptidase E (CPE) is a prohormone/proneuropeptide processing enzyme and mice bearing CPE mutations exhibit an obese and diabetic phenotype. Studies on the CPE knockout (KO) mice revealed poor prohormone processing, resulting in deficiencies in peptide hormones/neuropeptides such as insulin, gonadotropin releasing hormone and cocaine- and amphetamine-regulated transcript (CART). Here we show that in contrast to the expected phenotype of an obese animal model, the CPE KO mice have low bone mineral density (BMD) accompanied by elevated plasma calcium, CTX-1 (carboxy-terminal collagen crosslinks) and osteocalcin, indicators of increased bone turnover. Receptor Activator for Nuclear Factor kappa B Ligand (RANKL) expression was elevated relative to osteoprotegerin (OPG) in the femur of KO animals suggesting increased osteoclastic activity in the KO mice. Leptin increases RANKL expression via the sympathetic nervous system and reduces RANKL expression by increasing CART levels; however, the CPE KO mice lack detectable levels of bioactive CART in the hypothalamus. The melanocortin and neuropeptide Y (NPY) systems in the hypothalamus have also been implicated in bone remodeling since MC4R KO and NPY KO mice have increased BMD. However, reduction of alpha-MSH, the primary ligand of the MC4R by up to 94% and the lack of detectable NPY in the hypothalamus of CPE KO do not recapitulate the single gene KO phenotypes. Finally, the increased levels of osteocalcin secreted from osteoblasts, which releases insulin, may be a response to the diabetic state of the CPE KO mice. This study highlights the complex physiological interplay between peptides involved in energy metabolism and bone formation and furthermore suggests the possibility that patients, bearing CPE and CART mutations leading to inactive forms of these molecules, may be at a higher risk of developing osteoporosis.