Bone mass protective potential mediated by bovine milk basic protein requires normal calcium homeostasis in mice

• Published in: Nutrition (Burbank, Los Angeles County, Calif.) Vol. 91-92; p. 111409
• Main Authors: Ono-Ohmachi, Aiko, Ishida, Yuko, Morita, Yoshikazu, Kato, Ken, Yamanaka, Hitoki, Masuyama, Ritsuko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2021; Elsevier Limited
• Subjects: Acid phosphatase; Acid phosphatase (tartrate-resistant); Acid resistance; Animals; Biomedical materials; Bone Density; Bone loss; Bone marrow; Bone mass; bone mineral metabolism; Bone resorption; Bone turnover; Bones; Calciferol; Calcium; Calcium absorption; Calcium homeostasis; calcium status; Cell culture; Cow's milk; Deactivation; Diet; Dietary supplements; Evaluation; Homeostasis; Hypercalcemia; Hyperparathyroidism; Inactivation; Intestine; Macrophages; Mice; Mice, Knockout; Milk; Milk basic protein; Milk Proteins; Mineral metabolism; Mineralization; Nutrition; Osteoclastogenesis; Parathyroid; Parathyroid hormone; Phenotypes; Physiological effects; Protein turnover; Proteins; Receptors, Calcitriol; Signaling; Software; Statistical analysis; Tibia; VDR knockout mice; Vitamin D; vitamin D receptor; Whey protein; Switzerland; Japan; parathyroid hormone; vitamin D receptor; Whey protein; calcium status; VDR knockout mice; bone mineral metabolism
• ISSN: 0899-9007; 1873-1244
• DOI: 10.1016/j.nut.2021.111409

•Calcium status required for bone protections by milk basic protein (MBP) was studied.•Systemic- or intestine-specific vitamin D receptor knockout mice were used.•In severe hyperparathyroidism, MBP failed to rescue impaired bone mineralization.•Contrary to the parathyroid hormone, MBP inhibited osteoclast differentiation responding to the receptor activator of nuclear factor κB ligand–osteoprotegerin axis.•Normal calcium homeostasis is essential for the functional threshold of dietary MBP.
Milk provide protective effects against bone loss caused by an impaired calcium balance. Although the effects of some elements have previously been confirmed, the involvement of milk basic protein (MBP) in bone mineral metabolism remains poorly characterized. Moreover, the importance of mineral nutrition sufficiency to establish the effect of MBP must be evaluated.
First, to evaluate the physiological conditions required for MBP activity, we examined the bone and mineral phenotypes of mice that suffer from insufficient calcium absorption due to a lack of intestinal vitamin D signaling. Second, to determine whether vitamin D signaling affects the effect of MBP on bone resorption, in vitro osteoclastogenesis were assessed using bone marrow cells.
In mice with systemic vitamin D receptor (Vdr) inactivation, dietary MBP supplementation was unable to normalize hypercalcemia and hyperparathyroidism and failed to rescue bone mineralization impairments. In contrast, calcium and bone homeostasis responded to MBP supplementation when Vdr inactivation was restricted to the intestines. Hyperparathyroidism in intestine-specific Vdr knockout mice was also improved by MBP supplementation, along with a decrease in bone resorption in response to the level of serum tartrate-resistant acid phosphatase 5b. These results corresponded with a reduction in tartrate-resistant acid phosphatase-stained osteoclast numbers and the eroded surface on the tibia. MBP treatment dose-dependently suppressed osteoclastogenesis in cultured bone marrow macrophages regardless of vitamin D activity. These effects of MBP were blunted when parathyroid hormone was added to the culture medium, which is in line with the in vivo phenotype observed with systemic Vdr inactivation and suggests that severe hyperparathyroidism limits MBP activity in the bone.
Therefore, adaptive calcium homeostasis is an essential requirement when MBP exerts protective effects through the inhibition of bone resorption.