Osteoblast-lineage calcium/calmodulin-dependent kinase 2 delta and gamma regulates bone mass and quality

Abstract

Bone regulates its mass and quality in response to diverse mechanical, hormonal, and local signals. The bone anabolic or catabolic responses to these signals are often received by osteocytes, which then coordinate the activity of osteoblasts and osteoclasts on bone surfaces. We previously established that calcium/calmodulin-dependent kinase 2 (CaMKII) is required for osteocytes to respond to some bone anabolic cues in vitro. However, a role for CaMKII in bone physiology in vivo is largely undescribed. Here, we show that conditional codeletion of the most abundant isoforms of CaMKII (delta and gamma) in mature osteoblasts and osteocytes [Ocn-cre: Camk2d / Camk2g double-knockout (dCKO)] caused severe osteopenia in both cortical and trabecular compartments by 8 wk of age. In addition to having less bone mass, dCKO bones are of worse quality, with significant deficits in mechanical properties, and a propensity to fracture. This striking skeletal phenotype is multifactorial, including diminished osteoblast activity, increased osteoclast activity, and altered phosphate homeostasis both systemically and locally. These dCKO mice exhibited decreased circulating phosphate (hypophosphatemia) and increased expression of the phosphate-regulating hormone fibroblast growth factor 23. Additionally, dCKO mice expressed less bone-derived tissue nonspecific alkaline phosphatase protein than control mice. Consistent with altered phosphate homeostasis, we observed that dCKO bones were hypo-mineralized with prominent osteoid seams, analogous to the phenotypes of mice with hypophosphatemia. Altogether, these data reveal a fundamental role for osteocyte CaMKIIδ and CaMKIIγ in the maintenance of bone mass and bone quality and link osteoblast/osteocyte CaMKII to phosphate homeostasis.

Tricarboxylic Acid Cycle Regulation of Metabolic Program, Redox System, and Epigenetic Remodeling for Bone Health and Disease

“…Bone mass homeostasis is a dynamic process of mineralized component turnover balanced by osteoblast/osteocyte-mediated bone formation [1] and osteoclastic resorption [1]. Osteoblasts produce key osteoclastogenic factors, such as receptor activator of nuclear factor-kB ligand (RANKL), inflammatory cytokines or chemokines, for coupling Antioxidants 2024, 13, 470 2 of 20 osteoclastic cells for bone remodeling [2].…”

“…Osteoblasts produce key osteoclastogenic factors, such as receptor activator of nuclear factor-kB ligand (RANKL), inflammatory cytokines or chemokines, for coupling Antioxidants 2024, 13, 470 2 of 20 osteoclastic cells for bone remodeling [2]. Osteocytes play an important role in sclerostin production and transmit biomechanical or biophysical stimulation for bone mass homeostasis [1]. Under menopause, aging, hyperglycemia, or chronic inflammation conditions, bone remodeling goes far beyond mineral acquisition, turning the well-arranged bone trabecular network into a porous microstructure to accelerate the development of osteoporosis [3].…”