A review of osteocyte function and the emerging importance of sclerostin

Abstract

➤ Osteocytes, derived from osteoblasts, reside within bone and communicate extensively with other bone cell populations to regulate bone metabolism. The mature osteocyte expresses the protein sclerostin, a negative regulator of bone mass.➤ In normal physiologic states, the protein sclerostin acts on osteoblasts at the surface of bone and is differentially expressed in response to mechanical loading, inflammatory molecules such as prostaglandin E2, and hormones such as parathyroid hormone and estrogen.➤ Pathologically, sclerostin dysregulation has been observed in osteoporosis-related fractures, failure of implant osseous integration, metastatic bone disease, and select genetic diseases of bone mass.➤ An antibody that targets sclerostin, decreasing endogenous levels of sclerostin while increasing bone mineral density, is currently in phase-III clinical trials.➤ The osteocyte has emerged as a versatile, indispensable bone cell. Its location within bone, extensive dendritic network, and close communication with systemic circulation and other bone cells produce many opportunities to treat a variety of orthopaedic conditions.

Fig. 1

Osteocyte control of local bone environment. Osteocytes orchestrate bone resorption and bone deposition by controlling osteoclast and osteoblast activity. Osteocytes release RANKL (receptor activator of nuclear factor kappa-β ligand) to induce osteoclast differentiation, as well as OPG (osteoprotegerin) to downregulate osteoclastogenesis. Importantly, osteocytes also release FGF-23 (fibroblast growth factor-23), BMPs (bone morphogenetic proteins), and sclerostin to regulate osteoblast activity. Denosumab and sclerostin antibody are two antibodies that interact with bone cell biology to increase bone mass.

Fig. 2

Osteocytes in native bone. Osteocytes reside within a highly organized three-dimensional matrix and communicate via dendrites to other osteocytes, the bone marrow, and osteoblasts.

Fig. 3

Osteocyte differentiation. Osteocytes differentiate from osteoblasts. The precise mechanism of differentiation is unknown; however, several distinct markers are expressed during osteocyte maturation. RUNX2 = runt-related transcription factor-2, COL 1 = type-I collagen, OCN = osteocalcin, DMP1 = dentin matrix acidic phosphoprotein 1, Alk Phos = alkaline phosphatase, PHEX = Pi-regulating endopeptidase on chromosome X, MEPE = matrix extracellular phosphoglycoprotein, and FGF23 = fibroblast growth factor-23.

Fig. 4

Sclerostin and disease. Many orthopaedic conditions act on the osteocyte to increase sclerostin expression (red) or decrease expression (green) and, subsequently, downregulate or upregulate bone formation, respectively. PTH = parathyroid hormone.