ReviewEffects of PTH on osteocyte function
Introduction
Few crucial advances in the field in the past several years have markedly increased our understanding of the function of osteocytes. The evidence that sclerostin, the product of the Sost gene, is expressed and secreted primarily by osteocytes and inhibits bone formation by osteoblasts, fueled research attempting to identify regulators of this gene as well as other osteocyte products that impact the function of osteoblasts and osteoclasts. The discovery that parathyroid hormone (PTH), a central regulator of bone homeostasis, inhibits sclerostin expression generated a cascade of studies that revealed that osteocytes are crucial target cells of the actions of PTH. This review highlights these investigations and discusses their significance for advancing our understanding of the mechanisms by which osteocytes regulate bone homeostasis and for developing therapies for bone diseases targeting osteocytes.
Section snippets
Osteocytes
Osteocytes, former osteoblasts regularly distributed throughout the mineralized bone matrix, are the most abundant cells in bone comprising more than 90% of cells within the matrix or on bone surfaces [1], [2]. Entombed during the process of bone deposition, osteocytes remain highly connected with cells on the bone surface and among themselves, via cytoplasmic processes that radiate from their bodies and travel along canaliculi excavated in the mineralized matrix. Osteocyte projections reach
PTH and its receptor
PTH is an 84-amino acid polypeptide synthesized and secreted by the parathyroid glands in a calcium-regulated manner. The hormone maintains serum calcium homeostasis, controls renal phosphate reabsorption and vitamin D3 1α-hydroxylation and modulates bone turnover, through actions mediated by the PTH/PTH-related peptide (PTHrP) receptor (PPR). The receptor is expressed in bone and kidney, but is also found in a variety of other tissues not regarded as classical PTH targets.
Among bone cells,
Osteocytes and the bone remodeling compartment (BRC)
The ability of osteocytes to reach bone surfaces together with the recent evidence demonstrating that osteocytes express molecules that regulate osteoclast and osteoblast function, provides the basis for the long hypothesized role of the osteocyte network of coordinating the remodeling of bone. Osteocyte apoptosis has been shown to precede osteoclast accumulation and resorption [34], raising the possibility that osteocytes release molecules that induce lining cell retraction facilitating the
Regulation of FGF23 by PTH and its consequences for systemic and local FGF23 signaling
Osteocytes are richer than osteoblasts in genes related to mineralization and phosphate metabolism, including phosphate-regulating neutral endopeptidase (Phex), DMP1, and matrix extracellular phosphoglycoprotein (MEPE). Osteocytes also produce FGF23, a hormone produced in bone that plays a crucial role in phosphate (Pi) homeostasis by inhibiting its renal reabsorption [20], [21], [22], [23], [24].
High dietary Pi and the active form of vitamin D3, 1,25-dihydroxy-vitamin D3 (1,25-D3) are major
Cross talk between the PTH receptor and mechanotransduction in osteocytes
Osteocytes are ideally positioned to integrate the responses of bone to mechanical and hormonal stimuli. Both mechanical loading and PTH promote new bone formation by downregulating the expression of sclerostin; and mice lacking the Wnt coreceptor LRP5 [66] or overexpressing Sost [67] exhibit a defective response to loading. These findings suggest a potential crosstalk between mechanotransduction and PTHR1 signaling.
Earlier studies by Chow et al. demonstrated a blunted osteogenic response to
Osteocytic PTHR and lacunae/canalicular remodeling during lactation
The role of PPR signaling in osteocytes during lactation has been recently elucidated [74]. It is known that lactation, both in humans and in rodents, is associated with a rapid and reversible loss of bone mineral density, but the molecular and cellular mechanisms of this skeletal loss were still unknown. To investigate the role of the PPR and PTHrP, known to be elevated during lactation [75], Qing and colleagues studied skeletal responses to lactation in control and osteocyte-specific PTHR-KO
Closing remarks and future directions
Only few years have passed since the first reports demonstrating the regulation of sclerostin expression by PTH and it is now known that actions of the PPR in osteocytes regulate several genes greatly impacting bone homeostasis. The number of publications on osteocytes and PTH has triplicate in the last ten years, in part due to the development of in vivo tools for the analysis of these remarkable cells (addressed in the article of Kalajzic et al. in this issue). Development of new and improved
References (75)
- et al.
SOST is a ligand for LRP5/LRP6 and a WNT signaling inhibitor
J Biol Chem
(2005) - et al.
Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling
J Biol Chem
(2005) - et al.
Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein
Am J Hum Genet
(2001) - et al.
Meox2Cre-mediated disruption of CSF-1 leads to osteopetrosis and osteocyte defects
Bone
(2012) - et al.
Mineralized tissue cells are a principal source of FGF23
Bone
(2007) - et al.
Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX
J Biol Chem
(2003) - et al.
Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo
Bone
(2011) Molecular and cellular mechanisms of the anabolic effect of intermittent PTH
Bone
(2007)- et al.
Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism
J Biol Chem
(2003) - et al.
SOST is a target gene for PTH in bone
Bone
(2005)
Calcitonin impairs the anabolic effect of PTH in young rats and stimulates expression of sclerostin by osteocytes
Bone
Does osteocytic SOST suppression mediate PTH bone anabolism?
Trends Endocrinol Metab
Osteoblastic expansion induced by parathyroid hormone receptor signaling in murine osteocytes is not sufficient to increase hematopoietic stem cells
Blood
Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease
Kidney Int
Ultrastructural changes in osteocytes in microgravity conditions
Adv Space Res
The WNT co-receptor LRP5 is essential for skeletal mechanotransduction, but not for the anabolic bone response to parathyroid hormone treatment
J Biol Chem
Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading
Bone
Constitutively active parathyroid hormone receptor signaling in cells in osteoblastic lineage suppresses mechanical unloading-induced bone resorption
J Biol Chem
Function of osteocytes in bone
J Cell Biochem
The amazing osteocyte
J Bone Miner Res
Osteocyte control of bone formation via sclerostin, a novel BMP antagonist
EMBO J
Sclerostin ss an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist
J Exp Med
Chronic elevation of PTH in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis
Endocrinology
Lrp4, a novel receptor for dickkopf 1 and sclerostin, is expressed by osteoblasts and regulates bone growth and turnover in vivo
PLoS One
Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)
Hum Mol Genet
Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength
J Bone Miner Res
Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease
Genome Res
PTH receptor signaling in osteocytes governs periosteal bone formation and intra-cortical remodeling
J Bone Miner Res
Sclerostin antagonism in adult rodents, via monoclonal antibody mediated blockade, increases bone mineral density and implicates sclerostin as a key regulator of bone mass during adulthood
J Bone Miner Res
Sclerostin monoclonal antibody treatment of osteoporotic rats completely reverses one year of ovariectomy-induced systemic bone loss
J Bone Miner Res
Evidence for osteocyte regulation of bone homeostasis through RANKL expression
Nat Med
Matrix-embedded cells control osteoclast formation
Nat Med
Osteocyte Wnt/beta-catenin signaling is required for normal bone homeostasis
Mol Cell Biol
FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting
J Clin Invest
Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism
Nat Genet
Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia
Proc Natl Acad Sci U S A
Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro
J Bone Miner Res
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