Resorption Controls Bone Anabolism Driven by Parathyroid Hormone (PTH) Receptor Signaling in Osteocytes

Abstract

Background: Contribution of resorption to bone anabolism by PTH receptor signaling in osteocytes is unknown. Results: Pharmacologic/genetic approaches demonstrated that remodeling-or modeling-based bone formation differentially operate in specific surfaces. Conclusion: Resorption is critical for anabolism in periosteal/endocortical bone surfaces, but tempers bone gain in cancellous bone. Significance: Targeting bone compartment-specific actions of PTH receptor signaling could enhance the therapeutic potential of the pathway.

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

“…Similar high bone mass and high bone turnover phenotype is found in mice with activation of the PTH receptor in osteocytes (18,19,(38)(39)(40). Remarkably, however, the mechanisms underlying the skeletal phenotypes of these two mouse models are diametrically opposite.…”

Anabolic and Catabolic Pathways of Parathyroid Hormone on the Skeleton

“…These results indicate that PTH receptor signaling in osteocytes can regulate bone mass through modeling-or remodeling-based bone formation mechanisms depending on the bone compartment. 139 Supporting the idea that PTH-induced bone formation may occur independently of bone resorption, a recent study in postmenopausal women showed that the combination of denosumab, a potent RANKL inhibitor, with PTH(1-34) was more effective to increase bone mass than either therapy alone. 140 At 12 months, the increase in BMD at the lumbar spine was greater in the denosumab and teriparatide combination group (n = 30; 9.1%) than the teriparatide alone (n = 31; 6.2%, p = 0.014) or denosumab alone groups (n = 33; 5.5%, p = 0.0005).…”

“…This attenuation of the PTH anabolic effect was explained by a reduced number of osteoclasts and lack of osteoclast activity in the MCP-1-null mice. 57 However, according to the studies of Rhee et al 139 bone resorption may influence bone formation differently depending on the bone compartment. In this study, transgenic mice with activated PTH receptor signaling in osteocytes, and as a result increased bone mass, were either crossed with mice overexpressing the Wnt antagonist Sost/sclerostin to specifically inhibit bone formation, or treated with alendronate in order to block resorption-dependent bone formation.…”

Physiologic Actions of PTH I

“…In animal studies, bone formation in trabecular bone and on the endocortical surface appears to result from a combination of Wnt-driven increased osteoblast number and resorption-dependent osteoblast activity. 158 In animal studies bone formation induced by osteocytic PTH receptor signaling on the periosteal surface depends on Wnt signaling but not on bone resorption, 158 suggesting that the periosteal new bone formation that has been observed after intermittent PTH administration likely reflects predominantly modeling effects.…”