Mechanisms involved in skeletal anabolic therapies.
Since parathyroid hormone (PTH) is the only proven anabolic therapy for bone, it becomes the benchmark by which new treatments will be evaluated. The anabolic effect of PTH is dependent upon intermittent administration, but when an elevated PTH level is maintained even for a few hours it initiates processes leading to new osteoclast formation, and the consequent resorption overrides the effects of activating genes that direct bone formation. Identification of PTH-related protein (PTHrP) production by cells early in the osteoblast lineage, and its action through the PTH1R upon more mature osteoblastic cells, together with the observation that PTHrP+/- mice are osteoporotic, all raise the possibility that PTHrP is a crucial paracrine regulator of bone formation. The finding that concurrent treatment with bisphosphonates impairs the anabolic response to PTH, adds to other clues that osteoclast activity is necessary to complement the direct effect that PTH has in promoting differentiation of committed osteoblast precursors. This might involve the generation of a coupling factor from osteoclasts that are transiently activated by receptor activator of nuclear factor-kappaB ligand (RANKL) in response to PTH. New approaches to anabolic therapies may come from the discovery that an activating mutation in the LRP5 gene is responsible for an inherited high bone mass syndrome, and the fact that this can be recapitulated in transgenic mice, whereas inactivating mutations result in severe bone loss. This has focused attention on the Wnt/frizzled/beta-catenin pathway as being important in bone formation, and proof of the concept has been obtained in experimental models.
Martin
T J
TJ
St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy Vic 3065, Australia. jmartin@svi.edu.au
Quinn
J M W
JM
Gillespie
M T
MT
Ng
K W
KW
Karsdal
M A
MA
Sims
N A
NA
D045930:Anabolic Agents / Q000627:therapeutic use*; D000818:Animals; D001846:Bone Development / Q000502:physiology*; D001847:Bone Diseases / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000502:physiology; D018016:Receptors, Parathyroid Hormone / Q000502:physiology; D015398:Signal Transduction
D045930:Anabolic Agents; D010281:Parathyroid Hormone; D018016:Receptors, Parathyroid Hormone