Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition

Abstract

The WNT pathway has become an attractive target for skeletal therapies. High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties. Sclerostin-neutralizing antibody is highly osteoanabolic in animal models and in human clinical trials, but antibody-based inhibition of another potent LRP5/6 antagonist, Dkk1, is largely inefficacious for building bone in the unperturbed adult skeleton. Here, we show that conditional deletion of Dkk1 from bone also has negligible effects on bone mass. Dkk1 inhibition increases Sost expression, suggesting a potential compensatory mechanism that might explain why Dkk1 suppression lacks anabolic action. To test this concept, we deleted Sost from osteocytes in, or administered sclerostin neutralizing antibody to, mice with a Dkk1-deficient skeleton. A robust anabolic response to Dkk1 deletion was manifest only when Sost/sclerostin was impaired. Whole-body DXA scans, μCT measurements of the femur and spine, histomorphometric measures of femoral bone formation rates, and biomechanical properties of whole bones confirmed the anabolic potential of Dkk1 inhibition in the absence of sclerostin. Further, combined administration of sclerostin and Dkk1 antibody in WT mice produced a synergistic effect on bone gain that greatly exceeded individual or additive effects of the therapies, confirming the therapeutic potential of inhibiting multiple WNT antagonists for skeletal health. In conclusion, the osteoanabolic effects of Dkk1 inhibition can be realized if sclerostin upregulation is prevented. Anabolic therapies for patients with low bone mass might benefit from a strategy that accounts for the compensatory milieu of WNT inhibitors in bone tissue.

Osteogenic Dkk1 Mediates Glucocorticoid-Induced but Not Arthritis-Induced Bone Loss

“…Consistent with earlier studies, osteoprogenitor‐ as well as osteocyte‐specific Dkk1 deletion was accompanied by an increased sclerostin serum level. This compensatory mechanism has been confirmed in many studies, and in fact, increased sclerostin has been proposed to mask some of the anabolic effects of Dkk1 . As sclerostin neutralization also prevents systemic bone loss in arthritis mice, blockade of both sclerostin and Dkk1 using bispecific antibodies as proposed by Florio and colleagues may be an effective strategy to prevent inflammation‐induced bone loss …”

“…This compensatory mechanism has been confirmed in many studies, and in fact, increased sclerostin has been proposed to mask some of the anabolic effects of Dkk1. (10,31,32) As sclerostin neutralization also prevents systemic bone loss in arthritis mice, (33) blockade of both sclerostin and Dkk1 using bispecific antibodies as proposed by Florio and colleagues may be an effective strategy to prevent inflammation-induced bone loss. (31) Whereas osteoblast-derived Dkk1 does not seem to play a major role in the development of arthritis and only partially mitigated arthritis-induced bone loss, lack of Dkk1 in osteogenic cells completely protected against GC-induced bone loss.…”

Osteocyte Death and Bone Overgrowth in Mice Lacking Fibroblast Growth Factor Receptors 1 and 2 in Mature Osteoblasts and Osteocytes

“…Consistent with loss of most osteocytes and concurrent increased bone formation, Sost expression was decreased and markers of Wnt/β‐catenin signaling, Lrp5 and Lef1, were increased in OC‐ Fgfr1/2 DCKO mice compared with Fgfr1/2 DFF control mice. Notably, in 12‐week‐old mice, levels of Dkk1 were increased, possibly as a mechanism to compensate for loss of Sost . Similar to 3‐week‐old OC‐Fgfr1/2 DCKO mice, levels of Fgf23 remained high in 12‐week‐old mice, despite the decreased number of live osteocytes.…”

“…In response to mechanical loading, expression of Sost and Dkk1 is suppressed, at least in part through osteocyte production of prostaglandin E2 . Interestingly, Dkk1 and Sost reciprocally regulate each other's expression; however, the anabolic activity of Dkk1 is only revealed in the absence of Sost . Osteocytes also respond to parathyroid hormone (PTH), which likewise functions to suppress Sost , accounting for some of the anabolic effects of PTH .…”

“…(3)(4)(5)(6)(7)(8)11,12) Interestingly, Dkk1 and Sost reciprocally regulate each other's expression; however, the anabolic activity of Dkk1 is only revealed in the absence of Sost. (13) Osteocytes also respond to parathyroid hormone (PTH), which likewise functions to suppress Sost, accounting for some of the anabolic effects of PTH. (14) Osteocytes are a major source of the cytokine receptor activator of NF-κB ligand (RANKL).…”