Osteoclasts may play key roles in initiating biomaterial-induced ectopic bone formation

Abstract

Current studies have identified that biomaterials in the form of sintered calcium phosphate (CaP) ceramics with specific physicochemical properties can induce bone formation in heterotopic sites without additional cells or growth factors, termed osteoinductive biomaterials, which display great potential in repairing large segmental bone defects. However, the underlying mechanism of osteoinduction remains elusive, preventing the optimal design of biomaterials with better osteogenic potential. Recently, accumulative evidence has illustrated that osteoclasts could recruit mesenchymal stem cells (MSCs) and enhance osteogenic differentiation of MSCs by secreting various cytokines, such as collagen triple helix repeat containing 1 (CTHRC1), sphingosine-1-phosphate (S1P), and complement factor 3a (C3a) during bone remodeling. Interestingly, a recent study found that osteoclastogenesis occurred prior to the bone formation during biomaterial-induced ectopic bone formation, and bone formation was blocked once osteoclastogenesis was inhibited with the anti-RANKL antibody at the early stage, which suggest that osteoclasts may play a critical role in the osteoinduction. However, whether osteoclasts could initiate biomaterial-induced ectopic bone formation remains unclear. Consequently, for the first time, we hypothesize that osteoclasts formed in non-osseous environments are perceived as a “starting signal” and osteoclastogenesis is the initiator of biomaterial-induced ectopic bone formation, which may provide useful instruction for osteoinductive materials modification and benefit the development of treatment strategies for heterotopic ossification (HO) in the future.

Introduction

The repair and reestablishment of large segmental bone defects, caused by tumors and trauma, have always been clinically challenging for doctors and scientists [1], [2]. Large segmental bone defects usually refer to those defects which exceed 2–2.5 times the diameter of the affected bone. Although bone has self-renewal capacities, it cannot be completely repaired by the body’s healing capacity when the defects exceed a critical size. In such cases, specialized treatments are required to fill the defects [3]. Traditionally, transplantation of autologous bone is still the prime choice in repairing bone defects. However, autologous bone transplantation is often limited by the restricted bone volume in the donor area and another surgical wound with postoperative complications (such as infection and fracture), causing a great burden to patients [4], [5]. Moreover, the allograft is another choice; however, the clinical use of allograft is limited due to the risk of immunogenic rejection and disease transmission. Although synthetic grafting biomaterials would overcome the above drawbacks, these materials exhibit insufficient osteoinductive capacities which makes it difficult to achieve the repair of large segmental bone defects. With the development of bone tissue engineering, scaffolds combined with osteoinductive growth factors (such as bone morphogenetic protein 2) and/or cells with osteogenic ability (such as mesenchymal stem cells (MSCs)) become a new alternative for repairing large segmental bone defects. However, there are still many obstacles before it can be used in clinical due to the expensive costs and teratoma formation [6]. Consequently, materials with osteoinductive capacities become an attractively novel strategy, which have the unique ability to induce new bone formation at heterotopic sites by optimizing their physicochemical properties without the addition of any exogenous osteoinductive growth factors or osteogenic cells. Various CaP biomaterials, including hydroxyapatite, biphasic calcium phosphate, and tricalcium phosphate, were found to induce bone formation when implanted at ectopic sites (intramuscular implantation and subcutaneous implantation) [7], [8], [9], which hold prospective potential for the development of novel therapies for repairing large critical-sized bone defects. Importantly, osteoinductive ceramics showed equal efficiency in large bone repair compared with autologous bone grafts in iliac implantation in sheep [10]. However, the biological mechanism of biomaterials inducing new bone formation in heterotopic sites is still unresolved [11]. Thanks to the identification of new modes of cell–cell communication between osteoclasts and osteoblasts over the years, the central role of osteoclasts in bone remodeling and biomaterial-induced ectopic bone formation have been increasingly appreciated [12], [13], [14].