## 1 Introduction  
Osteonecrosis (ON) of the femoral head is a progressive and disabling disease, affecting active patients between the third and fifth decade of life with a high burden on the healthcare system [1; 2; 3]. The pathogenesis of ON involves the interplay of genetic, local and metabolic aspects with a different incidence rate among men and women (ratio male/female: 4:1) [4; 5; 6; 7]. It is possible to identify two major types of ON aetiologies. The aetiology in ON patients with post-traumatic femoral head (PTFH) ON includes previous traumatic events; non-traumatic femoral head (NTFH) ON aetiology includes corticosteroid use, alcohol abuse, obesity, autoimmune diseases, and immunosuppressive therapies [7; 8; 9]. The pathology reflects a dynamic course leading to femoral head collapse because of subchondral bone fractures and inadequate bone repair [10; 11; 12]. Skeletal complications and pain in ON patients occurs because of abnormal osteoblastic and osteolytic activities [13; 14]. In particular, ON patients showed impaired action of the OPG/RANKL/RANK signalling pathway [9; 14]. [PERSON] and his group observed a similar behaviour whereby ON patients displayed increased levels of osteoprotegerin (OPG), receptor activator of nuclear factor-kB (RANK), and its ligand (RANKL) genes in ON necrotic areas [15]. Beyond such classical signalling pathways, scientists have even started testing the role of cannabinoids (CN) in bone repair, as bone-marrow-derived osteoclasts and osteoblasts [16], MC3T3 E1 osteoblast-like cells [17] and osteocytes express CN receptors [18]. Beyond the critical role of bone in the ON setting, scientists have pointed great attention towards the articular cartilage, because of its close anatomic continuity and communication with the underlying subchondral bone [19; 20]. In particular, several authors stressed the clinical significance of considering structural cartilage changes following the mechanical stress induced by the collapse of the subchondral bone in ON [21; 22; 23]. However, these changes contribute to altering the biomechanics of the joint leading to OA progression and finally to joint destruction. There is no gold-standard treatment for ON because of the controversial results [24; 25]. Selecting treatment options for ON depends on many factors, including the pathology stage, patients' age and health conditions, and lesion size and location [26; 27]. In particular, treatments for ON management in the pre-collapse stage include non-surgical (weight control), pharmacological or biophysical techniques, and mesenchymal stromal cell (MSC)-based therapy [27; 28; 29; 30; 31]. Total hip arthroplasty is among the best therapeutic alternatives after the collapse of the femoral head. However, it has its disadvantages (e.g., infection, revision, and dislocation) [24; 25]. Therefore, many scientists focused on femoral head regeneration. In 2002, [PERSON] and his group reported promising results following MSC therapy in ON patients in the pre-collapse stage at 5 to 10 years of clinical follow-up [29]. A recent review summarised that MSCs could regenerate the necrotic area of the femoral head by injecting the suspension into the lateral artery of the circumflex or loading on carriers via core decompression and implantation [32]. Testing the crosstalk between cartilage and the underlying subchondral bone is essential to achieve global comprehension of physiological responses in ON disease. Differences between ON patients with various aetiologies could give first perspectives for tailored-based therapies. In this light, we conducted a small-scale preliminary (pilot) study aimed at evaluating histopathological features in two ON patient groups with NTFH and PTFH. Study design foresaw investigating several mediators modulating the osteochondral unit to get more knowledge of potential therapeutic targets for ON.