Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development

Piezo proteins are mechanically activated ion channels, which are required for mechanosensing functions in a variety of cell types. While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for bone-anabolic processes, there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage. Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis (OA) development. Mice with chondrocyte-specific inactivation of Piezo1 (Piezo1Col2a1Cre), but not of Piezo2, developed a near absence of trabecular bone below the chondrogenic growth plate postnatally. Moreover, all Piezo1Col2a1Cre animals displayed multiple fractures of rib bones at 7 days of age, which were located close to the growth plates. While skeletal growth was only mildly affected in these mice, OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age. Likewise, when OA was induced by anterior cruciate ligament transection, only the chondrocyte inactivation of Piezo1, not of Piezo2, resulted in attenuated articular cartilage degeneration. Importantly, osteophyte formation and maturation were also reduced in Piezo1Col2a1Cre mice. We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes. Finally, we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes. Collectively, our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes, but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA

High prevalence and undertreatment of osteoporosis in elderly patients undergoing total hip arthroplasty

We detected a high prevalence of low bone mineral density assessed by DXA in 268 elderly patients with end-stage osteoarthritis scheduled for total hip arthroplasty (18% osteoporosis, 41% osteopenia). Therefore, and due to the identified concomitant undertreatment, routine DXA measurements should be considered in elderly patients prior to surgery.!##!Introduction!#!Bone quality represents a decisive factor for osseointegration, durability, and complications of an implanted prosthesis. Although the risk of osteoporosis increases with age and the assessment of bone mineral density (BMD) prior to total hip arthroplasty (THA) is recommended in elderly patients, a systematic, unbiased analysis of such patients is not available in the literature.!##!Methods!#!In this retrospective study, we examined 268 elderly patients (age ≥70 years) who underwent dual-energy X-ray absorptiometry (DXA) within 3 months prior to primary THA. Demographics, medical history, radiographic OA grade, and stem fixation method (i.e., cemented or cementless) were obtained.!##!Results!#!In total, 153 (57%) cemented and 115 (43%) cementless stem fixations during THA were performed. Forty-nine patients (18%) were diagnosed with osteoporosis (T-score ≤-2.5), 110 patients (41%) with osteopenia (T-score ≤-1.0), and 109 patients (41%) with normal BMD (T-score >-1.0). Importantly, 36/49 patients (73%) with osteoporosis were not diagnosed before, resulting in a relevant undertreatment. Female sex and low body mass index (BMI) were the main factors negatively influencing the bone mineral density (BMD).!##!Conclusions!#!Due to a high incidence of undiagnosed and untreated osteoporosis in elderly patients with potential effects on the success of osseointegration as well as other clinical outcomes, DXA measurements should be included in the clinical routine for these patients prior to THA

CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization in osteopetrotic individuals

Osteopetrosis is an inherited disorder of impaired bone resorption with the most commonly affected genes being CLCN7 and TCIRG1, encoding the Cl(-) /H(+) exchanger CLC-7 and the a3 subunit of the vacuolar H(+)-ATPase, respectively. We, and others have previously shown that the disease is frequently accompanied by osteomalacia, and that this additional pathology is also found in Tcirg1-deficient oc/oc mice. The remaining question was, whether osteoid enrichment is specifically associated with TCIRG1 inactivation, or whether CLCN7 mutations would also cause skeletal mineralization defects. Here we describe a complete osteologic assessment of one family carrying a novel mutation in CLCN7 (D145G), which impairs the activation and relaxation kinetics of the CLC-7 ion transporter. The two siblings carrying the mutation in the homozygous state displayed high bone mass, increased serum levels of bone formation markers, but no impairment of calcium homeostasis when compared to the other family members. Most importantly however, undecalcified processing of an iliac crest biopsy from one of the affected children clearly demonstrated a pathological increase of trabecular bone mass, but no signs of osteomalacia. Given the potential relevance of these findings we additionally performed undecalcified histology of iliac crest biopsies from seven additional cases with osteopetrosis caused by a mutation in TNFRSF11A (n = 1), CLCN7 (n = 3) or TCIRG1 (n = 3). Here we observed that all cases with TCIRG1-dependent osteopetrosis displayed severe osteoid accumulation and decreased calcium content within the mineralized matrix. In contrast, there was no detectable bone mineralization defect in the cases with TNFRSF11A- or CLCN7-dependent osteopetrosis. Taken together, our analysis demonstrates that CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization, and that there is a need to modify the current classification of osteopetrosis